HK1182659A - Thermotherapy method for treatment and prevention of cancer in male and female patients and cosmetic ablation of tissue - Google Patents

Abstract

This invention relates to the method includes the steps of monitoring temperatures of the skin surface adjacent the body, positioning at least one energy applicator around the body, delivering energy to the at least one energy applicator to selectively irradiate the body tissue with energy and treat at least one of cancerous and benign conditions of the body, adjusting the level of power to be delivered to the at least one energy applicator during treatment based on the monitored skin temperatures, monitoring the energy delivered to the at least one energy applicator, determining total energy delivered to the at least one energy applicator, and completing the treatment when the desired total energy dose has been delivered by the at least one energy applicator to the body.

Description

Thermotherapy for treating and preventing cancer and cosmetic tissue ablation in male and female patients

The application is the divisional application of the international application number PCT/US2003/026681, the international application date is 2003-8-27, the date of entering China is 2005-4-15, the Chinese national application number is 03824300.8, and the invention is named as the thermotherapy for treating and preventing cancer and ablating cosmetic tissues of male and female patients.

Background

The present invention relates generally to a minimally invasive method for treating tube cancer, adenocarcinoma, intraductal hyperplasia, and benign lesions such as fibroadenoma, breast tissue cysts, with focused energy such as adaptive phased array microwave energy or single applicator (applicator) hyperthermia. The breast tissue to be treated may be in a male or female patient, and thus the method of the invention may be used to treat patients with small to large breasts. In addition, the methods of the invention can be used to treat healthy tissue containing undetected microscopic pathologically altered cells at high water content to prevent the occurrence or recurrence of cancer, precancer, or benign breast lesions.

In order to treat primary breast cancer with heat, one-fourth or more of the tissue of the breast, for example, must be heated. It is well known that about 90% of all breast cancers occur in ductal tissue (lactiferous ducts) and most of The rest occur in glandular tissue lobules (milk sacs) (Harris et al, "The New England Journal of Medicine" Vol.327, pp.390-398, 1992). Breast cancer usually involves a large area of the breast and existing conservative treatment methods have a significant risk of local failure for this cancer (Schnitt et al, cancer, Vol.74(6) pp.1746-1751, 1994). For early breast cancers of either T1(0-2 cm) or T2(2-5 cm), the entire breast is at risk and is usually treated with breast preservation surgery in combination with full breast irradiation to destroy any microscopic cancer (cancer that cannot be seen visually without relying on a microscope or mammography) cells that may be present in the breast tissue (Winchester et al, CA-A cancer journal for Clinicians, Vol.42, No.3, pp.134-162, 1992). Successful treatment of invasive ductal carcinoma (cancer that has spread through the duct) with a wide range of intraductal components (EICs) is very difficult because most of the breast is treated. In the united states, over 800,000 suspicious lesions are biopsied annually with about 205,000 carcinomas detected, the remainder being non-malignant lesions such as fibroadenomas and cysts. The american cancer society estimates that 203,500 new female patients with breast cancer and 1,500 male patients will be present in the united states in 2002. (Cancer Facts & Figures 2002, American Cancer Society, Atlanta, Georgia, P.4, 2002).

Thermotherapy for breast cancer can be effectively performed in multiple ways, and in most cases thermotherapy must be able to cover a wide area in the breast at the same time. Extensive heating of the breast can destroy most or all of the microscopic cancer cells in the breast and can reduce or prevent recurrence of the cancer. This approach is also used in radiation therapy, where the entire breast is X-rayed to kill all microscopic cancer cells. Tumor heating prior to lumpectomy to kill most or all tumor cells may reduce the likelihood of inadvertent dissemination of viable cancer cells during lumpectomy, thereby reducing the probability of local recurrence of breast tumors. Sometimes, the affected breast contains two or more masses, known as multifocal carcinomas. In this case, the heating range must be over a large range of the breast. Locally advanced breast Cancer (called T3) (Smart et al, "A Cancer Journal for Clinicians", Vol.47, pp.134-139, 1997) is more than 5 cm in size and is typically treated by mastectomy. Preoperative hyperthermia (hyperthermia) treatment of locally advanced breast cancer can effectively shrink the tumor to the point that it may allow for lumpectomy of the breast to be treated, similar to the preoperative chemotherapy used today. Preoperative thermotherapy for locally advanced breast cancer may also completely destroy the tumor, thus eliminating the need for any surgical intervention.

It is well known that microwave energy can preferentially heat high-moisture tissue, such as breast tumors and cysts, as compared to lower-moisture tissue, such as breast adipose tissue. Numerous clinical studies have established that Hyperthermia (temperature elevation) induced by absorption of electromagnetic energy in the microwave band significantly enhances the efficacy of radiotherapy in the treatment of malignancies in humans (Valdagni et al, International Journal of Radiation Biology Physics, Vol.28, pp.163-169, 1993; Vergaard et al, International Journal of Hyperthermia, Vol.12, No.1, pp 3-20, 1996; Vernon et al, International Journal of Radiation Biology Physics, Vol.35, pp.731-744, 1996; van der Zee et al, Proceedings of the 7^thInternational Congress on HyperthermicOncology, Rome, Italy, April 9-13, Vol.II, pp.215-217, 1996; falk and Issel et al, "Hyperthemic in Oncology", International Journal of Hyperthermia, Vol.17, No.1, 2001, pp.1-18). Radioresistant cells such as S-phase cells can be killed directly as a result of an increase in temperature (Hall, Radiobiology for the radiologic, 4)^thEdition, JB Lippincott Company, Philapthia, pp.262-263, 1994; perez and Brady, Principles and Practice of RadiationOncology, 2^ndEdition, JB Lippincott Company, Philapthia, pp.396-397, 1994). Thermotherapy with microwave irradiation devices is usually performed several times, each time for about 60 minutes with heating to about 43 ℃ for malignant tumors. It is known that the time required to kill tumor cells decreases by about half for each 1 ℃ increase in temperature at about 43 ℃ (Sapareto et al, International Journal of Radiation Oncology Physics, Vol.10, pp.787-800, 1984). Thus, for a treatment at 43 ℃ for about 60 minutes, only about 15 minutes is required at 45 ℃, which is commonly referred to as an equivalent dose (t ℃.)_43℃Equivalent minutes). It has been clinically established that thermotherapy can be usedEnhancing the effect of chemotherapy (Falk and Issels, 2001). When treating with non-invasive microwave applicators, it is difficult to ensure proper heating of the semi-deep (deep) tumor, while also preventing surrounding shallow healthy tissue from incurring pain or damage due to undesirable heat buildup. Specific Absorption Rate (SAR) in tissue is a characteristic parameter commonly used to represent tissue heating. SAR is proportional to the temperature rise of the tissue over a given time. For microwave energy, SAR is also proportional to the product of the square of the electric field and the conductivity of the tissue. The absolute value of SAR is given in [ Watt/kilogram ]]。

Non-coherent-array or Non-adaptive phased array thermotherapy systems are generally capable of heating superficial tumors, but have limited application to heating deep tumors or tissues because they tend to overheat shallow tissues in the middle causing pain and/or burns. Single applicator thermotherapy with TEM air-cooled microwave waveguide applicators of the present assignee has been successful in the treatment of cancers including superficial layers of recurrent breast cancer (chest wall cancer) (Shindig et al, "Clinical Experience with Hyperthermia in joining Therapy with Radiation Therapy" Oncology, Vol.50, pp.353-361, 1993). A non-adaptive phased array for thermotherapy of deep tissues as described in the first published Report is a theoretical study (von Hippel et al, Mass instruments of technology, Laboratory for instrumentation Research, Technical Report 13, AD-769843, pp.16-19, 1973). U.S. patent No.3,895,639 to Rodler describes dual-channel and 4-channel non-adaptive phased array thermotherapy circuits. Recent developments in thermotherapy systems have effectively targeted the use of adaptive phased array technology to heat deep tissues. Adaptive phased array technology has been derived from the development of microwave Radar Systems (Skolnik, Introduction to Radar Systems, Second Edition, McGraw-Hill Book Company, 1980, pp.332-333; Compton, Adaptive Antennas, Concepts and Performance, Prentice Hall, New Jersey, p.1, 1988: Fenn, IEEE Transaction on Antennas and Performance, Vol.38, Number 2, pp.173-185, 1990; U.S. Patents Nos.5,251,645; 5,441,532; 5,540,737; 5,810,888).

Bassen et al show in Radio Science, Vol.12, No.6(5), Nov-Dec 1977, pp.15-25: an electric field probe can be used to measure the electric field distribution pattern (pattern) in tissue, and in particular examples are shown in which the measured electric field has a focused peak at the central tissue site. The report also discusses a concept related to measuring the electric field in real time within a living sample. However, Bassen et al did not develop the concept of measuring the electric field in real time with an electric field probe into an adaptive phased array.

The adaptive phased array thermotherapy system utilizes electric field feedback measurements to focus microwave energy into deep tissue while rejecting any microwave energy that may overheat surrounding healthy tissue. Preclinical findings indicate that adaptive microwave phased arrays have the ability to provide deep heating while also sparing deep torso and breasts from Hyperthermia (Fenn et al, International Journal of Hyperthermia, Vol.10, No.2, March-April, pp.189-208, 1994; Fenn et al, International Journal of Oncology Management, Vol.7, No.2, pp.22-29, 1998; Fenn et al, Proceedings of the Surgical Applications of Energy resources, 1996; Fenn et al, International Journal of Hyperthermia, Vol.15, No.1, pp.45-61, 1999; and Gavrilov et al, International Journal of Hyperthermia, Vol.15, Vol. 6, pp. 507, 1999).

The difficulty in thermotherapy deep breast tissue with microwave energy is mostly to generate sufficient heat at a predetermined depth while protecting the superficial skin from burns. Multiple non-invasive applicators using adaptive microwave phased arrays and invasive and non-invasive E-field probes can produce a suitably focused beam at the tumor site. The focused beam is ineffective for healthy tissue, as described in U.S. patent nos.5,251,645; 5,441,532; 5,540,737; 5,810888, all of which are incorporated herein by reference. Ideally, the focused beam of microwave radiation is focused primarily on the tumor with only a small amount of energy being delivered to the surrounding healthy tissue. To control the microwave power during treatment, a temperature sensitive feedback probe is inserted into the tumor (Samaras et al Proceedings of the 2)^nd International Symposium，Essen，Germany，June 2-4，1997，Urban&Schwarzenberg, Baltimore, 1978, pp.131-133), and accurate placement of the probe into the tumor is often difficult. In addition, for cancers that are scattered throughout the breast in the duct and breast tissue, thermotherapy is difficult because the temperature sensitive feedback probe does not have a well defined target location. In other cases, it is desirable not to insert the probe (whether a temperature probe or an electric field probe) into the breast tissue so as to prevent infection or dissemination of cancer cells as the probe passes through the tumor region.

There are two different practices for the medical care of benign cysts, namely the lack of any treatment and the draining of the cysts. Medical acceptance has been placed on the standpoint of not treating cysts, as the only known methods for removing cysts are invasive surgical procedures. For cysts, an alternative to surgical resection is to drain them, i.e. puncture them and remove the fluid from the cyst. Although the draining method can temporarily relieve the pain associated with cysts, cysts may regrow if the draining procedure fails to remove the cysts entirely. Therefore, there is a need to provide a non-invasive method of removing such benign cysts.

The above needs are met by the present assignee's method. The method is for heating breast cancer, the method comprising the steps of: inserting an electric field sensor probe into the breast; detecting the skin surface temperature; placing two microwave applicators on opposite sides of the breast; setting an initial power and phase of the microwaves delivered to each microwave applicator to focus the electric field onto the inserted electric field sensor; adjusting the microwave power delivered to the breast in dependence on the detected skin temperature; the breast being treated is monitored for microwave energy received, and the treatment is completed when the total microwave energy delivered by the microwave applicators reaches the desired dose.

In addition, the above-described methods of the assignee of the present invention have been used in applications such as where the placement of the temperature feedback sensor cannot be well determined or where it is not desirable to insert a temperature probe into breast tissue. In the preferred method taught by the assignee, only a single minimally invasive electric field sensor is required. In the case of advanced breast cancer (e.g., 5-8 cm tumor), the method is capable of destroying a significant portion of the cancer cells in the breast and shrinking the tumor or lesion (i.e., reducing its size to, for example, 2-3 cm), thus making it possible to replace the mastectomy with a surgical lumpectomy. In the alternative, the entire advanced breast cancer lesion may be destroyed and surgery may not be necessary. For early stage breast cancer or small breast lesions, the assignee's method can use heat (i.e., hot lump removal) to destroy all breast cancer cells or benign lesions without having to perform a surgical lump removal procedure. In addition, the assignee's method may be used to enhance the effectiveness of radiation therapy or for targeted drug delivery and/or targeted gene therapy delivery using thermosensitive liposomes as described in U.S. Pat. No.5,810,888. The assignee's method may be used with a newly developed temperature sensitive liposome formulation with chemotherapeutic agents such as doxorubicin, as described in U.S. patent No.6,200,598 to needleham, 3/13/2001, wherein the agents are released at a temperature of about 39-45 ℃.

