Patent Application
20090076502
The present invention relates generally to electric field delivery to a prostate tissue of a patient. More particularly, the present invention provides systems and methods for delivering alternating current and controlled, mild heating to a prostate tissue of a patient for destruction of cancerous and/or hyperplastic tissue.
The prostate gland is a walnut-sized gland located in the pelvic area, just below the outlet of the bladder and in front of the rectum. It encircles the upper part of the urethra, which is the tube that empties urine from the bladder. The prostate is an important part of the male reproductive system, requiring male hormones like testosterone to function properly, and helps to regulate bladder control and normal sexual functioning. The main function of the prostate gland is to store and produce seminal fluid, a milky liquid that provides nourishment to sperm, and increases sperm survival and mobility.
Cancer of the prostate is characterized by the formation of malignant (cancerous) cells in the prostate. Prostate cancer is the leading cancer related cause of death in men in the United States. There are currently over 2 million men in the United States with prostate cancer, and it is expected that there will be approximately 190,000 new cases of prostate cancer diagnosed, with 28,000 men dying from the disease in 2008.
In addition to risks of morbidity due to prostate cancer, most men over 60 years old experience partial or complete urinary obstruction due to enlargement of the prostate. This condition can originate from prostate cancer, or more typically, from benign prostatic hyperplasia (BPH), which is characterized by an increase in prostate size and cell mass near the urethra.
Common active treatment options include surgery and radiation. Surgery often includes the complete surgical removal of the prostate gland (“Radical Prostatectomy”), and in certain instances the regional lymph nodes, in order to remove the diseased tissue from the body. In some instances, a nerve sparing prostatectomy is attempted in an effort to maintain erectile function in the patient after treatment. Side effects associated with radical prostatectomy can include pain, inflammation, infection, incontinence, shorter penis and impotence.
Radiation therapy is another treatment option for prostate cancer and is characterized by the application of ionizing radiation to the diseased area of the prostate. Ionizing radiation has the effect of damaging a cells DNA and limiting its ability to reproduce. For Prostate Cancer treatment, two methods of radiation therapy include External Beam Radiation Therapy (EBRT) and internal radiation, commonly known as Brachytherapy. EBRT involves the use of high-powered X-rays delivered from outside the body. The procedure is painless and only takes a few minutes per treatment session, but needs to be over extended periods of five days a week, for about seven or eight weeks. During EBRT, the rays pass through and can damage other tissue on the way to the tumor, causing side effects such as short-term bowel or bladder problems, and long-term erectile dysfunction. Radiation therapy can also temporarily decrease energy levels and cause loss of appetite.
Brachytherapy involves the injection of tiny radioactive isotope containing ‘seeds’ into the prostate. Once positioned in the tissue, the radiation from the seeds extends a few millimeters to deliver a higher radiation dose in a smaller area, causing non-specific damage to the surrounding tissue. The seeds are left in place permanently, and usually lose their radioactivity within a year. Internal radiation also causes side effects such as short-term bowel or bladder problems, and long-term erectile dysfunction. Internal radiation therapy can also temporarily decrease energy levels and cause loss of appetite. It is also common for the implanted seeds to migrate from the prostate into the bladder and then be expelled through the urethra during urination. Most significant, however, is the change in the texture of the prostate tissue over time, making the subsequent removal of the gland, as described above, complicated and difficult as a secondary treatment.
Given the significant side-effects with existing treatments such as radical prostatectomy and radiation therapy, less invasive and less traumatic systems and procedures have been of great interest. One such more minimally invasive system developed in recent years includes so called “Trans-urethral Needle Ablation” or TUNA, which involves passing a radio-frequency (RF) device such as a catheter probe or scope into the urethra for delivery of high frequency energy to the tissue. The RF instruments include electrode tips that are pushed out from the side of the instrument body along off-axis paths to pierce the urethral wall and pass into the prostatic tissue outside of the urethra. High-frequency energy is than delivered to cause high-temperature ionic agitation and frictional heating to tissues surrounding the electrodes. The high-temperature induced in the tissue, e.g., up to 90-100 degrees C. or more, is non-specific to cancerous tissue and destroys both healthy and non-healthy tissue.
Another technique developed in recent years for treating BPH is Trans-urethral Microwave Thermo Therapy (or “TUMT”). This technique involves use of a device having a microwave probe or antenna located near its distal end and connected to an external generator of microwave power outside the patient's body. The microwave probe is inserted into the urethra to the point of the prostate for energy delivery and microwave electromagnetic heating. Since the microwave probe delivers substantial heating that can cause unwanted damage to healthy tissues or to the urethra, devices typically make use of a cooled catheter to reduce heating immediately adjacent to the probe. The objective is to carefully balance cooling of the urethra to prevent damage to it by the heating process, while at the same time delivering high temperature heating (greater than 50 degrees C.) to the prostatic tissue outside of and at a distance from the urethra. In this procedure, the prostatic tissue immediately around the urethra and the urethra itself are deliberately spared from receiving an ablative level of heating by attempting to keep the temperatures for these structures at less than 50 degrees C. Unfortunately, controlling the tissue heating due to the applied microwave energy is difficult and unintended tissue damage can occur. Further, destruction of tissue beyond the cooled region is indiscriminate, and control of the treatment zone is imprecise and limited in the volume of tissue that can be effectively treated.
Accordingly, there is a continuing interest to develop less invasive devices and methods for the treatment of BPH and prostate cancer that is more preferential to destruction of target tissue and more precisely controllable.
The present invention provides systems, devices and related methods for applying electric fields, which can be delivered for preferential and/or controllable cancerous cell destruction and tissue ablation. Methods and devices of the present invention will generally be designed to advance an electrode or plurality of electrodes to a target tissue region and apply an electric field to the target tissue region. The electrode or plurality thereof can be positioned such that the applied electric field radiates throughout the target tissue region, including, for example, where the electric field radiates outwardly and in a plurality of directions, e.g., radially, through the target tissue. In certain embodiments, the energy is applied so as to deliver mild and controlled heating of the target tissue.
Thus, the present invention includes systems and devices, as well as methods for delivering electric fields to prostate tissue. Electric field delivery can include establishing an electric current flow through a target tissue region comprising prostate tissue so as to preferentially ablate or destroy cancerous cells in the target tissue region.
For a fuller understanding of the nature and advantages of the present invention, reference should be made to the ensuing detailed description and accompanying drawings. Other aspects, objects and advantages of the invention will be apparent from the drawings and detailed description that follows.
The present invention provides systems and devices, and related methods for prostate tissue ablation. According to the present invention, an electrode or plurality of electrodes can be introduced into a target tissue region and an electric field applied to the target tissue region for controlled and/or preferential destruction of cancerous cells.
Various probe and electrode configurations and/or arrangements may be selected for use according to the present invention and may depend at least partially on the nature and location of the target area. One embodiment of a probe configuration that has been demonstrated to be particularly effective includes probes or electrode configuration with electrodes positioned such that energy delivery includes generating current fields in a plurality of different directions throughout a treatment volume. Further, electrodes can be activated in a bipolar electrical arrangement, including activation in pairs or group combinations, such that tissue disposed between electrodes or within a treatment volume substantially defined by the electrodes acts as a medium through which current field is established or as a current pathway.
In one example, electrodes of a system include a plurality or array of electrodes that can be differentially activated in distinct groups or pairs for establishing different orientations of current field throughout the target tissue. Electrodes can include a plurality of separately controlled electrodes or groups of electrodes, either physically coupled together (e.g., attached to a housing, deployable from a probe, etc.) or can be uncoupled physically and individually positionable and electrically addressable. In some cases, electrode positioning and activation can be selected to establish a current field that is oriented radially through a inner or center of a treatment volume. For example, a probe can be configured such that an inner or centrally located electrode is surrounded by radially spaced electrodes in a bipolar arrangement, and current flow established between the inner electrode and the outer spaced electrodes. Alternatively, a flow center can be established by defining a volume with positioned electrodes and activating a series of opposing electrodes to establish radial current flow through the volume and to destroy cancerous tissue. Regardless of the precise electrode configuration, in one aspect of the present invention, the applied therapeutic field can be contained substantially within the desired treatment region or volume of the target tissue, with current flowed through the target tissue radially or in a plurality of different directions.
Establishment and application of energy delivery utilizing the described energy parameters and/or field delivery (e.g., orientation) can offer several advantages. First, energy delivery according to the present invention further advantageously allows a more controlled or precise therapeutic energy dose both in terms of delivery of the desired current and resulting effects, as well as more accurate delivery to the target or intended tissue. For example, current flow is established between electrodes in a bipolar arrangement, with current flow established and substantially contained between the spaced electrodes. Further, tissue heating can be more precisely controlled to prevent or minimize excessive heating and/or hot spots that can cause unintended damage to healthy or non-target tissues. For example, energy delivery can be selected (e.g., frequency ranges between about 50 kHz to about 300 kHz) such that tissue heating occurs significantly or predominately due to tissue resistance, limiting or minimizing the high-frictional heating observed at high frequencies (e.g., 500 kHz or greater), the latter of which can include significant tissue temperature gradients throughout the treated tissue, with drastic tissue temperature changes occurring as a function of electrode distance. While heating may occur due to both tissue resistance and frictional heating, with relative reduction of high friction type heating, a more constant and controlled heating between opposing electrodes may be delivered.
In one aspect of the inventive methods, relative electrode positioning can be selected so as to further allow more precise control of the desired effect (e.g., induction of mild hyperthermia) of the applied field on the tissue. Factors such as differential conductive properties and resistance or tissue impedance e.g., differences in muscle, adipose, vasculature, etc.), as well as differential perfusion of blood through vascularized tissue, can effect the ability to control and/or predict effects of delivered current field through certain tissues and varying tissue volumes. Thus, in one embodiment, distances between activated electrodes can controlled and in some cases confined to shorter distances, such as a few centimeters or less, for improved control and predictability of current effects (e.g., tissue heating, field delivery, field orientation, etc) on the targeted tissue.