The method of the above-mentioned assignee kills cancer cells while sparing normal glandular, tubular, connective, and adipose tissues of the breast. Thus, thermal lumpectomy in accordance with the present invention avoids damage to healthy tissue and is a conservative treatment of the breast.

Although the assignee's method may be implemented with adaptive microwave phased array technology, generally, focused energy may be used to heat and ablate (abllate) tissue in a region. The focused energy may include electromagnetic waves, ultrasonic waves, or waves of various radio frequencies. That is, any energy may be focused to heat and ablate tissue within a region.

Although the above-described assignee's method non-invasively removes cysts from breast tissue, it presents other problems due to the externally applied focused microwaves and mechanical pressure to compress the breast. It is then necessary to improve the safety of such non-invasive cancer hyperthermia.

Summary of The Invention

Applicants' inventive method of treating cancerous or benign conditions of a body organ or superficial region overcomes the disadvantages of the prior art by selectively irradiating the affected tissue with focused energy. The method of the invention may comprise the steps of: inserting an electric field sensor probe to an appropriate depth in the organ tissue (if two or more energy applicators are employed), monitoring the skin surface temperature adjacent the organ or portion of the body being treated, positioning at least one energy applicator (i.e., one or two applicators) about the organ or body being treated, setting the initial power level delivered to each energy applicator, setting the initial relative phase delivered to each energy applicator, focusing the energy onto the electric field probe located within the organ tissue (if two or more energy applicators are employed), delivering energy onto at least one energy applicator to selectively irradiate the organ tissue or body tissue being treated with the focused energy and treat at least one cancerous or benign condition of the organ or body being treated, adjusting the power level delivered to each energy applicator during treatment based on the monitored skin temperature, monitoring the energy delivered to the at least one energy applicator, determining the total energy delivered to the at least one energy applicator, and displaying the total energy in real time during the treatment, and completing the treatment when the desired total energy dose has been delivered to the organ by the energy applicator. The preferred organ being treated is the breast, and in a preferred method, the energy applicators are positionable in a ring around the breast (or other organ).

According to the present invention, a preferred method of treating cancerous or benign conditions of an organ or body by selectively irradiating the organ or body tissue with energy may comprise the steps of: injecting a substance that enhances heating of organ or body tissue at an appropriate depth to be treated, monitoring skin surface temperature adjacent the organ or body to be treated, positioning at least one energy applicator about the organ or body to be treated, setting an initial power level delivered to each of the at least one energy applicator, delivering energy to the at least one energy applicator to selectively irradiate the organ or body tissue with energy and treat cancerous or benign conditions of the at least one organ or body, adjusting the power level delivered to each of the at least one energy applicator during treatment as a function of the monitored skin temperature, monitoring the energy delivered to the at least one energy applicator, determining the total energy delivered to the at least one energy applicator, and displaying the total energy in real time during treatment, and when a desired total energy dose has been delivered by the at least one energy applicator to the organ or body to be treated The treatment is completed while the body is in motion. That is, applicants envision that the methods of the present invention may be practiced with a single applicator and may employ any energy that may be focused on cancerous or benign lesions of the organ or body being treated.

According to the present invention, the microwave absorbing pad and the metal shield are attached to the microwave thermotherapy applicator and the breast compression plate. These safety precautions are incorporated into the method of the assignee's invention such that when adaptive phased array thermotherapy is applied to compressed breast tissue to treat breast tumors (malignant or benign), the electric field strength and temperature near the base of the breast, chest wall area, and head, eyes, etc., outside the main microwave applicator opening are reduced.

To minimize invasive skin incisions, electric field sensors and temperature sensors are incorporated into a single catheter and used with the assignee's method. As a result, improved patient comfort and reduced risk of infection are achieved due to the need to make only a single minimally invasive skin incision. In an alternative embodiment with a single microwave applicator, no electric field sensor is required, and temperature monitoring controls the power delivered to the applicator. Thus, if a surface temperature sensor is employed, no invasive skin incision is required.

In addition, the adaptive microwave phased array thermotherapy method can be used to perform simple thermotherapy on early breast cancer. Alternatively, the adaptive phased array thermotherapy approach may be combined with chemotherapy and/or gene modifier therapy to treat primary breast tumors in locally advanced breast cancer. Alternatively, hyperthermia simplex thermotherapy of the breast may be used as a pre-surgical tool to reduce the rate of second and third invasive procedures on a lumpectomy patient. An additional use of adaptive microwave thermotherapy is that it can be used to improve the prevention of breast cancer, where thermotherapy can be used with tamoxifen or other antiestrogen drugs to block estrogen from binding to estrogen receptors of breast cancer and can be used to kill cancer cells directly by heating.

In another method of the present invention, a single air-cooled energy applicator located on a patient's breast may be used to heat the breast tissue, where the temperature of the breast tissue is measured either with an inserted temperature probe or with a temperature sensor attached to the skin of the breast. This method may be used in situations where the breast does not extend into the opening formed by the two or more energy applicators (i.e., in what is known as a small breast patient), or where the tumor or tissue being treated is located at the edge of the opening formed by the applicators. Depending on the location of the tumor or tissue being treated, the patient may be prone or supine to receive treatment with a single air-cooled energy applicator.

A tubular material or band may be employed to encircle the torso region of the patient to pressurize the breast tissue toward the chest wall. The width of the material corresponds to the width of the breast being treated so that it flattens the breast, thereby reducing blood flow near the tumor or tissue being treated and reducing the depth of the tumor or tissue being treated relative to the skin.

In another embodiment of the invention, a single applicator may be positioned on the breast or superficial region with benign or malignant tumors, such as the head, neck, torso, arms or legs, so that the emitted energy is directed to one of the tumors (for treating cancerous or benign lesions) and the upper portion of the breast where breast cancer is predominantly occurring (for preventing cancer). Applicants contemplate a non-invasive temperature monitoring system, although invasive temperature probes may be employed depending on the location of the tissue being treated and the ability to obtain a treatment temperature on the treated tissue. For example, with a single applicator, one or more surface temperature sensors may be employed to monitor skin temperature, and then its output may be used as a feedback signal to control the microwave power level delivered to the microwave applicator. A microwave energy dose of up to about 360 kilojoules, preferably about 90 kilojoules, may be applied to the treated breast (e.g., 200 watts of microwave power for about 30 minutes, preferably about 50 watts of microwave power for about 30 minutes) to destroy the tumor, for example, prior to lumpectomy, or to eliminate microscopic breast cancer after lumpectomy.

Certain proteins are known to be capable of preventing cancer cell spread, while others are known to be capable of preventing cancer cell spread. In the case of breast cancer, it has been found that the level of the anti-apoptotic protein Bc1-2 is high in the early stages of breast cancer, particularly those cancer cells that are Estrogen Receptor (ER) positive and tumor suppressor protein p53 immune negative. The Bc1-2 protein family reduces Apoptosis (so-called Apoptosis) in Breast Cancer cells, so that Cancer cell death is not rapid and therefore spread (Zapata, et al, "Expression of Multiple Apoptosis-regulation Genes in Human Breast Cancer Lines and Primary turbines", Breast Cancer Research and Treatment, Vol.47; 129-. Other anti-apoptotic proteins in breast cancer are Bcl-X_LMcl-1, and BAG-1. It is hypothesized that pro-apoptotic proteins like Bax, Bak, and CPP32 that prevent cancer cell spread are not affected by thermotherapy. Similar proteins to other types of tumors and of applicantsThe invention contemplates the treatment of various types of cancer. Applicants theorize that the heating application accomplished with at least one energy applicator in accordance with the present invention selectively heats the anti-apoptotic proteins in the site or organ being treated, thereby promoting and increasing the production of protein inhibitors of the anti-apoptotic proteins in the tumor region that would inhibit the anti-apoptotic proteins and inhibit the spread of cancer and other related pathologies or diseases. That is, the heating created by the application of power to the at least one energy applicator kills the anti-apoptotic proteins or causes the production of protein inhibitors that target the anti-apoptotic proteins, thereby inhibiting the growth of the cancer or other lesion.

The selective irradiation according to the method of the invention generates sufficient heat to damage the DNA and infers that proteins responsible for the ability of the cancer cells to repair themselves are removed or deleted from their associated DNA molecules during heating according to the invention using one or more energy applicators. As a result of the removal of this protein, cancer cells should die naturally through the process of apoptosis. Cytotoxins or substances that poison living cells are associated with radiation, chemotherapy, or heat. It is concluded that these cytotoxins damage the DNA molecule and delete the proteins responsible for cell repair. Removal or deletion of proteins responsible for repair will increase the ability of the cytotoxin to cause apoptosis and necrosis of cancer cells.

Applicants have also contemplated a method of destroying or melting fat and other unwanted tissue for cosmetic purposes. For example, cellulite currently treated with the traumatic painful liposuction procedure can be successfully removed from the leg by injecting a highly conductive material, such as a saline solution, into the low conductivity fat, and then emitting microwave radiation or other energy toward the body to melt the fat deposits. Cellulite is a mass or deposit of fat and fibrous tissue that makes the covered skin uneven. The loose fibrous tissue together with the fat can give the cellulite a lumpy appearance. The emission of microwave radiation or other energy into the body can contract the connective tissue, thereby tightening the loose tissue and smoothing the unsightly, lumpy appearance. To localize or refine the energy absorbed by cellulite or other unwanted tissue being treated, a small dose of a highly conductive material can be injected into a preselected region of the cellulite or other unwanted tissue of the body other than the surrounding tissue, such that the energy is preferentially absorbed by the preselected region, thereby enhancing heating of the preselected region. The injection of the high conductivity material may be performed about half an hour prior to exposure to microwave radiation or other energy. The high conductivity material may be a salt solution or a material having a metal compound. Materials with high electrical conductivity may be injected with other drugs or agents to enhance heating of the preselected area. At least one energy applicator may be selected that is external to the body or inserted into a natural body cavity (e.g., transurethral or transrectal) depending on the area of the body being treated. A microwave blanket or other protective covering may be employed to protect the body area from scattered energy.

Exposure to microwave radiation or other energy should ideally cause the fatty deposits infused by the highly conductive material to denature and/or flow. If the fat is denatured, it is theoretically naturally resorbed by the body and thus may not be removed. In this case, the encapsulation of the body area exposed to heat generated by microwave irradiation or other energy can smooth out the mass. The wrapped body should have sufficient pressure to remodel or pre-shape the body undergoing treatment. However, if fat is to be removed, it is easier to remove the liquefied fat from the area being treated than known liposuction procedures that employ vacuum assisted suction. The melted fat may be aspirated from the area to be treated using a long tube or needle associated with known liposuction procedures. Since the fat being treated will be in a fluid or liquid state upon exposure to microwave radiation or other energy, the removal process should be easier, quicker, and less painful than known liposuction processes that attempt to remove solid fat deposits by suction.

Other objects and advantages of the present invention will become apparent from the following description and the accompanying drawings.

Brief Description of Drawings

The invention will be better understood from a reading of the following detailed description taken in conjunction with the drawings in which like elements are given like reference numerals throughout the several drawings and in which:

FIG. 1 shows a detailed side view of a female breast;

FIG. 2 shows several examples demonstrating the progression of ductal and mammary tissue ductal carcinoma, and lobular carcinoma of the breast;

FIG. 3 shows the values of permittivity and conductivity of normal breast tissue and breast tumors as measured by three different studies. Unlike the other two studies C and J, study b (burdette) was measured through the breast skin, and the measurement data reflected this difference;

FIG. 4 shows the measured water content of breast fat, breast/connective tissue, benign fibrocystic breast, and breast cancer (according to Campbell and Land, 1992);

FIG. 5 illustrates a system of the present invention for heating a breast under compression;

FIG. 6 shows a patient in a prone position with the breast compressed and an E-field probe inserted at a desired depth of focus in the breast;

FIG. 7 is a graph showing the calculated value of focused microwave energy as a function of compressed breast tissue thickness;

FIG. 8 is a three-dimensional view of a computer simulated heating of a breast by opposing dual microwave waveguide applicators;

FIG. 9 is a side view of a 915MHz Specific Absorption Rate (SAR) heating model calculated for a homogeneous normal breast heating with central focus;

FIG. 10 is a top view of a 915MHz specific absorption rate heating model calculated for a central focus versus homogeneous normal breast heating;

FIG. 11 is an end view of a 915MHz SAR heating model calculated for central focusing on homogeneous normal breast heating;

figure 12 is a top view of a calculation of a 915mhz specific absorption rate heating model corresponding to the presence of two simulated breast tumors, each 1.5 cm in diameter, with a 5 cm separation between the two tumors. Wherein the 50% SAR contour model coincides with the contour of the selectively heated tumor;

figure 13 is a one-dimensional cut through the central plane of the 915mhz specific absorption rate heating model of figure 12 corresponding to the presence of two simulated breast tumors, each 1.5 cm in diameter, with a 5 cm separation between the two tumors. The SAR curves in the figures present sharp peaks corresponding to selectively heated tumors;

FIG. 14 shows a breast thermotherapy system in accordance with the invention, with a safety device applied including a microwave absorbing pad applied on the top surface of the waveguide applicator and a metal shield covering the open top region of the waveguide;

FIG. 15 illustrates a side view of a simple T-shaped hypothetical breast with a microwave absorbing pad, a metal shield, an air gap, and an electric field focusing and temperature sensor composite probe;

FIG. 16 illustrates a side view of a breast-shaped phantom together with a microwave absorbing pad, a metal shield, an air gap, and an electric field focusing and temperature sensor composite probe;

FIG. 17 shows a press plate having a rectangular window in a vertical plane, with a microwave absorbing pad attached to the top surface of the press plate;

FIG. 18 shows a side view of the waveguide applicator and compression plate with a metallic shield on the upper portion of the side of the compression plate facing away from the breast skin;

FIG. 19 shows a temperature versus time curve measured when the simple T-shaped hypothetical breast described above is heated by an adaptive phased array applicator without a shield and an absorbent pad;

fig. 20 shows a temperature versus time curve measured when the simple T-shaped hypothetical breast described above is heated by an adaptive phased array applicator with a shield and an absorbent pad.