Another advantage of the present inventive methods and systems is that energy delivery and application of mild hyperthermia as described has been observed to be surprisingly effective in preferentially damaging and destroying cancerous cells compared to non-cancerous or healthy cells/tissue. Preferential destruction, as described herein, refers to establishing current flow as described with application of hyperthermia, generally below about 50 degrees C., such that cytotoxic effects of treatment are, on average or as a whole, more destructive and/or lethal to cancerous or hyperplastic cells (e.g., cells exhibiting or predisposed to exhibiting unregulated growth) compared to non-cancerous or healthy cells. In some instances, establishing current flow and induction of mild hyperthermia as described herein is remarkably effective in preferentially destroying cancerous cells with limited or no observable damage to non-cancerous tissues.
Furthermore, and without being bound by any particular theory, electrode configuration and field application as described in certain embodiments (e.g., radially and/or in a plurality of different directions) may take advantage of tumor or mitotic cell physiology to increase treatment effectiveness, and can include a more optimal or effective orientation of the applied field with respect to dividing cells of the target region. For example, energy application can be accomplished such that current fields are substantially aligned at some point during energy delivery with division axes of dividing cells (e.g., cancerous cells), thereby more effectively disrupting cellular processes or mitotic events (e.g., mitotic spindle formation and the like). As cancerous cells are dividing at a higher rate compared to non-cancerous cells, field application in this manner may preferentially damage cancerous cells compared to healthy or non-dividing cells. It will be recognized, however, that energy application likely has several or numerous cytotoxic effects on cells of the target region and that such effects may be cumulatively or synergistically disruptive to a target cell, particularly to cells disposed or pre-disposed to unregulated growth (i.e., cancerous cells). Other cytotoxic or disruptive effects of the energy application as describe herein may occur due, for example, to application of mild hyperthermia (e.g., mild heating of tissue between about 40 to 48 degrees C.; or less than about 50 degrees C.); ion disruption, disruption of membrane stability, integrity or function; and the like.
As discussed above, various electrode or probe configurations can be utilized according to the present invention. In one embodiment, electrodes can include an array of needle electrodes, which can be fixed to common support (e.g., housing) or separately positionable and controlled. Such a plurality or array of electrodes can include a straight-needle array including electrically conductive material such as stainless steel, gold, silver, etc. or combination thereof. An array of straight-needle electrodes can be coupled to a rigid needle support or housing that can ensure correct positioning of each individual needle relative to the others. The needles can be arranged parallel to one another with opposing rows and/or columns of electrodes ensuring the field is delivered to and contained within the target area. Needle length and needle spacing can vary depending on the actual dimensions of the target tissue. Individual needle placement can be guided using imaging (e.g., ultrasound, X-ray, etc.) and relative needle position can be maintained with a rigid grid support (e.g., housing, template, etc.) that remains outside the body. The needle assembly will electrically connect to the control system or module, e.g., via insulated wires and stainless steel couplings.
In another embodiment, a probe can include one or more electrodes that are deployable from an elongate probe housing or catheter. Such embodiments may be particularly useful for treatment of target areas more difficult to access with an array of fixed needles. Such deployable type probes, and others described herein, can be inserted percutaneously through the skin of the patient and into the target tissue. As above, appropriate imaging technology can be used to guide the precise placement of the probe in the target site. In one embodiment, a deployable type probe can include outer polyurethane sheath housing pre-shaped deployable shape memory metal tines and a stainless steel central electrode tip. Conductive surfaces can further be coated with a highly conductive material.
Another embodiment of the probe can include one or more expandable elements (e.g., balloon) that can be individually positioned around a target area or organ and then deployed and “inflated” to achieve maximum surface area and optimal distribution of the therapeutic field. In one example, an electrically active segment of the expandable element can include an electrically conductive material (e.g., silver, gold, etc.) coated or deposited on a mylar balloon. Prior to deployment and inflation, the expandable element can be contained inside a flexible catheter that can be guided to the treatment area. Once the delivery catheter is positioned, the “balloon” can be deployed and expanded via the circulation of fluid through the balloon, which can have a selected or controlled temperature and may act as a heat sink. The therapeutic field can than be delivered via the silver coating on the mylar balloon. Two or more probes deployed in this fashion will serve to contain the field within the treatment area.
Electrodes and probes of the present invention can be coupled to control system or control module designed to generate, deliver, monitor and control the characteristics of the applied field within the specified treatment parameters. In one embodiment, a control system includes a power source, an alternating current (AC) inverter, a signal generator, a signal amplifier, an oscilloscope, an operator interface and/or monitor and a central processing unit (CPU). The control unit can manually, automatically, or by computer programming or control, monitor, and/or display various processes and parameters of the energy application through electrodes and to the target tissue of the patient. While the control system and power source can include various possible frequency ranges, current frequency delivered to target tissue will be less than about 300 kHz, and typically about 50 kHz to about 250 kHz. Frequencies in this range have been observed as effective in precisely controlling the energy application to the target tissue, controlling thermal effects primarily to mild thermal application, and preferentially destroying cancerous cells with limited or no observable damage to non-cancerous tissues.