FIG. 21 is a side view of a small breast between two energy applicators;

FIG. 22 schematically illustrates an alternative heating method of the invention in which a single energy applicator heats a tumor of a small breast of a prone patient;

FIG. 23 is a side view of the heating method of FIG. 22 using a temperature probe inserted into the tumor;

FIG. 24 schematically illustrates an alternative heating method of the invention in which a single energy applicator heats a tumor of a small breast of a supine patient;

FIG. 25 is a side view of the heating method of FIG. 24 with a temperature probe inserted into the tumor;

FIG. 26 schematically illustrates the heating method of FIG. 22, wherein a band pressurizes the small breast; and

fig. 27 schematically illustrates the heating method of fig. 22, wherein a water-coupled pill bag (bolus bag) is attached to the mouth of a single energy applicator.

Detailed description of the preferred embodiments

Dielectric properties of breast tissue

FIG. 1 shows a detailed lateral view of a female breast (mammogram-AUser's Guide, National countil on Radiation Protection and Measurements, NCRP Report No.85, 1 August 1987, p.6). The amount of breast and adipose tissue within the breast can vary widely, from predominantly adipose tissue to extremely dense breast tissue. The male breast is inferred to have a similar composition. High-water content Breast cancer cells typically form in lactiferous ducts and mammary tissue lobules as shown in fig. 2 (cited in dr. susan Love's Breast boost, Addison Wesley, mass., 1990, pp.191-196). Abnormal cell growth in the milk ducts is the first indication, called intraductal hyperplasia, followed by the appearance of atypical intraductal hyperplasia. When the milk ducts are close to full, the condition is known as intraductal carcinoma in situ (DCIS). These three conditions are collectively referred to as precancers. Eventually when the intraductal carcinoma breaks the wall of the canal, such a lesion is called invasive ductal carcinoma. Cancer also forms in the same way in the lobules of the breast. All of the above mentioned cells are usually high water content in the breast, except for pure adipose tissue (low water content) and pure breast/connective tissue (low to medium water content).

The microwave radiation band generally considered by the present invention for clinical thermotherapy is mainly the industrial, scientific, medical (ISM) band of 902 to 928 mhz. Although little has been reported on microwave heating of female breast tissue, it is well known that microwave energy can selectively heat breast cancer compared to surrounding fatty breast tissue. The main works in this respect are four: 1) chaudhary et al, Indian Journal of Biochemistry and Biophysics, Vol.21, pp.76-79, 1984; 2) loines et al, Medical Physics, Vol.21, No.4, pp.547-550.1994; 3) surowiec et al, IEEE Transactions on biomedical engineering, vol.35, No.4, pp.257-263, 1988; and 4) Campbell and Land, Physics in Medicine and Biology, Vol.37, No.1, pp.193-210, 1992. In another work, Burdette, AAPM Medical Physics monograms, No.8, pp.105, 130, 1982, measured data of breast tissue is carried, however, measured through the skin and may not represent the breast tissue itself. The dielectric properties of normal breast tissue and breast tumor tissue are typically characterized by dielectric constant and conductivity, as shown in fig. 3. At 915MHz, the average dielectric constant of a normal breast is 12.5 and the average conductivity is 0.21S/m, regardless of the data in the Burdette work. In contrast, breast tumors had an average dielectric constant of 58.6 and an average conductivity of 1.03S/m. It should be noted that the data in the works of Chaudhary et al (C) and Joines et al (J) are measured at room temperature (25 ℃). It should also be noted that the dielectric constant generally decreases and the conductivity generally increases as the temperature increases. The dielectric constant of normal breast is generally similar to that of low-water content adipose tissue, while the dielectric constant of breast tumors is generally similar to that of high-water content muscle tissue. Normal breast tissue contains a complex of fat, mammary and connective tissue. Details of 17 tissues including skin, muscle, fat are carried in Gabriel et al, phys. med. biol., vol.41, pp.2271-2293, 1996. Details on selected breast, breast duct, fat, and cancerous tissues are carried in the Surowiec et al work, but these include only measured data in the 20kHz to 100MHz range. The measurement data at 100MHz may be used to infer the electrical properties of breast tissue at 915 MHz. The applicant is not aware of the presence of measurements of dielectric properties of breast tissue such as the ductus lactici and mammary gland in the frequency band of interest, namely 915 MHz.

The works of Campbell and Land carry the dielectric performance parameters measured at 3.2GHz and the water content of breast fat, breast and connective tissue, benign tumors (including fibroadenoma), and malignant tumors. These moisture content data may be correlated to the relative heatable properties of breast tissue, i.e., tissue with high moisture content heats up faster than tissue with low moisture content. The measured water contents (contents by weight) were as follows: breast fat (11 to 31%), breast and connective tissue (41 to 76%), benign tumors (62 to 84%), and malignant tumors (66 to 79%), wherein selected values are shown in fig. 4. Thus, depending on the water content, it is expected that benign breast lesions and breast tumors will heat up significantly faster than breast, connective, fat, etc., breast tissue. The best typical values for conductivity measured at 3.2GHz by Campbell and Land are as follows: breast fat (0.11 to 0.14S/m), breast and connective tissue (0.35 to 1.05S/m), benign tumors (1.0 to 4.0S/m), and malignant tumors (3.0 to 4.0S/m). Thus, the electrical conductivity of benign and malignant tumors is about 4 times greater than that of breast and connective tissues and about 30 times greater than that of pure adipose tissues. These data are consistent with conductivity data shown in figure 3 measured at 915mhz by Chaudhary et al and joins et al.

In addition, conductivity data for normal breast tissue at 3GHz, measured by Chaudhary in 1984, was 0.36S/m, which is consistent with the range of normal breast and connective tissue conductivities measured by Campbell and Land at 3.2GHz (0.35 to 1.05S/m). Thus, according to the best available data, breast fat is low in water content, breast and connective tissues are low to medium in water content, and breast tumors are high in water content. It is therefore expected that benign and malignant tumor cells will heat at a much higher rate and temperature than the surrounding fat, breast duct, and connective tissue cells. In other words, with this therapy, only microscopic and visible tumor cells are heated, while surrounding adipose, breast duct, and connective tissue cells are protected from destruction.

Tissue conductivity is a major control parameter when using microwave energy to heat tissue. The electrical conductivity of the tissue, also known as the ionic conductivity of the tissue, is given in [ S/m ]]. Electrical conductivity is a function of Tissue Properties, including mainly water content, and ion content, and temperature (f.a. duck, Physical Properties of Tissue, Academic Press, 1990, Chapter 6, pp.167-223). The electrical conductivity of tissue increases as its moisture content, ionic content, and temperature increase. For example, physiological saline has a higher ionic conductivity than pure water. The warm brine has a higher ionic conductivity than the cold brine. Invasive or infiltrating breast cancer cells report the presence of moderate to low differentiation, meaning that such cancer cells gradually lose normal cell function. When cancer cells lose the function of normal cells, they expand in size and absorb more water, thereby increasing the water content. The ionic conductivity of cancer cells is significantly increased by the ionic components in the water contained in the cancer cells. An ion is a particle that is either positively or negatively charged. The major ions in the tissue are mainly potassium (K +), calcium (Ca2+), sodium (Na +), and chloride (Cl-). The number of electrons of calcium ion is 2 less than that of protons, and therefore the bandPositive charge (2 +). Calcium is able to attract and hold two chloride ions (Cl-), while potassium is able to attract and hold only one chloride ion (Cl-). Calcium chloride (CaCl)₂) The calcium ions and chloride ions in the aqueous solution are dissociated or separated, and when dissolved in water, the mobility of the free calcium ions and chloride ions is increased, thereby increasing the ion conductivity of the aqueous solution. Tightly clustered (tighly clustered) calcium precipitates (commonly known as microcalcifications) present in mammograms are often associated with cancer (s.m. Love, dr. susan Love's break Book, 3)^rdEdition, Persus Publishing, 2000, pp.130-131). Microcalcification clustering in the milk ducts is often a hallmark of precancer. Large chunks of calcium are often associated with benign lesions such as fibroadenomas. Some of the calcifications present in the breast are calcium isolated from the bone, which is randomly deposited into the breast by the blood stream.

Measurements have been made of the protein and Ionic content of Fluids in Breast cysts (B. Garard, et al, "Proteins and Ionic Components in Breast waves", Endocrinology of cytological Breast diseases, eds. A. Angeli et al, Raven Press, New York, 1983, pp.191-195; H.L. Bradlow et al, "Cations in Breast waves", Endocrinology of cytological Breast waves, eds. A.Angeli et al, Raven Press, New York, 1983, pp.197-201). The liquid of the galactocele contains sodium (Na +), potassium (K +), chlorine (Cl-), calcium (Ca2+), and phosphoric acid (PO)₄-), and magnesium (Mg2+) ions. Bradlow mentions three classes of breast cyst fluid: the first is high potassium (K +) ion content and medium sodium (Na +) and chloride (Cl-) ion content; the second type is high potassium (K +) and sodium (Na +) ion content and medium chlorine (Cl-) ion content; the third category is high content of chloride (Cl-) ions and low content of potassium (K +) ions in sodium (Na +) ions. The high water content and high ionic content of a breast cyst make it easier to heat when heated with microwave energy than the surrounding normal healthy breast tissue.

There are several cysts: formation of large cysts that can reach the tumor; cysts comprising concentrated (dense) emulsions, known as "breast cysts"; cysts developed by dilation of the milk ducts; cysts caused by fat necrosis; cysts associated with intraductal papillomas and known as "papillary cystadenomas"; and cysts induced by estrogen intake. Large (very large) cysts can rapidly develop to reach and continue to maintain considerable size, although sometimes the size decreases somewhat or even disappears completely over time. A significant proportion of large cysts are found during the menstrual or premenstrual period and then grow rapidly and become painful and painful to the touch. Large cysts are sometimes accompanied by acute inflammation, pain, tenderness, and slight redness of the superficial skin. After the cyst fluid is aspirated out with a needle, signs of inflammation may be temporarily alleviated. After the liquid has been aspirated, only the fibrotic cyst wall remains. However, cyst fluid leaking into the surrounding breast tissue can cause intense irritation. Most, or about 95%, large volume cysts range in age from 30 to 54 years. The larger the range of breast openings, the more cysts that may be found in order to find cysts.

Fibroadenomas (a very common benign mass, also known as fibroids) are smooth and hard, ranging in size from 5 mm to about 5 cm. According to the small scale measurements, the moisture content of fibroadenomas is high (on average 78.5%, n 6) (Campbell and Land, Dielectric properties of Female Human Breast Tissue Measured in vitro at 3.2GHz, Phys Med Biol, 1992, vol.37(1), pp.193-210) and should therefore be heated by microwave energy faster than the surrounding healthy Breast Tissue. These benign lesions can be clearly detected by X-ray and ultrasound examination and, if necessary, can be surgically removed. Some patients suffer from multiple fibroadenomas, in which case surgical breast conservation surgery becomes unfeasible. Water content measurements of other benign tumors in Campbell and Land writings are as follows.

Benign fibrotic tumors: the median water content of one patient (26 years old) as measured in Campbell and Land literature was 65.5%, suggesting high water content. Fibrosis refers to the formation of fibrous tissue, which can exist as a reparative or reactive process. Fibrotic breast disease is a special type of fibrosis that inhibits and destroys the acini and ducts of the lobules in local areas of the breast and forms palpable tumors. Fibrosis is not as rigid (but not as rigid as cancer) and usually requires local resection; however, the margins of fibrotic disease are often not well defined because the shape of the lesion is an irregular disk rather than a cyst-like circle.

Benign fibrocystic adenomas (fibroadrosins tumors): the median water content of the measurements from one patient (27 years old) in Campbell and Land literature was 73.5%, suggesting high water content.

Benign epithelial proliferative tumors (also known as papillomas): the median water content of the measurements from one patient (40 years old) in Campbell and Land literature was 61%, suggesting high water content. Papillomas are papillary proliferations of the mammary duct epithelium that partially fill and dilate the small ducts. Papillomas are usually microscopic and often present with cystic disease, neoplastic adenosis (tumor adenosis), multiple papillomas, or some other neoplastic lesion.

Benign adenoma: the median water content of the measurements from one patient (43 years old) in Campbell and Land literature was 38%, suggesting a low water content. Benign adenomas are the proliferations of the acini of the breast lobules that appear as microscopic or sized tumors. These tumors (benign adenopathy) do not heat up significantly compared to the surrounding normal breast tissue. However, this conclusion is only based on one sample measurement and may not be representative of other adenomas.

In summary, benign lesions such as cysts, fibroadenomas, fibrolesions, fibrocystic adenomas, and epithelial hyperplasia (also known as papillomas) exhibit high water content and/or high ionic content and should be easily heatable with microwave energy; benign adenopathies may not heat as readily as high water content and/or high ion content cysts, but this conclusion is not certain since it is only based on data from a single patient.

For advanced breast cancers (e.g., tumor sizes of 5-8 cm), the present assignee's inventive method is able to destroy a significant portion of the breast cancer cells, either by heat alone or in combination with chemotherapy. The method may be used to shrink a tumor or lesion (i.e. reduce its size to, for example, 2-3 cm) by heating, so that a surgical lumpectomy may be used in place of a mastectomy. Ideally, advanced breast cancer can be completely destroyed (i.e., using thermal mastectomy or thermal chemical mastectomy) and no further surgery is necessary. Early stage breast cancer or small size breast lesions can be destroyed by the method of the invention as described below. That is, heat can be used to destroy all breast cancer cells or benign lesions (i.e., thermal ablation of the breast mass) so that surgical removal of the breast mass is not necessary.

The lump can be separately heated with thermotherapy before the first (or second or third) lumpectomy to reduce the necessity of a re-lumpectomy. Such resection is often necessary when the margins of the lumpectomy specimen are positive (cancer cells are detected). A second resection is necessary when about 30% of the lumpectomy specimens are positive for margin. Since the inventive method heats the target region from the outside inwards (unlike the RF ablation method, which heats from the inside outwards), the inventive method heats mainly the edge of the target. Thermotherapy in accordance with the invention can therefore be used to destroy cancer cells in the marginal region of the tissue to be excised prior to surgery. As a result, the expectation of cancer cells detected from the excised tissue margin after the operation is reduced, and the necessity of performing a second (or third) excision can be eliminated. Thermotherapy in accordance with the invention can be used theoretically as a method of thermal ablation of a breast mass that can replace invasive breast mass surgery. Thus, the thermotherapy of the invention can significantly reduce or entirely destroy the cancer cells in the breast.

Thermotherapy in accordance with the invention is also envisioned to be used in conjunction with gene modification factors to benefit patients having tissues containing genes such as BRCAl, BRCA2 or other abnormal genes (variant genes). It has been shown that patients with such abnormal genes have an increased risk of developing cancer and therefore the elimination of these genes will reduce the risk of developing cancer in the patient. Regardless of whether thermotherapy is used alone or in combination with chemotherapy and/or gene modifiers, the recurrence rate of breast cancer will be reduced by the ability to destroy any cancer cells present in the tissue margin region to render it cancer cell-free or to destroy or repair mutated genes that can cause cancer and other diseases. In addition, the method may be used as described in U.S. patent No.5,810,888, and/or targeted gene therapy for treating breast lesions, to enhance the effect of radiation therapy and/or delivery of targeted drugs to help destroy cancerous or abnormal cells in the limbic region. Breast cancer initially occurs in the mammary duct and subsequently invades the surrounding breast tissue and subsequently spreads out of the breast through the lymphatic and vascular systems. Thus, thermotherapy alone or in combination with chemotherapy and/or gene modifiers will reduce the rate of recurrence of breast cancer in the breast or other organs by killing cancer cells or mutated genes in the lymph and vascular systems of the breast.

Thermotherapy in accordance with the invention may be used alone or in combination with chemotherapy and/or genetic modification agents for the pre-treatment of other organs such as the prostate, liver, ovary, etc. In such organs, the presence of an abnormal or variant gene will lead to a high incidence of cancer. In addition, it may also be advantageous to use thermotherapy alone or in combination with chemotherapy and/or genetic modification factors when atypical cells are found in an organ by ductal lavage or other diagnostic techniques.

Thermotherapy for early breast cancer

A small cohort of patients with early stage breast cancer were subjected to phase II clinical thermotherapy using the Celsion Corporation Microfocus APA 1000 breast thermotherapy system. After one or two separate heat treatments, the number of the live tumor cells is obviously reduced by 70 to 90 percent. In some patients, thermotherapy alone can destroy breast cancer cells in their entirety prior to a scheduled lumpectomy, thereby eliminating the need for previously scheduled surgery and preventing local recurrence of breast cancer. In other patients, thermotherapy alone may reduce the necessity of performing a second or third lumpectomy procedure by destroying cancer cells in the margin region. These individual thermotherapies achieve an equivalent thermal dose (relative to 43 ℃) of about 200 minutes or more, a peak temperature at the tumor site of 48.3 ℃, and a microwave energy dose of about 250 kilojoules. In order to completely eradicate breast cancer, hyperthermia alone can be used with higher equivalent thermal doses and to achieve higher temperatures at the breast tumor site. To completely destroy (ablate) the tumor, the temperature at the tumor site may be in the range of 49 to 50 ℃ or even above 55 ℃, while the equivalent thermal dose may be about 400 minutes and the microwave energy dose may be as large as 500 kilojoules. With such significant heating and microwave energy doses, it is necessary to take additional safety measures to protect the breast skin and adjacent healthy tissue, such as the thoracic wall, from any heating damage.

Thermotherapy of Ductal Carcinoma In Situ (DCIS)

Treatment of ductal carcinoma in situ, also known as DCIS or intraductal carcinoma, is a major problem. It was reported (Cancer Fact and regulations 2001, American Cancer Society, inc., Atlanta, Georgia) that approximately 41,000 new cases of DCIS were expected to be diagnosed in 2001. In addition, 192,000 new cases of invasive breast cancer are expected. Of the 238,000 new breast Cancer cases diagnosed that exceeded expectations, 80.6% were aggressive, 17% were DCIS, and the remaining 2.4% were LCIS (lobular carcinoma in situ) (Cancer Fact and figueres 2001). The needle biopsy method of DCIS may underestimate the presence of invasive disease due to sampling errors. Sampling errors make it difficult for such examination methods to accurately diagnose the progression of the disease. Research reports indicate (D.P. Winchester, J.M. Jesk, R.A. Goldschmidt, "The Diagnosis and management of Dual Carcinoma In-Situ of The Breast", CA Cancer J Clin 2000; 50: pp.184-200) that 16% to 20% of DCIS patients diagnosed with needle biopsy procedures have been diagnosed with disease that has proven to be aggressive In subsequent surgical resection procedures. Accordingly, surgical resection is currently required for patients with DCIS in order to develop appropriate treatment strategies. For example, following a preliminary diagnosis of DCIS, and determination of whether aggressive cancer has occurred by lumpectomy and pathological analysis, lymph nodes (particularly labeled lymph nodes) may have to be biopsied and treated. At this time, it may be required to perform a periodic systemic treatment. The primary purpose of any pathological analysis of DCIS patients is to determine their risk level of future invasiveness in order to develop appropriate therapeutic strategies and thereby avoid possible under-or over-treatment.

Based on mammograms and pathological analysis of DCIS disease, treatment may be performed in some cases with breast conservation surgery, which has acceptable cosmetic results. However, long-term follow-up of patients with total mastectomy and radiotherapy in DCIS has shown that up to more than 19% of DCIS patients develop local recurrence, and more than 50% of these local recurrence patients are invasive. For DCIS patients with lumpectomy alone, the recurrence rate can be as high as 26%.

To understand the effect of reduced survival due to local recurrence, the following factors may be considered: for DCIS patients who are negative for the margin of the lesion after surgery and are treated with standard postoperative radiation, at least 80% of the patients are locally controlled for a long period of time. That is, in long-term follow-up, about 20% of patients will relapse locally. Of these 20% of relapsing patients, 10% will be non-invasive relapses and another 10% will be invasive relapses. Treatment with mastectomy on non-invasive relapsing patients will achieve 100% substantial local control. Invasive local recurrence patients will have a five-year survival rate of 75% after mastectomy, i.e. 25% of them will not survive for five years. Thus, for a patient with a lumpectomy DCIS, 10% of the patients will later suffer a non-invasive recurrence and must undergo mastectomy; another 10% of patients will suffer invasive recurrence and have to undergo mastectomy, and 25% of them will die within five years. Thus, about 2.5% of DCIS patients who have received breast preservation therapy (lumpectomy and radiation therapy) will die within five years due to local recurrence. Since there are 41,000 cases of DCIS per year, 2.5% of patients mean that 1,025 DCIS patients die in five years per year due to invasive recurrence. Given these percentage figures, most patients will choose a breast-preserving treatment approach. However these patients will suffer from the enormous side effects of the radiation therapy component of breast conservation therapy. It should also be noted that radiation therapy is an expensive and time consuming treatment procedure (typically 20 to 30 fractionated treatments are required).

One new treatment approach for Ductal Carcinoma In Situ (DCIS) is one or two thermotherapies after lumpectomy. Such treatment approaches can achieve a recurrence rate equal to or less than that achieved by post-lumpectomy radiotherapy, with fewer side effects. The cost of thermotherapy is expected to be lower than that of radiotherapy, thus reducing overall medical costs. Several hyperthermia treatments can be performed simultaneously with conventional radiotherapy to increase the killing effect on Ductal Carcinoma In Situ (DCIS).

Thermotherapy for locally advanced breast cancer in intact breast

According to the invention, thermotherapy can be used in conjunction with chemotherapy to destroy and/or reduce the primary breast for advanced breast cancerCancer thus allows a more conservative lumpectomy to replace the mastectomy. In some cases, preoperative chemotherapy may be required for a patient's breast cancer treatment regimen. Such chemotherapy will involve four cycles or four times of standard preoperative and postoperative chemotherapy as described by NSABP B-18(Fisher et al, 1997, J.clinical Oncology, vol.15(7), pp.2483-2493; and Fisher et al, 1998, J.clinical Oncology, vol.16(8), pp.2672-2685): one cycle every 21 days, 60 mg/m of Doxorubicin (Doxorubicin) was administered per cycle²And 600 mg/m cyclophosphamide (Cytoxan)². Tumor size was measured by clinical examination and ultrasound imaging at the beginning of each chemotherapy cycle. In accordance with one embodiment of the invention, focused phased array microwave thermal treatment may be performed on the same day or within 36 hours of the first, second, and third administrations of the pre-operative doxorubicin-cyclophosphamide (AC) chemotherapy. This warming treatment is not performed prior to surgery while the remaining (fourth) cycle of AC chemotherapy is being performed so that any skin-related thermal effects (e.g., blistering of the skin) have sufficient time to subside. A final assessment of whether the breast was subjected to mastectomy or more conservative lumpectomy could not be made until the fourth cycle of chemotherapy was completed. Other combination chemotherapy for breast cancer, such as doxorubicin and Docetaxel or FAC (5-fluorouracil, doxorubicin, and cyclophosphamide), may also be used in conjunction with thermotherapy as a pre-cancer treatment (new adjuvant) prior to the second treatment for breast cancer. Applicants also contemplate that thermotherapy can be used to shrink breast tumors prior to chemotherapy drug infusion.

It is well known that pre-operative AC chemotherapy causes some reduction in tumor size in about 80% of breast cancers. The tumor shrinkage is usually detectable at the end of the first course of AC chemotherapy, and is typically observed by ultrasound imaging about 21 days after the end of the first course of AC chemotherapy. There is not enough data to demonstrate that combination of thermotherapy and AC chemotherapy can shrink tumors to the same size as AC chemotherapy alone. However, in another embodiment, it is desirable to administer at least one dose of chemotherapy to the patient prior to the thermotherapy treatment in order to achieve significant tumor shrinkage. If three thermotherapies are planned, each thermotherapy will be performed on the same day or within 36 hours of the second, third, and fourth pre-operative chemotherapy, respectively. If two thermotherapies are planned, each thermotherapy may be performed on the same day or within 36 hours of the second, third or third, fourth or second, fourth preoperative chemotherapy, respectively.