Energy application according to the present invention can further include mild or low levels of hyperthermia. In some embodiments, small changes/elevations in temperature in the target tissue region may occur, but will typically be no more than about 10 degrees C. above body temperature, and may be about 2 degrees to less than about 10 degrees C. above body temperature (e.g., normal human body temperature of about 38 degrees C.). Thus, local tissue temperatures (e.g., average tissue temperature in a volume of treated tissue) during treatment will typically be less than about 50 degrees C., and typically within a range of about 40-48 degrees C. In one embodiment, average target tissue temperature will be selected at about 42-45 degrees C. As target tissue temperatures rise above about 40-42 degrees C. curing treatment, the cytotoxic effects of energy delivery on cancerous cells of the target region are observably enhanced, possibly due to an additive and/or synergistic effect of current field and hyperthermic effects. Where mild hyperthermic effects are substantially maintained below about 48 degrees C., the energy delivery according to the present invention appears to more preferentially destroy cancerous cells compared to healthy or non-cancerous cells of the target tissue region. Where energy delivery induces tissue heating substantially in excess of about 45-48 degrees C. (e.g., above about 48-50 degrees C.), the preferential cytotoxic effects on cancerous cells may begin to diminish, with more indiscriminate destruction of cancerous and non-cancerous cells occurring. Thus, a significant advantage of treatment methods according to the present invention includes the ability to precisely and accurately control energy delivery and induced hyperthermic effects, such that tissue hyperthermia can be accurately controlled and maintained in a desired temperature range(s)—e.g., temperature ranges selected for more targeted or preferential destruction of cancerous cells compared to non-cancerous cells.
Tissue temperatures can be selected or controlled in several ways. In one embodiment, tissue temperatures can be controlled based on estimated or known characteristics of the target tissue, such as tissue impedance/conductivity, tissue volume, blood flow or perfusion characteristics, specific heat capacity of the tissue, tissue density, and the like, with energy application to the tissue selected to deliver an approximated controlled mild increase in tissue temperature. In another embodiment, tissue temperature can be actively detected or monitored, e.g., by use of a thermosensor feedback unit, during treatment, with temperature measurements providing feedback control of energy delivery in order to maintain a desired target tissue temperature or range. Temperature control measures can include electronics, programming, thermosensors, thermocouples, and the like, coupled with or included in a control unit or module of a system of the invention.
Energy application and induction of hyperthermia in a target tissue region according to the present application can include delivery of various types of energy delivery. As described, application of generally intermediate frequency range (e.g., less than about 300 kHz) alternating current in the RF range has been observed as effective in establishing mild heating and hyperthermia, as well as current fields in a controlled manner so as to provide a cytotoxic effect, and in some instances, a preferential destructive effect to cancerous cells of a target tissue volume/region. It will be recognized, however, that additional energy applications and/or ranges may be suitable for use according to the present invention, and that systems and methods of the present invention may be amenable to use with other or additional energy applications. For example, energy application can include current flow having frequencies found generally in the RF range, as well as microwave range, including higher frequencies such as 300-500 kHz and above, and may further be amenable to use with direct current applications. Applied current can be pulsed and/or continuously applied, and energy delivery can be coupled with a feedback-type system (e.g., thermocouple positioned in the target tissue) to maintain energy application and/or tissue heating in a desired range. Methods of the present invention can include any one or more (e.g., combination) of different energy applications, induced temperatures, etc. as described herein.
In certain embodiments, particularly where energy application is selected for lower power delivery/ablation, the control system can be designed to be battery powered and is typically isolated from ground. In such an embodiment, AC current is derived from the integrated power inverter. An intermediate frequency (e.g., less than 300 kHz; or about 50 kHz to about 250 kHz) alternating current, sinusoidal waveform signal is produced from the signal generator. The signal is then amplified, in one non-limiting example, to a current range of 5 mA to 50 mA and voltage of up to 20 Vrms per zone. Field characteristics including waveform, frequency, current and voltage are monitored by an integrated oscilloscope. Scope readings are displayed on the operator interface monitor. An integrated CPU monitors overall system power consumption and availability and controls the output of the signal generator and amplifier based on the treatment parameters input by the operator. The operator can define treatment parameters to include maximum voltage, maximum current or temperature, maximum power, and the like. In another embodiment, the applied field can be cycled on and off, e.g., at a high rate, to keep the temperature relatively constant and with the duty cycle (e.g., on time-off time) adjusted to accurately control temperature.
Imaging systems and devices can be included in the methods and systems of the present invention. For example, the target tissue region can be identified and/or characterized using conventional imaging methods such as ultrasound, computed tomography (CT) scanning, X-ray imaging, nuclear imaging, magnetic resonance imaging (MRI), electromagnetic imaging, and the like. In some embodiments, characteristics of the tumor, including those identified using imaging methods, can also be used in selecting ablation parameters, such as energy application as well as the shape and/or geometry of the electrodes or array of electrodes. Additionally, these or other known imaging systems can be used for positioning and placement of the devices and/or electrodes in a patient's tissues.