Following chemotherapy, thermotherapy may be performed to bring the tumor to a temperature between 43 ℃ and 46 ℃. The tumor received an equivalent thermal dose of about 50 minutes to 100 minutes and a microwave energy dose of about 100 kilojoules to 300 kilojoules per treatment. At the end of the fourth or last chemotherapy, a decision is made based on the size and location of the tumor, the size of the breast, the patient's health, the patient's age, etc., based on the same criteria, and a decision is made as to whether the patient will subsequently undergo mastectomy or partial mastectomy (lumpectomy) to retain the breast. After the pre-operative thermal chemo-complex treatment regimen is performed, all patients are routinely under standard care (including drug and radiation care). Under the direction of the physician, patients who are estrogen receptor positive will receive 10 mg of tamoxifen twice a day within five years from the day after the end of the last chemotherapy. In addition, radiation therapy is also administered to the appropriate patient as part of standard care to the breast and lymph nodes.

Thermotherapy for benign breast lesions

The current phase II clinical thermotherapy of malignant breast lesions is performed by celsion corporation Microfocus APA 1000 breast thermotherapy system. The therapeutic system has obvious killing effect on various breast cancers and benign breast lesions (cysts) through single thermotherapy. In such clinical treatments, tumor temperatures in the range of 47 ℃ to 50 ℃ or up to about 55 ℃ or more are required in order to completely eliminate benign breast lesions. The above temperature conditions, together with equivalent thermal doses up to 360 minutes and microwave energy doses up to 400 kilojoules, will destroy benign breast lesions. According to a preferred treatment procedure of the invention, the patient typically receives an analgesic (naproxen sodium tablet 220 mg) to withstand the pain of a benign breast lesion, which allows the patient to receive one or more thermotherapy sessions at a time.

Thermotherapy and pharmacotherapy for the prevention of breast cancer in situ

Current standard of care for preventing breast cancer is either preventive mastectomy (surgical removal of the entire breast) or Tamoxifen (Tamoxifen) treatment. Tamoxifen (and other drugs such as raloxifene) is an antiestrogen that has affinity for estrogen and prevents estrogen from binding to breast cancer. In the NASBP-1 Breast Cancer preservation Trial, 13,175 participants received either tamoxifen (20 mg daily within five years) or a control. In a group receiving Tamoxifen (trade name Nolvadex), a reduction in the risk of invasive breast Cancer was observed in 49% of participants (Fisher B. et al, "Tamoxifen for Prevention of Breast Cancer: Report of the National Cancer Adjuvant Brease and Bowel project P-1 Study", Journal of the National Cancer Institute, Vol.90, pp.1371-1388, 1998; Morrm. and Jordan V.C., "Tamoxifen for the Prevention of Breast Cancer in High-risk man, Annals Surg col, Vol.7(1), 67-71, 2000). A new concept is to combine thermotherapy with tamoxifen prophylactic treatment, which may enhance estrogen blockade at the estrogen receptor of breast cancer, thereby further reducing the risk of invasive breast cancer. Enhancing the blocking effect on estrogen can be achieved by disrupting or modifying estrogen receptors and/or by directly killing breast cancer with heat.

Alternatively, the selective tissue irradiation of the present invention may be used in place of tamoxifen. The selective irradiation of the present invention can be used to selectively remove estrogen receptors, thereby preventing the absorption of estrogen and the binding of estrogen to breast cancer, which would otherwise benefit the growth of breast cancer. If thermotherapy is successful in removing estrogen receptors that are beneficial for breast cancer, applicants contemplate that thermotherapy alone may be an alternative to estrogen administration to a female patient to overcome symptoms of mood swings and hormonal imbalance. That is, hyperthermia alone can be used as a hormone replacement and at the same time can prevent the appearance of potential breast cancer. If hormone replacement may increase the risk of other cancers, such as ovarian cancer, cervical cancer, etc., thermotherapy may be used in conjunction with tamoxifen prophylactic therapy, as previously described.

In the clinical trial thus conceived, patients undergoing thermotherapy and tamoxifen prophylaxis will receive a standard dose of tamoxifen (20 mg per day over five years) and be thermotherapy at regular intervals during the five years. In an alternatively envisaged clinical trial, patients undergoing thermotherapy and tamoxifen prophylaxis will receive half the standard dose of tamoxifen. That is, they will receive 10 mg per day of tamoxifen or similar drug within five years and will be thermotherapy at regular intervals during the five years. Since patients participating in such clinical trials are not expected to have definite lesions, the target area for clinical trials will simply be limited to the upper part of the breast. It is reported (mammogram-A User's Guide, NCRP Report No.85, National countion radiation Protection and Measurements, Bethesda, p.7, 1987) that about 70% of all breast cancers occur in the upper part of the breast from the nipple to above the base. To place the thermotherapy zone on the top of the breast, the compression site of the breast should be from the head to the tail of the breast, while the electric field focusing probe should be located approximately 0.5 to 1.5 centimeters cranial (measured from the breast central depth line) to the breast. During the period of time that the patient received tamoxifen, a thermotherapy was performed every approximately one year, each thermotherapy applying approximately 180 kilojoules of microwave energy to the breast (100 watts total, 30 minutes of action). Some control patients receiving only tamoxifen treatment are included in the control group participating in the envisaged clinical trial. Of the two channels that heat the patient, the initial microwave power for each channel may be about 50 watts. In phase I and phase II adaptive phased array breast thermotherapy clinical studies by Celsion Corporation, treatment of approximately 35 breast cancer patients demonstrated that such power levels were safe. The skin temperature can be monitored by a skin temperature sensor and the microwave power of the two heating channels adjusted accordingly so that the skin temperature remains below about 41 ℃ during the thermotherapy treatment.

When one of early breast cancer, locally advanced breast cancer, and benign breast lesions is thermotherapy and is prophylactically treated with the thermotherapy of the present invention, it is desirable to maintain the skin temperature below about 40 ℃ to 42 ℃. However, as noted above, the resulting tumor temperature is between about 43 ℃ to about 50 ℃ or higher.

When performing phase I and phase II clinical trials of the Celsion Microfocus 1000 outer focus adaptive phased array microwave system, the applicant noted that in a few cases the skin tissue near the base of the breast near the thoracic wall was excessively heated. It has also been found that mechanical compression of breast tissue sometimes causes non-thermal blistering at the edges of the compression plate where the pressure is greatest. Accordingly, the present invention improves upon the assignee's adaptive phased array microwave system to mitigate and/or reduce these side effects.

Method for heating ductal and breast cancer and surrounding breast tissue

Figure 5 shows a preferred system for heating cancer within an intact breast using an adaptive microwave phased array hyperthermia system with electric field and temperature feedback. In order to reliably heat deep tissues at microwave frequencies, two or more coherent applicators 100 must be placed around the body (breast), the applicators 100 being controlled by an adaptive phased array algorithm. The black circle labeled as focal point 190 represents a tumor or healthy tissue to be heated. In a preferred embodiment, an E-field feedback probe 175 is used to focus the microwave radiation, and several temperature feedback sensors 410 attached to the surface of the breast are used to help regulate the microwave power level to heat the tumor to the desired temperature. A dual channel adaptive phased array is provided to heat the deep tissue of the compressed breast in a similar positional relationship to that of an X-ray mammogram. Preferably, the E-field probe is used with an adaptive phased array fast-acceleration gradient search algorithm (fast-acceleration gradient algorithm) as described in U.S. Pat. No.5,810,888 to Fenn to focus microwave radiation onto a treatment site.

In addition, air-cooled waveguide applicator openings are preferred for providing a heating model capable of heating large volumes of breast tissue containing ductal and breast cancer. The air used to cool the waveguide openings may be chilled, conditioned, or room temperature air. High-water breast and ductal carcinoma tissue is expected to heat faster than normal breast tissue due to the difference in dielectric properties of high-water and fatty breast tissue at a frequency of 915 mhz. Thus, the target heating region will concentrate on high-water content cancerous tissue (carcinomas and precancers) and benign lesions such as fibroadenomas and cysts and will rarely reach normal (healthy) breast tissue.

The breast to be treated is sandwiched between two compression plates 200, which compression plates 200 are made of an insulating material, such as plexiglass, which is transparent to microwaves. For thermotherapy of the entire breast, there are many possible advantages to pressurizing the breast. The compression of the breast during treatment results in a reduced penetration depth of microwave heating required, and the compression of the breast also reduces blood flow rate and thus improves the ability to heat the tissue. Pressurizing the breast flattens the breast surface, which improves the interface and electric field coupling relationship between the microwave applicator and the breast tissue, allowing treatment of a wide range of breast sizes with only one pair of poles. Air cooling of the breast compression plates is required during thermotherapy, which helps to avoid possible thermal convergence points at the skin surface. The patient is held in a prone position and his breast is compressed, as when a 20 to 40 minute stereotactic needle biopsy procedure (Bassett et al, A Cancer Journal for Clinicians, Vol.47, pp.171-190, 1997) is performed, which maximizes the amount of breast tissue located between the compression devices. The slight compression may cause the breast tissue to be immobilized, thereby avoiding any potential problems associated with patient movement. The pressure plate 200 may include small holes therein. The compression plate 200 is compatible with X-ray and ultrasound imaging techniques to enable accurate positioning of the central breast/duct region by them and to assist in placing the invasive E-field probe sensors in the correct position. The thickness of the compressed breast may vary between about 4 to 8 centimeters to allow the patient to tolerate the thermotherapy for 20 to 40 minutes or more. One study of patient comfort in X-ray mammography to compress the breast showed that only 8% of 560 female subjects felt X-ray mammography painful (defined as feeling very uncomfortable or intolerable). The mean thickness of the compressed breast in this study was 4.63 cm with a standard deviation (1. sigma.) of 1.28 cm (Sullivan et al, Radiology, Vol.181, pp.355-357, 1991). It is therefore said that a 20-40 minute or more thermotherapy is feasible in the case of a slight compression of the breast.

Prior to hyperthermia, the breast is sandwiched between two compression plates 200 and an invasive electric field feedback sensor 175 is inserted into the breast at the central breast/duct/tumor tissue site (focal point 190) in a direction parallel to the polarization of the microwave applicator 100. The purpose of the E-field probe 175 is to monitor the amplitude of the focused electric field and apply the gradient search algorithm of the adaptive phased array to adjust the phase shifters to give maximum feedback signal. A non-invasive temperature probe 410 is strapped or otherwise secured to the breast surface to monitor skin temperature. The temperature probe is typically oriented perpendicular to the electric field polarization direction so as not to be heated by microwave energy. The dual-applicator adaptive phased array of the invention, in conjunction with the electric field feedback probe, allows the phase shifters to be adjusted to generate converging electric fields that can heat deep tissue.

Fig. 6 and 14-17 illustrate one embodiment of a safety method for use in an externally focused adaptive phased array thermotherapy for treating breast tumors (both malignant and benign). In the preferred embodiment shown in fig. 6, the patient lies with his breast hanging through an opening in the treatment table 210 in a prone position, with the breast 220 to be treated sandwiched between two flat plastic compression plates 200. Such pressurization results in immobilization of the breast tissue, reduced blood flow rate, and reduced penetration depth requirements for microwave radiation. Treatment table 210 may be similar to tables used in stereotactic Imaging breast needle biopsies such as those produced by Fischer Imaging (Denver, Colorado). The treatment table 210 is made of metal and a soft cushion is laid on the table top to make the patient comfortable. The metallic treatment table 210 functions as a robust support structure for breast imaging. For breast thermotherapy, the metallic treatment table 210 acts as a microwave radiation shield, which completely shields the entire body of the patient, particularly the patient's head and eyes, from stray microwave radiation from the microwave applicator 100. The metallic treatment table 210 may be made of aluminum or steel or plastic and covered with a metal foil or mesh. The table mat 212 may be a foam material and may contain microwave absorbing material to provide additional shielding from stray microwave radiation from the applicators.

The breast compression plate is made of microwave transparent plastic. One or more rectangular or circular apertures may be included on the breast compression plate to allow imaging of breast tissue and placement of the minimally invasive E-field feedback probe 175 to a desired depth of focus. Insertion of the E-field feedback probe 175 may be guided by an ultrasonic transducer. In order to provide additional protection against the skin from microwave field strengths, one or more cooling fans (not shown) are also provided in the system.

As shown in fig. 5, two or more temperature feedback probe sensors 410 are attached to the skin surface of the breast, the sensors 410 generating temperature feedback signals 400. Two air-cooled microwave waveguide applicators 100 are provided on opposite sides of the compression plate 200. A 915mhz microwave oscillator 105 is equally located on node 107 and feeds two phase shifters 120. The phase control signal 125 controls the phase of the microwave signal in the range of 0 to 360 electrical degrees (electrical degrees). From the phase shifter 120, the microwave signal is fed to a microwave power amplifier 130, which amplifier 130 is controlled by a computer generated control signal 135, which control signal 135 sets the initial microwave power level. Coherent 915mhz microwave power is delivered to the two waveguide applicators 100 while the phase shifters 120 in the two channels are adjusted to maximize the electric field amplitude on the electric field feedback probe 175 and focus the microwave energy onto the probe 175, so that the microwave power is maximized at the focal point location 190. Treatment is then initiated.

During hyperthermia treatment, the microwave power level delivered to each applicator 100 is measured and fed to the control center as a feedback signal 500. The power control signal is manually or automatically adjusted to control the skin temperature and equivalent thermal dose measured by the skin sensor 410 to avoid excessive temperatures that can burn or blister the skin. During treatment, the amount of compression of the breast can be adjusted, if necessary, by adjusting the compression plate 200 to provide patient comfort. Each time the compression of the breast is adjusted or the breast is repositioned, the phase shifter 120 readjusts/focuses until the E-field probe sensor 175 receives maximum power. Computer 250 calculates the total microwave energy delivered to the microwave applicators from the time treatment is initiated and displays the results on computer display 260. Treatment is complete when the total microwave energy delivered to the microwave applicator 100 reaches a desired value. Alternatively, the total microwave energy may be calculated based on the E-field feedback signal 450 received by the E-field probe sensor 175 and the duration of the treatment may be controlled based on the calculation. To determine the effectiveness of thermotherapy, pathological analysis of the breast, including X-ray and magnetic resonance imaging, and needle biopsy of breast tissue, is performed both before and after the desired dose of microwave energy thermotherapy is administered.

In an alternative embodiment, the single invasive electric field probe 175 is replaced by two non-invasive electric field probes 185 disposed on the skin surfaces on opposite sides of the breast. The total microwave power measured by the two E-field probes is minimized by adjusting the microwave phase shifter 120 (as described in U.S. Pat. No.5,810,888), which results in a focused E-field probe at a location in the center of the breast. With such an embodiment, there is no risk of infection due to insertion of the probe, no scar formation on the breast skin due to making an incision in the skin and inserting the probe, and no risk of any spread of cancer cells due to passage of the probe through the tumour lesion. Also, since both the temperature probe and the electric field probe of such an embodiment can be arranged on the breast skin, this method will work well even if there is no single defined target area.

Each channel of the phased array (on either side of node 107) preferably includes an electronically adjustable microwave power amplifier 130 (adjustable between 0 and 100 watts), an electronically adjustable phase shifter 120 (adjustable between 0 and 360 degrees), and an air-cooled linearly polarized rectangular waveguide applicator 100. The applicator 100 may be a TEM-2 type applicator manufactured by Celsion Corporation, Columbia, MD.. The dimensions of the rectangular opening on the preferred dual TEM-2 type metal waveguide applicator are 6.5 cm x 13.0 cm.

Although the preferred embodiment discloses microwave energy of about 915MHz, the frequency of the microwave energy of the thermotherapy system can be from about 100MHz to about 10 GHz. The frequency of the microwave energy may be selected from 902MHz to 928 MHz. In fact, lower frequency energy can be used to destroy or arrest cancer cells.

In a preferred embodiment, the initial microwave power delivered to each waveguide applicator is about 20 watts to about 60 watts. To deliver the desired microwave energy dose and avoid overheating the skin, the microwave power delivered to each waveguide applicator may be adjusted between about 0-150 watts by the end of the entire treatment.

The purpose of the dielectric loading (dielectring) on the sidewalls of the rectangular waveguide region of the Applicator 100 is to obtain good impedance matching conditions for microwave radiation from the TEM Applicator (Cheung et al, "Dual-beam TEM Applicator for Direct-Contact heating of dielectric encapsulated metallic use reactor", Radio Science, Vol.12, No.6(s) Supplement, pp.81-85, 1997; gaucherie eds., Methods of experimental thermal heating, Springer-Verlag, New York, pp.33, 1990). An example is shown in the 1997 Cheung et al work, in which a mouse tumor was heated in tandem with two opposed incoherent microwave applicators, and no electric field probe was used in the experiment. Cooling air through the waveguide openings is provided by means of a fan (not shown) which is mounted behind a perforated conductive screen which acts as a parallel reflective bottom surface for the input monopoles feeding the microwaves. The effective cross-sectional dimension of the cooling air channel of the TEM-2 applicator, after deducting the thickness of the dielectric plate in contact with the waveguide sidewalls, is about 6.5 cm x 9.0 cm. Due to the difference in dielectric properties of high moisture content tumor and normal breast tissue at a frequency of 915mhz, high moisture content ductal and breast cancer and benign lesions are expected to heat up faster than normal breast tissue. Thus, the 50% SAR (specific absorption rate) region will concentrate in high water content (cancerous, precancerous, and benign lesions including fibroadenomas and cysts) tissue with little involvement of normal tissue.

In a preferred embodiment, a 0.9 mm outer diameter invasive electric field coaxial monopole probe (semi-rigid RG-034) with a 1 cm protruding center conductor was used, which was used to measure the electric field to the tissue and provide feedback signals for determining the relative phase required by the electronic phase shifter prior to treatment. This type of coaxially fed monopole probe has been used in the past to accurately measure linearly polarized electric fields in compressed breast models (Fenn et al, International Symposium on Electromagnetic Compatibility, 17-19May 1994, pp.566-569; International Journal of Hyperhermia, Vol.10, No.2, March-April, pp.189-208, 1994). The linearly polarized electric field probe was inserted into the body through a fluoroplastic catheter of 1.5 mm outer diameter. Thermocouples have also been used to measure local temperature within the tumor during treatment (physics Instrument, inc., model T copper-constantan thermocouples, encapsulated in fluoroplastic catheters having an outer diameter of 0.6 mm). The response time of such a temperature probe is about 100 milliseconds with an accuracy of 0.1 deg.c.

Heating test of compressed living breast tissue

As part of the FDA approved project, Celsion corporation, the assignee of the present invention, started phase I clinical studies at 12 months 1999. Several volunteers with breast tumors participated in the test, with their tumors varying from 3 to 6 cm in maximum size. They were treated in the trial with an adaptive microwave phased array while an electric field and temperature probe was inserted into the breast tissue. The patient received 40 minutes of thermotherapy and was mastectomy after about one week. The clinical study includes measuring the power delivered to the microwave applicators, which is used to calculate the delivered microwave energy dose rather than to control the duration of the treatment. Details of this phase I clinical study are described in Gardner et al, "Focused Microwave phase Array thermal for Primary Brease Cancer", Annals Surg Oncol, Vol.9(4), pp.326-332, May6, 2002.

The E-field probe is used with an adaptive phased array fast acceleration gradient search algorithm as described in U.S. Pat. No.5,810,888 to Fenn to focus microwave radiation onto a treatment site. The intratumoral temperature sensed by the invasive temperature probe is used as a real-time feedback signal during the treatment process. The feedback signal is used to control the microwave output power level of a variable power amplifier that sets and maintains the focal temperature of the tumor site in the range of 43 ℃ to 46 ℃. The power and phase delivered to the two channels of the phased array are adaptively adjusted by the computer through a digital-to-analog converter.

The breast compression plate is made of acrylic (plexiglass), a low-loss dielectric material that is nearly transparent to the microwave field. The compression plate includes a square opening about 5.5 cm long that is adapted to receive a small ultrasonic transducer (typically 4 cm long) to facilitate placement of the minimally invasive probes (E-field and temperature probes). The square openings also improve the flow of air to cool the skin.

Based on the results of recent adaptive phased array microwave thermotherapy clinical trials, applicants have seen that microwave energy at doses between 138 kilojoules (or kilowatt-seconds) and 192 kilojoules can produce equivalent thermal doses in the range of 24.5 minutes to 67.1 minutes at 43 ℃ for live breast tissue compressed to 4.5 cm to 6.5 cm, as set forth in table 1 below.

TABLE 1 equivalent thermal dose (minutes) and total microwave energy (kilojoules) delivered in four compression in vivo breast experiments

Thus, the total microwave energy dose can be used to estimate the required heating time. Thus, applicants have recognized that an invasive temperature probe can be replaced by a non-invasive equivalent temperature sensing means, and that the duration of treatment can be controlled based on the total microwave energy dose. In table 1, the average thermal dose was 45.1 minutes and the average total microwave energy was 169.5 kilojoules. In these four tests, the maximum energy value (192.0kJ) deviates only 13% from the mean value and the minimum energy value deviates only 14% from the mean value. As previously mentioned, compression of the breast during the trial will likely eliminate the effect of blood flow on the total energy of the microwaves required for treatment, which may help explain why the deviation of the energy required dose during the trial is so small. Applicants also observed that post-treatment breast imaging of these four experimental patients typically indicated significant tumor destruction, with little or no damage to the patient's skin, breast fat, and normal breast, breast duct, and connective tissue.

According to a preferred embodiment of the method, the total microwave energy delivered to the waveguide applicator to determine whether treatment is complete is between 25 kilojoules and 250 kilojoules. The total amount of microwave energy dose that can destroy any cancerous or precancerous tissue is about 175 kilojoules. But the required microwave energy dose may be as low as 25 kilojoules under certain conditions. In another embodiment of the invention, microwave energy doses of up to 400 kilojoules may be used to completely destroy cancerous tumor cells.

Table 2 below lists the compressed thickness of breast tissue in these four experiments. It should be noted that where the minimum compressed thickness (4.5 cm) corresponds to the minimum energy dose delivered (138kJ), both of these data appear in trial 4. As seen by the applicant and will be demonstrated theoretically below: the smaller the thickness of the compressed breast, the smaller the dose of microwave energy required to effectively arrest or destroy a cancerous, precancerous, or benign lesion (as compared to a large breast thickness).

TABLE 2 thickness after compression of breasts in four compression in vivo breast tissue experiments

It is clear from these clinical studies that in order to focus microwave energy onto the area to be treated, it is important to properly select the initial microwave power level (P) delivered to each applicator₁，P₂) And the phase difference between the two applicators. The data obtained for the four compressed breast experiments are listed in table 3:

TABLE 3 initial microwave power and initial power selected to focus radiation onto compressed living breast tissue

Initial microwave phase

As shown in tables 1 and 3, 30 to 40 watts of initial microwave power delivered by each applicator is sufficient to achieve a significant therapeutic dose. In addition, the initial microwave phase difference between the two applicators varies between-10 degrees and-180 degrees without any definite tendency, provided that the microwave radiation must be converged by the electric field sensor.

For the compressed breast test of comparable thickness (tests 2, 3 corresponding to thicknesses of 6.5 cm and 6.0 cm), the microwave power level was kept constant for the first few minutes to determine the rate of temperature rise within the tumor, which is in fact a measure of SAR (specific absorption rate). As a result, it was found that the time required for the intratumoral temperature to rise by 1 ℃ was 2.5 minutes for an initial power of 30 watts. The time required for the intratumoral temperature to rise by 1 ℃ was only 1.5 minutes for an initial power of 40 watts.

During hyperthermic treatment, the skin temperature must be monitored, in order to be significantly above about 41 ℃The duration cannot exceed a few minutes. Equivalent thermal doses of skin can be calculated and used as feedback signals by the method disclosed by Sapareto et al in International Journal of Radiation Biology Physics, Vol.10, pp.787-800, 1984. Additional delivery of an equivalent thermal dose to the patient of more than a few minutes must generally be avoided. According to the invention, the respective powers (P) of the two applicators can be adjusted manually or automatically by computer during the treatment₁，P₂) Adjustments are made to ensure that the skin temperature is not too high.

Applicants have seen that doppler ultrasound methods can be used to measure blood flow in the tissue within and around the tumor before and during treatment to plan and adjust the microwave energy dose. For example, when the breast is compressed and/or the tumor is heated to a treatment temperature, the blood flow rate within the tumor may decrease, which may require a reduced energy dose. Alternatively, a needle biopsy of breast tissue may be performed prior to treatment to measure the moisture content and dielectric properties of breast tumor tissue and determine the required microwave energy dose from the measurement data. For example, if the moisture content and conductivity of the tumor tissue is high, the microwave energy dose may be reduced. In addition to the above factors, the size of the tumor also affects the required microwave energy dose. Large tumors are more difficult to heat than small tumors, and therefore require a larger dose of microwave energy. A trial period of low microwave energy dose may be included during the planned period of initial treatment to assess the heating performance of the tumor, followed by completion of treatment with the full dose of microwave energy.