A target tissue will include prostate tissue or tissue including cancerous prostate cells and/or hyperplastic tissue of the prostate or prostate region. Thus the present invention includes delivery of electrical fields and ablation therapy to a target tissue including prostate tissue by making use of the techniques, systems and probes described herein. Prostate tissue can be accessed for delivery of electrical fields as described herein can by using a variety of methods. For example, prostate tissue access can include any of a variety of currently know access/surgical methods used for existing prostate treatment techniques, which will be modified for delivery of the ablation treatment as described herein. Surgical access can include, for example, techniques commonly employed for surgical intervention for prostate cancer that involves radical prostatectomy via an abdominal (retropubic) or perineal approach, or various robotic methods. Rather than removing the prostate tissue via surgical excision, however, electrodes of a probe according to the present invention can by positioned in the target tissue including prostate cells/cancerous cells and current applied to the tissue as described herein. While the present techniques can provide an alternative therapy to other techniques such as radical prostatectomy, in some cases other surgical techniques can optionally be used in addition or conjunction with the ablation techniques of the present invention. For example, treatment may first be delivered via ablation therapy of the present invention and followed (e.g., at a later time) by other surgical techniques, such as partial or entire prostatectomy. Such an approach may in some instances improve outcomes and/or reduce complications commonly associated with other treatments such as surgical removal of the prostate, e.g., by reducing the amount of tissue in need of surgical removal.
Other known prostate tissue access techniques besides more traditional surgical access can be employed in delivery of ablation therapy of the present invention. For example, surgical techniques commonly used in hyperthermic ablation methods can be employed for ablation therapy according to the present invention, including various transurethral access methods, such as those commonly employed in transurethral needle ablations, transurethral microwave ablation, ultrasound (high-intensity focused ultrasound), electrical vaporization (transurethral electrical vaporization of the prostate), and the like. Various other techniques, including minimally invasive techniques, can be employed, including laparoscopic techniques (e.g., percutaneous puncture/laparoscopic techniques), transrectal access or puncture, and the like. Various monitoring techniques can be used in conjunction with ablation. For example, imaging systems and devices (see, e.g., as described below), diagnostic monitoring (e.g., prostate-specific antigen (PSA) testing), etc. can be used to evaluate and/or monitor disease state and/or treatment progression.
Thus, energy delivery probes, according to the present invention, can be advanced and positioned according to various prostate tissue access techniques. Methodologies and access techniques, as noted above, can include without limitation open surgical techniques, laparoscopic or minimally invasive surgical access, puncture and/or advancement (e.g., percutaneous puncture) of probes and/or electrodes through the perineum, as well as transurethral and/or transrectal access. Exemplary probe configurations and positioning, according to certain embodiments of the present invention, are generally described further below.
Referring to
In another embodiment, a probe can include a plurality of needle electrodes fixed to or positioned on a body or housing of a device.
In use, as shown in
In another embodiment of the present invention, systems and methods can include a plurality of electrodes (e.g., needle electrodes) that can be individually advanced and positioned in the target/prostate tissue, and electrically activated for energy delivery (see, e.g.,
A system and method for delivering electric fields according to the present invention is described with reference to
A system for implementing a method according to the present invention is shown in
A guide template 100, according to an exemplary embodiment of the present invention, is described in further detail with reference to
Electrode positioning and energy delivery is further described with reference to
Another advantage of methods using the described electrode array or plurality of the present invention is that relative electrode positioning can be limited to smaller distances so as to further allow more precise control of the desired effect of the applied field on the tissue. Factors such as differential conductive properties and resistance or tissue impedance (e.g., differences in muscle, adipose, vasculature, etc.), as well as differential perfusion of blood through vascularized tissue, can limit the ability to control and/or predict effects of delivered current field traversing larger distances through tissue. In the present invention, distances between activated electrodes can be limited to shorter distances, such as a few centimeters or less, for improved control and predictability of current effects (e.g., tissue heating, field delivery, orientation, etc) on the targeted tissue. Thus, activated electrodes in a pair or group can be spaced less than about 4 cm apart. For example, adjacent electrodes of a pair or group will typically be positioned within about 0.1 cm to about 2 cm of each other. Distances of about 0.5 cm have been shown to be particularly effective in providing controlled and predictable field delivery, controlled tissue heating, as well as substantial therapeutic effect.
As described above, a plurality of electrodes can be positioned in the target tissue of the prostate of a patient and the electrodes can be activated in pairs or groups to deliver the therapeutic current field to destroy cancerous tissue. A particular electrode of an array need not be confined to a single unit, but can be activated at different times in conjunction with different electrodes of the plurality. For example, differential activation can include activating a specific or selected series of electrode groups in a particular or predetermined order. In one embodiment, a series of selected pairs or groups can be activated in seriatim and/or in a predetermined order, with activation control typically being determined by operation or instructions (e.g., programming) of a control system or module. Sequences of group activations can be controlled and repeated, manually or by automation, as necessary to deliver an effective or desired amount of energy.