Simplified microwave radiation theory

Microwave energy output from hyperthermia applicators radiates as spherical waves in the near field region of the body, with the amplitude of the resulting electric field being in part inversely proportional to the distance r from the applicator. In addition, the attenuation of the amplitude is exponentially related to the product of the attenuation constant α of the body tissue and the transit distance (or penetration depth) d of the microwave in the body. Phase of electric fieldThe product of the phase propagation constant β and the distance d varies linearly with the distance d. For the sake of simplicity, only the case of two opposing applicators is analyzed here, and it is assumed that the applicators radiate microwaves in a manner approximating plane waves. Mathematically, the plane wave electric field as a function of tissue depth may be given by the equation E (d) E₀exp (-alpha d) exp (-i beta d), wherein E₀I is An imaginary number (Field and Hand, An Introduction to the Practical Aspect of clinical Hyperthermia, Tylor) representing the surface electric Field (usually representing An amplitude and phase angle)&Francis，New York，pp.263，1990)。

At a frequency of 915mhz, plane wave electromagnetic energy decays at about 3 db per cm in high moisture content tissue such as breast ducts or breast tumors, and at about 1 db per cm in normal tissue. Thus, a significant portion of the microwave energy radiated by the individual radiating electrodes is absorbed by the intervening superficial body tissues as compared to the microwave energy deep into the deep tissues, which may create thermal convergence points in the superficial tissues. Since the maximum depth to which the skin surface is protected by air or moisture cooling is only about 0.25 to 0.5 cm, in order to avoid forming a thermal convergence point, it is necessary to introduce a second phase-coherent applicator that radiates microwaves of the same amplitude as the first applicator. The use of a second applicator that is phase coherent theoretically increases the power (and therefore the energy) delivered to the deep tissue by a factor of 4 compared to the use of a single applicator alone (Fieldand hand, pp.290, 1990).

The phase characteristics of the electromagnetic field radiated from two or more poles (known as a phased array) can have a significant effect on the distribution of energy delivered to different tissues. The relative Specific Absorption Rate (SAR) in homogeneous tissue is approximated by the square of the electric field amplitude | E². SAR is proportional to the temperature increase over a given period of time. A simplified case in which the microwave radiation is focused at a central point of the homogenized breast tissue will be described in detail below. As described in Fenn et al (International Symposium on Electromagnetic Comp. Fenn et al)Compatibility, Sendai, Japan, Vol.10, No.2, May 17-19, 1994, pp.566-569, 1994), the effect of reflections of multiple microwave signals in a breast body model is negligible.

Microwaves at a frequency of 915mhz have a wavelength of about 9.0 cm (dielectric constant of about 12.5, conductivity of about 0.21S/m (averaged from Chaudhary et al 1984 and joins et al 1994)), microwave loss of 1 db/cm, attenuation constant α equal to 0.11 rad/cm, and propagation constant β equal to 0.60 rad/cm in homogeneous normal breast tissue. For a body model with a thickness of 4.5 cm, the electric field radiated by the single applicator on the left side surface is E₀The electric field radiated to the central site (depth 2.25 cm) was-i0.8E₀(where i represents a phase shift of 90 degrees), the electric field radiated to the right side surface is-0.6E₀. The electric field of the two phase-coherent applicators acting on both side surfaces is 0.4E₀And the electric field acting on the central site (with a depth of 2.25 cm) is-i0.6E₀. Thus, the SAR on the surface is significantly lower for the breast than for the central site (only a factor of 16). The microwave field is transmitted through 4.5 cm thick breast tissue with a 180 degree phase shift and partially cancels or balances the electric field into the tissue with a 0 degree phase shift. It is expected that superficial breast tissue will be cooler than deep tissue due to destructive interference of microwaves traveling away from the central focal point. The SAR values are low for the opposite side surfaces of the breast, which effectively concentrates the microwave energy deep into the breast.

An adaptive phased array system consistent with this invention uses two microwave channels fed by a common oscillator 105. The system includes two electrically adjustable phase shifters 120 to focus the microwave energy onto the E-field feedback probes 175. Adaptive phased array systems consistent with the invention have significant advantages over non-adaptive phased arrays. A dual-channel non-adaptive phased array can theoretically generate a zero, maximum, or intermediate electric field depending on whether the two microwaves are 180 degrees out of phase, 0 degrees out of phase, or some intermediate value. The system according to the invention can be adjusted to a phase of the microwaves delivered to the two microwave applicators in the range of-180 degrees to 180 degrees before or during treatment to generate a focused electric field in the breast tissue.

Since adaptive phased arrays consistent with this invention are capable of automatically focusing the electric field in the presence of a dispersed configuration throughout the tissue, such arrays should be capable of providing more reliable deep focused heating than manually tuned or pre-treated phased arrays, as described in U.S. Pat. No.4,589,423 to Turner. In addition, an adaptive phased array system consistent with a preferred embodiment of the present invention does not use an invasive metallic temperature probe that dissipates or otherwise alters the electric field at the tumor site.

Calculation of microwave energy

The unit of electrical energy consumption is typically expressed in kilowatt-hours. The microwave energy W delivered by one applicator may be mathematically

W＝Δt∑P_i (1)

Is shown (Vitrogen, Element of Electric and Magnetic Circuits, RinehartPress, San Francisco, pp.31-34, 1971). Where Δ t is the period of time (in seconds) during which microwave power measurements are made at equal intervals, and the operator ∑ is summed over the treatment period, P_iIs the microwave power (in watts) in the ith time period.

Microwave energy W is in units of watt-seconds, which is also referred to as joules. For example, if the respective microwave powers of 30W, 50W and 60W are measured in three consecutive 60-second time periods, the microwave energy W delivered in these 180-second time periods is 60(30+50+60) 8400W-second 8400 joule 8.4 kilojoule.

To better understand the focused microwave energy W ' output by the two applicators per unit time deposited on a central site of homogeneous breast tissue of different thickness (denoted by D) ' (where ' denotes the initial (p)rime)), the following calculation can be made. Let P₁And P₂Respectively, representing the microwave power output by the two applicators. The electric field radiated by each applicator is proportional to the square root of the power input to the applicator. Assuming that the electric fields from the two applicators are symmetric, the phases of the two electric fields at the central focal point coincide. Assume again that the power output from the two applicators is equal, i.e., P₁＝P₂Assuming that the electric field radiates in a plane wave model, the focused energy per unit time at the central point can be expressed as P

W’(D)＝|E|²＝4P exp(-αD)。 (2)

The 915mhz microwave energy collected per unit time at the central site of various normal breast tissues ranging from 4 cm to 8 cm thick was calculated using equation (2), where the attenuation constant of the breast tissue was taken to be 0.11 rad/cm. The calculation results are shown in table 4 and fig. 7.

TABLE 4 relative values of microwave energy concentrated in the center of simulated normal breast tissue by two opposing 915MHz plane waves

For a given power level, the energy occurring at the focal spot is higher when the focal spot is moved towards the skin.

Phasor thermal dose calculation

The cumulative equivalent thermal dose or total equivalent thermal dose relative to 43 ℃ can be cumulatively calculated by the following formula (Sapareto et al, International Journal of Radiation Oncology biology, Vol.10, pp.787-800, 1984):

t_43℃equivalent (minute) ═ Δ t ∑ R^(43-T)， (3)

Where the operator sigma sums a series of temperature measurements over the treatment period, T being the series of temperature measurements (T)₁，T₂，T₃，T₄… …), Δ T is the period of time (in seconds and converted into components) over which the measurement is carried out at equal intervals, R is taken to be equal to 0.5 if T > 43 ℃ and to 0.25 if T < 43 ℃. The calculation of the equivalent thermal dose is useful for assessing any possible thermal damage to the breast tissue or skin.

Detailed calculation of specific absorption rate in simulated breast tissue

To evaluate The heating model of normal breast tissue and tumor-bearing normal breast tissue when exposed to microwave radiation, three-dimensional Specific Absorption Rate (SAR) heating model calculations were performed using finite-difference time-domain theory and computer simulation (Taflove, Computational Electrical: The finite-difference time-domain method, Arech House, Inc., Norwood, Massachusetts, p.642, 1995). As shown in FIG. 7, the computer simulated model was two opposing TEM-2 waveguide applicators (Celsion Corp., Columbia, Maryland) operating at 915 MHz. The two applicators coherently collectively focus the microwave beam on a central location of a 6 cm thick homogeneous normal breast tissue (a mixture of fat and breast). Applicants also hypothesize that the microwave radiation passes through a sheet of plexiglass sheet to simulate the compression plate used to compress the breast in an adaptive phased array thermotherapy system.

The sidewalls of each metal waveguide are provided with a high dielectric constant material that is designed to match and shape the radiation within the waveguide opening. The waveguide applicator is linearly polarized in the y-direction as shown in figure 8. Each applicator is attached to a 3 mm thick plexiglas plate parallel to the waveguide opening. Between the two opposing TEM-2 applicators is a 6 cm thick body model of a homogeneous normal breast. Air is simulated in the remaining volume with a small cubic calculation unit.

To calculate the distribution of SAR, the electric field amplitude is squared and multiplied by the conductivity of the tissue. The problem is usually discussed in terms of a distribution model of SAR at a level of 50% relative to the maximum (50% is usually used to represent the effective heating area). If the effects of blood flow and heat conduction are neglected, SAR is proportional to the initial temperature rise per unit time.

SAR calculations were performed on homogeneous normal breast tissue in three principal planes (xy, xz, yz), the results of which are shown in fig. 9 to 13. Fig. 9 shows a side view of the 50% and 75% iso-surface models of SAR for homogeneous normal breast tissue (xy-plane, z-0). The contour line in fig. 9 is generally bell-shaped and is located in the center of the space between the two applicators TEM-2. Fig. 10 is a top view of the 50% and 75% iso-surface models of SAR (xz-plane, y-0). The 75% contour in FIG. 10 is a small ellipse surrounded by a 50% SAR contour of a bilobed ellipse. The size of the 75% SAR contour region in fig. 10 is small due to the shape of the electric field model of this type of applicator radiation. Fig. 11 is an end view of the 50% and 75% iso-surface models of SAR (yz plane, x is 0). The 75% contour profile in FIG. 11 is a small circle surrounded by a 50% SAR contour profile region of a bivalve ellipse. The size of the contour region approximates the size of the waveguide opening.

The results shown in fig. 9-11 demonstrate that large volumes of deep breast tissue can be heated with an adaptive phased array of two TEM-2 (temperature-2) waveguide applicators while substantially not heating shallow tissue. Any high water content tissue exposed to this large heating range will be preferentially heated over the surrounding normal breast tissue. To demonstrate this selective (preferential) heating characteristic, two simulated tumors (dielectric constant 58.6, conductivity 1.05S/m) of 1.5 cm diameter were embedded in a normal breast tissue model with a 5 cm separation between the two simulated tumors in FDTD (finite difference time domain) simulation calculations. A top view of the calculation results is shown in fig. 12. Comparing fig. 10 and 12, it can be seen that the SAR model has changed significantly, while the two high water content tumor regions are selectively preferentially heated. To demonstrate the sensitivity of this selective heating, fig. 13 shows the calculated SAR model variation along the z-axis (x ═ 0). In the figure, sharp peaks appear at the location of both tumors, which further demonstrates that high water content cancers have a selective heating effect than the surrounding normal breast tissue. Similar calculations are expected for benign breast lesions such as fibroadenomas and cysts.

Fig. 14 illustrates the application of two safety measures to the applicator 100 of the external focused adaptive phased array thermotherapy system shown in fig. 5. In a preferred embodiment, a 1 to 2 cm wide shielding strip 605 of foil is masked over an area of the top of the rectangular waveguide opening 600 to prevent stray radiation from impinging on the base of the breast near the chest wall area. In addition, the waveguide applicator 100 (e.g., TEM-2 waveguide applicator from Celsion Corporation) is covered over its entire top surface with a thin Microwave absorbing pad 610 (e.g., a 0.125 inch thick sheet absorber from Cuming Microwave Corporation, with an attenuation constant of 40 dB/inch). The microwave absorbing pad 610 is capable of attenuating or suppressing any microwave surface current that would reradiate microwave energy toward the base of the breast and the chest wall area. The microwave absorbing pad 610 is glued or otherwise attached to the top surface of the waveguide applicator.

Fig. 15 shows a side view of an applicator 100 of an external focused adaptive phased array thermotherapy system and breast compression plates 200 positioned on either side of a simplified T-shaped breast model 700, the T-shaped model 700 being used to simulate a body's breast in a microwave heating experiment. Applicator 100 includes a pad 610 and a microwave shielding strip 605 thereon. An insulating pad 620 is also provided between the compression plate 200 and the upper portion of the T-shaped mold 700, which represents the thoracic wall and muscle portion supporting the breast tissue. The compression plate 200 is also provided with a T-shaped breast model enclosure, preferably made of plexiglass or other plastic. In a preferred embodiment, the T-shaped upper portion of the pressing plate 200 extends between the pad 610 and the pad 620 and has a certain thickness as shown in fig. 15. The upper section of the T-shaped body breast model 700 contains model material equivalent to muscle (M.Gauthriee eds.: Methods of external hyperthermic Heating, Springer Verlag, p.11(chou formation), 1990), while the lower section of the model 700 contains Fat-Dough model material equivalent to breast (J.J.W.Lagendijk and P.Nilsson. "Hyperthermia Dough: A Fat and Bone equivalent phase to Test Microwave/radio frequency Hyperthermia Heating System", Physics in Medicine Biology, Vol.30, No.7, pp.709-712, 1985). The cushion 620 is soft for patient comfort. The liner 620 also contains microwave absorbing material to reduce stray microwave energy.