Such differential activation advantageously allows delivery of fields throughout the target tissue and in a plurality of different directions. As shown in
Treatment time according to the present invention can be selected based on a variety of factors, such as characterization of the tissue, energy applications selected, patient characteristics, and the like. Energy application to a target tissue region during treatment according to the present invention can be selected from a few minutes to several hours. Though, effective treatment is expected to occur in about 5 minutes to 90 minutes. Effective preferential destruction of cancerous prostate cells has been observed in less than one hour, and in many cases about 15-30 minutes of energy application. Treatment can include a single energy delivery period or dose, or multiple phases or doses of energy application. As described above, electrodes can be positioned in a first location and energy delivered, then moved to subsequent location(s) for subsequent energy delivery. Treatment can occur in phases or repeated, and/or may be coupled with additional or alternative treatments or energy delivery methods.
As described above, electrodes will include a distal portion having an electrically active region for delivering the desired current field to the target tissue. Various electrode configurations and designs can be utilized and the current invention is not limited to any particular electrode design. Electrodes, for example, can be differentially insulated such that current delivery occurs at a non-insulated or thinly insulated region of the electrode.
As noted above, access to the target tissue or prostate tissue can be gained through the urethra of the patient. Referring to
The urethral probe 172 includes a proximal end and a distal portion having an expandable member 178, such as a balloon configured for expansion in the urethra (U) of the patient. The proximal end is positioned outside the patient's body during use, and can include a hub or handle 180 that can be coupled to a controller or control unit, and power source 182. The expandable member 178 includes conductive electrode elements 184 patterned or disposed on an outer surface of the expandable member 178. The probe will include an elongated body 174 extending from the proximal portion of the device to the distal portion, and the elongated body can include an inner lumen or passage with electrical coupling members, such as insulated wires, for coupling the electrode elements 184 of the expandable member 178 to the proximal end and/or an externally positioned controller and/or power source 182. As indicated in
The probe will be designed to include electrode elements that can be positioned in the desired location and used for delivery of electric fields to the target tissue for treatment according to the present invention. Various embodiments of electrode elements can be included in the present invention and the probe can be designed or configured for delivery of electrical fields, for example, between the expandable member and opposing electrode(s) (e.g., secondary electrodes) positioned in or in the vicinity of the prostate tissue, with current fields in some embodiments established between electrodes and typically in a plurality of directions (e.g., radially) through a volume of tissue. Electrode elements 184 of the expandable member 178 can include conductive material deposited or patterned on a surface or at least a portion of the expandable member 178 that is brought into contact with the walls of the urethra (U) during treatment. In one embodiment, the expandable member 178 can be configured in a deployable configuration, such that the expandable member 178 may be positioned within the probe shaft and then deployed from the probe (e.g., from the distal end or tip of the probe) and expanded at the desired location. For example, the expandable member can be positioned or disposed within in the probe shaft or portion of the elongate body (e.g., shaft lumen) during advancement and positioning of the probe, and deployed from the probe once a desired position in the patient's urethra has been reached. Alternatively, in another embodiment, the expandable member or balloon (e.g., electrode patterned balloon) can be coupled and positioned along the length of the probe on an outer surface, with inflation or expansion of the expandable member controlled by an external pressure source coupled to the proximal portion of the probe.
A probe may include one or more electrodes (e.g., secondary electrodes) that can be positioned within the probe and deployed from the probe and into the prostate tissue. For example, such secondary electrodes can be positioned in the probe shaft or body during advancement and positioning of the probe, and deployed from the probe once a desired position has been reached. Deployable probes can include needle-like electrodes, which can include a shape memory metal and configured to assume a desired shape when deployed, e.g., as discussed further below.
During use, field delivery can occur with current flow between an electrode elements of the urethral probe and electrode(s) spaced from the urethral probe, such as electrodes positioned in the prostate tissue or in the rectal area. As above, electrode elements, including electrodes of the expandable member, will be connected to an external power source 182 or power unit (e.g., power source of control system or unit), which will include a means of generating electrical power for operation of the system and probe, and application of electrical current to the target tissue as described herein. The power unit can include or be operably coupled to additional components, such as a control unit, driver unit, user interface, and the like (see, e.g., infra).
System 170 further includes an imaging device 186, such as an ultrasonic imaging probe, for providing images of tissues for example during positioning and/or use of the probe 172. The device 186 includes a distal imaging portion 188 including electronics and imaging components (e.g., ultrasonic scanning transducer), which can be inserted in the patient's rectum (R) and positioned against the rectal wall near the prostate (P). Imaging device 186 can include those commonly used for diagnostic medicine (see, e.g, above). The imaging portion 188 can scan a region of the tissue to generate an image of the tissue, rectal wall, prostate (P), urethra (U), and/or the probe located in the patient's urethra (U). The imaging device 186 can be connected to an image processing unit 190 and a display unit 192, as is common practice. In use, the display 192 provides images (e.g., real-time ultrasonic images) of the prostate (P) with the position of the probe 172 relative to the prostate (P) and target area, the bladder (B), etc. to help guide or confirm positioning of the probe 172 within the prostate (P) prior to delivery of treatment energy.
As discussed above, a probe of a system, e.g., as illustrated in
In yet another aspect, access and delivery of the desired current may be gained through the rectal cavity. An energy delivery probe can be inserted into the rectum of a patient and electrodes positioned adjacent to the rectal wall or advanced through the rectal wall and into the prostate tissue of the patient. Various probe and/or electrode configurations may be suitable for delivery of the current in accordance with the present invention. A probe can include, for example, elongated device or catheter with one or more needle-like electrodes including, e.g., electrodes deployable from a catheter lumen. Alternatively, an energy delivery probe can include one or more inflatable devices or balloons having electrode patterns disposed on a surface. Such balloons may be similar to those described above with respect to transurethral access and current delivery. Rectal probes can be utilized in isolation, e.g., with electrodes of the rectal probe forming discrete energy delivery units (e.g., pairs or groups of bipolar electrodes), or electrodes of a rectal probe can operate in conjunction with other electrodes, such as electrodes of transuerethral probe or elongate electrodes inserted across the perineum of the patient. In the latter case, electrodes of the trans-rectal probe and separately positioned probe can be operated in bipolar mode such that current flow is established across tissue separating the different devices, and between the electrodes of the different devices.
A trans-rectal approach, according to one embodiment of the present invention, is described with reference to
A system according to an embodiment of the present invention is described with reference to
A control unit can include a, e.g., a computer or a wide variety of proprietary or commercially available computers or systems having one or more processing structures, a personal computer, and the like, with such systems often comprising data processing hardware and/or software configured to implement any one (or combination of) the method steps described herein. Any software will typically include machine readable code of programming instructions embodied in a tangible media such as a memory, a digital or optical recovering media, optical, electrical, or wireless telemetry signals, or the like, and one or more of these structures may also be used to transmit data and information between components of the system in any wide variety of distributed or centralized signal processing architectures.
Components of the system, including the controller, can be used to control the amount of power or electrical energy delivered to the target tissue. Energy may be delivered in a programmed or pre-determined amount or may begin as an initial setting with modifications to the electric field being made during the energy delivery and ablation process. In one embodiment, for example, the system can deliver energy in a “scanning mode”, where electric field parameters, such as applied voltage and frequency, include delivery across a predetermined range. Feedback mechanisms can be used to monitor the electric field delivery in scanning mode and select from the delivery range parameters optimal for ablation of the tissue being targeted.
Systems and devices of the present invention can, though not necessarily, be used in conjunction with other systems, ablation systems, cancer treatment systems, such as drug delivery, local or systemic delivery, surgery, radiology or nuclear medicine systems, and the like. Another advantage of the present invention, is that treatment does not preclude follow-up treatment with other approaches, including conventional approaches such as surgery and radiation therapy. In some cases, treatment according to the present invention can occur in conjunction or combination with therapies such as chemotherapy. Similarly, devices can be modified to incorporate components and/or aspects of other systems, such as drug delivery systems, including drug delivery needles, electrodes, etc.
The following examples are intended to illustrate but not limit the invention.
The present example describes a study designed to evaluate efficacy of different treatment parameters using the electric field delivery and ablation technology as described herein in the treatment of a human prostate cancer (CaP) xenograft model.
Design
Sixty 4 to 6-week old male CB-17 SCID mice were injected subcutaneously on the right flank with 2*106 cells of the C4-2B CaP cell line. After injection, animals enrolled once tumor volumes reached 200 mm3 (˜3-4 weeks) and randomized into one of five groups using the following design: 1) Control group—received placement of probe without current (n=10); 2) a groups receiving 15 mAmp for 15 min (n=13); 3) a group receiving 15 mAmp for 60 min (n=9); 4) a group receiving 25 mAmp for 15 min (n=10); and 5) a group receiving 25 mAmp for 60 min (n=10). Mice were treated with direct application of a low power, intermediate frequency (e.g., about 100 kHz) field through percutaneous placement of a probe (e.g., as shown in
A subsets of animals were sacrificed 7 days after treatment for histopathological evaluation of tumors. The remaining mice were sacrifice 14 days or more after treatment. Animals that had complete destruction of their tumors were observed for up to 30 days post treatment for recurrence. Tumor volumes were measured twice weekly and prostate specific antigen (PSA) levels were measured once a week.
The probe used was of the triangle configuration with a central anode and three outer cathodes (see, e.g.,
Prostate Tumor Xenograft Model
The C4-2B CaP cell line was obtained and implanted. This is an castration-resistant CaP cell line derived from a bony metastasis of the LNCaP cell line. This line was maintained under standard conditions and propagated when necessary. Tumor measurement were done with hand held caliper begin once tumors become palpable and twice weekly thereafter.
Animals included CB-17 SCID male mice were obtained from Fox Chase SCID mice, Charles River, Wilmington, Mass. Animals were eartagged and checked for health on arrival 11.07.07 and group housed (five animals per cage) at the vivarium. Animals were acclimated to the facility for 7 days before beginning the experiment. Statistical analyses were performed using unpaired student t-tests and ANOVA (Prism Graphpad, Graphpad Software, San Diego, Calif.). Statistically significance results were designated as P≦0.05. After fixation, tumors were serially sectioned in 2-3 mm increments from which 5 micron thick slides were cut and used for histopathology analysis.
Dose Groups
Animals were randomly sorted and assigned into five different treatment groups (see Table 1) and randomized.
All animals were closely observed daily for signs of lethargy, weight loss, paralysis, dyspnea, cyanosis, mucopurulent discharges, incontinence, diarrhea, changes in coat or body condition, or any other health problems that could indicate that the animal was becoming moribund (as defined by IACUC guidelines). All observations were documented and members of the research staff were notified if any abnormalities were found. Any animal found with apparent health problems was monitored at additional times, as needed. Any animal appearing moribund was promptly euthanized.
Mice were bleed (˜20 uL) from the tail vein once weekly starting with enrollment. Serum was removed after centrifugation for 8 min at 10000 RPM. PSA levels were then determined using IMx Total PSA Assay, Abbott Laboratories, Abbott Park, Ill. Intra-tumoral temperature measurements were made using thermocouples positioned in the tissue. Baseline temperature measurements were taken prior to application of power and at 15 minute intervals. Current delivery was selected to avoid damage due to severe temperature elevation (e.g., exceeding 50 degrees C.).
Results
Animals tolerated the procedure well with no observable adverse side effects attributed to the application of the treatment. The animals that received 15 mAmp of current applied to their tumors demonstrated a 17±4.7% (mean±SEM) decrease in enrollment tumor volume at the lowest nadir following treatment. These reductions were greater than (though not significantly different) from those seen in the control group (Control −10±6.9%, p=0.436). When comparing the groups receiving 15 mAmp/15 min vs. 15 mAmp/60 min there was no significant difference to tumor volume reductions (p=0.85). The animals that had 25 mAmp of current applied to their tumors had a 62±9.4% decrease in tumor volume at their lowest nadir. This is a significant decrease in tumor volume compared to both the control group (p=0.001) and 15 mAmp treated animals (p<0.001). There were no differences in tumor volume reduction measured between the group receiving 25 mAmp for 15 min and the group receiving 25 mAmp for 60 min (p=0.704). It was noted that 6/20 animals treated with 25 mAmp demonstrated a complete ablation/destruction of the tumor. Results of treatment on tumor volume are illustrated in
Prostate-Specific Antigen
PSA levels generally tracked well with treatment effectiveness and tumor volume reductions. PSA levels normalized to enrollment levels are shown in
Tissue Temperature
Intra-tumoral temperatures were measured immediately prior to and during each treatment in most study groups. Animal body temperature was typically around 37° C. Tumor tissue temperature of animals under anesthesia dropped below normal average body temperature. During treatment, the 15 mAmp treatment groups rose to a maximum temperature of 36±0.6° C. (mean±SEM). This represents a 6.5±1.1° C. elevation above baseline temperatures during treatment. The maximum temperature in the 25 mAmp treatments groups was significantly higher compared to the 15 mAmp treated groups (25 mAmp: 44±0.6° C.; p<0.001) with significantly higher elevations in temperature above baseline vs. 15 mAmp treated groups (15±0.6° C.; p=<0.001).
The described low-power, mild hyperthermia treatment demonstrated significant tumoricidal capabilities. The results show that efficacy is based on the current applied and with effective treatment occurring in shortest tested treatment times. Tissue heating due to treatment was limited to average treatment temperatures of about 44° C., which would seem to preclude as a cytotoxic factor effects of more extreme temperature application characterized by tissue charring and substantial protein cross-linking typically observed at temperatures well in excess of 50° C.
Further, elevations in temperature to this level have typically required far greater lengths of treatment than the observed treatment times shown to have effectiveness in this study. It is possible that both the elevations in temperature along with factors such as the application of alternating electrical current and/or field orientation cumulatively or synergistically allow for shorter time intervals necessary to derive at the desired tumor ablating effect.
It is further noted that further refinements and/or customization of delivery probes or positioned electrodes to individual tumors being treated may further improve treatment results. In some subjects, electrodes did not encompass the entire tumor or in some cases were entirely contained within the tumor margin and, therefore, less than the entire tumor was treated in such instances. Complete tumor destruction was seen in some animals and was observed more likely in instances where the tumor was more thoroughly contained within the treatment volume. Further, as a group, improved results were observed in the study group using the larger sized probe with 4 mm anode/cathode spacing, where on average tumors were more completely treated.
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. Numerous different combinations are possible, and such combinations are considered part of the present invention.
This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 60/972,698 (Attorney Docket No. 26533A-000700US), filed Sep. 14, 2007, the full disclosure of which is incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 60972698 | Sep 2007 | US |