Applicator 100 is designed to leave a gap region 635 between it and the breast tissue, the gap region 635 enabling an external fan or duct aligned with the gap to provide air flow to cool the sides of the breast base and the wall region of the thoracic cage. In a preferred embodiment, plastic tubes with flared OR tapered nozzles, such as manufactured by Lockwood products, inc., Lake Oswego, OR, may be used to direct cooling air into the gap region 635 to cool the breast region.

In a preferred embodiment, a fiber optic temperature sensor probe 415 and an electric field microwave focusing probe 175 are nested in parallel within a conduit. The tip of the fiber optic temperature sensor is positioned within the tumor site or focal position 190 and the E-field focusing probe 175 is positioned between the two compression plates at the same depth as the tumor. The fiber optic temperature sensor in the tumor may be a non-metallic material of the fluorine optical (fluorine) type that does not interfere with microwave energy (m.gaulthriee eds., Methods of External Hyperthermic Heating, Springer Verlag, p.119, 1990). The metallic E-field probe 175 is comprised of a very thin 0.020 inch diameter metallic coaxial cable (UT-20). The tip of the E-field focusing probe 175 is comprised of the center pin of the coaxial cable, which extends about 1 cm beyond the outer jacket of the coaxial cable. The tip of the E-field focusing probe was located about 0.5 cm from the tip of the fiber optic temperature sensor.

Fig. 16 shows a more realistic breast model 710, in which the breast is curved. For the breast, the curved portion can be made of a plastic (polyethylene) bag with a compressible lipid model material conforming to the shape of the breast. Compressible ultrasound breast imaging models can also be used in microwave experiments. In fig. 16, the position markers 7 and 8 are located on the skin near the base of the breast near the chest wall. Additionally, as shown, a portion of the coaxial metallic electric field converging probe 175 (the portion that enters below the breast segment) is not shielded by the breast tissue and is directly exposed to the microwave energy radiated by the two waveguide applicators 100. This microwave energy may overheat the exposed metal coaxial cable, resulting in burns to the skin near the point where the electric field focusing probe enters the breast skin. In such a case, it is desirable to remove the E-field focusing probe 175 from the breast after the microwave focusing step is completed, before heating of the breast is initiated. Preferably, the E-field focusing probe 175 is a coaxial cable with a center pin that extends out of the cable to form a monopole antenna. However, the focusing probe may also be made of a monopole or dipole antenna connected to a parallel transmission line of metallic or cable material. Alternatively, the focusing probe may be a monopole or dipole antenna with a microwave signal-to-optical signal converter connected to the fiber optic cable to avoid the metallic heating effect at the point of entry into the skin. The optical modulator used in this alternative embodiment may be, for example, a Mach Zehnder modulator.

Fig. 17 is a detailed three-dimensional view of the pressing plate 200 and the spacer 620 to which a safety improvement measure is added. The edge 210 of the compression plate is a potential source of skin damage because the edge 210 is a right angle formed by the intersection of the vertical and horizontal surfaces of the compression plate and the right angle edge is proximate to the thoracic wall and breast tissue. Accordingly, a microwave absorbing pad 620 is placed between the thoracic wall and the rim 210. The gasket 620 serves two purposes. First, the pad 620 contains a soft foam material that prevents the edges 210 from scratching or crushing the skin of the breast when the compression plate 200 compresses the breast. Second, the pad 620 contains microwave absorbing material that attenuates any stray microwave radiation from the applicator 100 to prevent overheating of nearby tissue. The compression plate or blade 200 may include one or more rectangular apertures 205 therein to allow an ultrasound transducer to be brought into contact with the skin through the apertures 205 to ultrasonically image the breast, while also allowing the electric field focusing probe and the temperature probe to be inserted therethrough into the tumor region of the breast. In another embodiment of the invention, as shown in the side view of the waveguide applicator 100, the compression plate 200, and the metallic shielding tape 615 illustrated in fig. 18, the metallic shielding tape 615 is glued or otherwise attached to the side of the compression plate 200 facing away from the breast skin.

Experimental results of the Shielding experiment

As described above, FIG. 15 shows the geometric position relationship of the breast tumor treated by the external focused adaptive phased array hyperthermia. In the experiment, microwave energy was radiated at a frequency of 915MHz with two Celsion corporation TEM-2 microwave applicators for thermotherapy treatment. For simplicity, the patient tissue was represented in the experiment as a T-shaped body breast model consisting of a plexiglass box, the lower part of which contains simulated breast tissue and the upper part of which contains simulated muscle tissue. In addition, a simulated breast tumor consisting of muscle body model tissue of about 1.5 cm in diameter was placed at position 1. 7 temperature probes (reference numbers #1 to #7) were used in the experiment. Probe No.1 is a fiber optic temperature probe, the remaining probes are thermocouple probes placed outside the simulated breast tissue skin. Probe No.1 is located at the desired focal position 190 where the simulated tumor is located. Probes 2 and 3 are located at the top corners of the compression plate 200 outside the main microwave electric field. Probes No.4 and 5 are located at the center of the microwave electric field where the electric field strength reaches a maximum. Probes 6 and 7 are located above probes 4 and 5, where the electric field strength is expected to be lower. An electric field focusing probe 175 is also disposed at the same depth as the probe number 1 location to focus the microwave energy. The electric field focusing probe 175 and the number 1 fiber temperature probe are sleeved together in a common teflon catheter with an outer diameter of 1.65 mm.

Two experiments were performed in which the microwave power delivered to each channel was 70 watts and the phase shifters in the array were all adaptive to focus the energy at the position of the central No.1 probe of a 6 cm thick body breast model. The first experiment did not use microwave absorbing materials or metal shields, as shown in fig. 5; a second experiment used microwave absorbing material and shielded the top 2 cm area of the applicator opening with a metal band, as shown in figure 15. In both experiments, the initial temperature rise slope (deg.C/min) measured by each sensor during the initial 30 second heating period was calculated as set forth in tables 5 and 6.

TABLE 5 measurement of the rate of temperature rise without microwave absorbing material and shield

The thoracic wall surface heats up faster than the simulated tumor site. The results of this experiment are graphically shown in fig. 19.

TABLE 6 measurement of rate of temperature rise when microwave absorbing material is laid on top of breast compression plate and waveguide applicator and shield is covered on top of applicator opening

As can be seen from Table 6, the simulated tumor sites heated at a significantly faster rate than other sites including the thoracic wall region. The results of this experiment are graphically shown in fig. 20. Thus, with the safety improvement, the tumor heats up faster, and the temperature rise at the sensor positions 2 and 3 decreases to half the temperature rise at the time of no safety. The results of these two experiments clearly demonstrate the significant effect of the microwave absorbing pad and the shielding tape covering the upper portion of the waveguide applicator opening in reducing heating of the surface near the thoracic wall. The temperature rise slopes of the sensor positions No.4 and No.5 are improved by adopting safety measures, but are only below half of the temperature rise slope of the tumor position. The additional air flow and cooling air will also contribute to a further reduction of the heating of the surface.

Small breast therapy (female and male)

In some cases, i.e., when the female or male breast is small (as compared to the treatment aperture formed by the opposing coherent array applicator), or the tumor is outside the coherent array applicator treatment aperture, other methods of heating the breast tumor may be contemplated. Fig. 21 shows a side view of the compressed breast 940 in a prone position with the tumor located slightly above the top of the applicator as shown by dashed line 101. In this way, the tumor is located just above the upper edge of the treatment aperture formed by the compression plate 200, where the monopolar feedback member 104 of the applicator 100 is disposed. This location of the tumor is due to the smaller breast of a male or female patient, or simply due to the closer proximity of the tumor to the chest wall. In these cases, it is conceivable that the tumor is difficult to heat because it is outside the initial heating range of the applicator 100. As previously mentioned, the example of fig. 21 shows the method with the patient in a prone position, and the vertical direction is represented by the positive y-axis.

An alternative treatment configuration of the present invention may employ a single air-cooled energy applicator 100 having a monopolar feedback member 104 positioned such that it emits energy toward the tumor to heat the breast tumor as shown in fig. 22 when the patient is in the prone position. The applicator 100 may be a rectangular or other shaped waveguide with the monopole feedback 104 located therein. The waveguide aperture of the applicator 100 should be positioned to cover the breast so that the tumor or tissue being treated is at or very near the midpoint or central region of the waveguide aperture, as generally shown in fig. 22-26. Fig. 22 shows a side view of the pendulous breast in the prone position and the position of the applicator waveguide 100, where the breast is small and such a breast may be of a female or male patient. It is desirable that the energy of a single applicator 100 be able to heat the tumor to the appropriate temperature with relative ease, since the tumor of fig. 22 is within the initial heating range of the applicator 100. This single applicator heating method may be used for temperature monitoring and power control of the applicator in a similar manner as described above with respect to fig. 5 and 14, as well as for terminating the treatment in a similar manner.

The applicator 100 is designed to be either non-contact, direct air coupled, or in direct contact with a low loss medium (as described below with reference to fig. 27). That is, the applicator 100 does not itself contact the skin of the breast being treated, but rather leaves a gap 106 through which air flows to form a coupling with the breast being treated. The temperature of the air flow through the gap 106 may vary between cooling and warming ranges depending on the circumstances to achieve different medical objectives. The coupling temperature of air to the energy of the breast being treated may range from 0 ℃ to 50 ℃. This varying temperature may be used to precondition conditions after treatment at the treatment site and/or the area being treated. For example, some situations suggest cooling or heating different depths of skin or tissue to achieve a desired therapeutic effect.

In another embodiment of the invention, a temperature probe may be inserted into the tumor to monitor the temperature of the heated tissue during treatment. These temperature measurements can be used to control the microwave power during the treatment. Figure 23 shows a view along the x-axis with the patient prone and the temperature probe 410 inserted into the tumor in a direction substantially perpendicular to the electric field. Alternatively, as shown in fig. 24, the patient may be supine and the breast tumor may be heated from above the breast. That is, the applicator 100 may be moved from a lower patient position in a prone position to an upper patient position in a supine position in order for the applicator to emit energy from above the breast 940. Figure 25 shows a view along the x-axis with the patient supine and the temperature probe 410 inserted into the tumor in a direction substantially perpendicular to the electric field. Notably, for a patient in a supine position, the breast at this time tends to be flatter due to gravity (i.e., gravity pulls the breast tissue toward the chest wall) as compared to the breast in a prone position (gravity pulls the breast back toward the chest wall). The advantage of the supine position is that the breast tissue is flat and the depth of the breast tumor relative to the breast skin becomes shallower. The prone position has the advantage of keeping the treatment area away from the chest wall area, providing a safe space for the chest wall tissue.

In some cases, it may be beneficial to apply compression to the breast with a cloth strap 1000 of a certain width compared to the breast, encircling the torso of the patient when the patient is lying prone or supine. Fig. 26 shows an example of applying a cloth belt to pressurize the breasts when the patient is lying prone. Pressurizing the breast in this manner flattens the breast tissue as shown in fig. 26, reducing blood flow near the tumor/tissue being treated and reducing the depth of the tumor or tissue being treated relative to the skin, thereby making it easier to heat the tumor or tissue being treated. The pressure belt is preferably made of a thin cloth-like material, such as nylon, which allows air flow from the applicator through the pressure belt, cooling the breast skin. As one example, the breast compression band may be worn like a tubular jacket during treatment. Some patients may be advantageously treated with a single applicator treatment method with or without pressurization. Similarly, a single applicator may be used for treatment when the patient is facing down (prone) or facing up (supine). A single applicator treatment can be used to directly heat the chest wall region and thus can be envisioned to be successful in treating or preventing both male and female breast cancer and preventing recurrence of these cancers.

If a small breast patient is treated for breast cancer or breast cancer prevention, a single applicator is aimed at the tumor or upper breast where breast cancer primarily occurs. In a preferred embodiment, a microwave energy dose of about 90 kilojoules (50 watts microwave power for 30 minutes) is applied to the breast to destroy breast tumors prior to lumpectomy or microscopic breast cancer cells following lumpectomy for DCIS. During the period of tamoxifen administration to prevent breast cancer, multiple treatments may be performed once a year, each with the same dose of thermotherapy. A skin temperature sensor may be used for monitoring and the single channel microwave power may be adjusted to maintain the skin temperature below about 41 ℃ during the hyperthermia treatment. In an alternative embodiment, a temperature sensor may be located within the treatment region and the measured tumor temperature may be used to control the microwave power delivered to the hyperthermia applicator to deliver an equivalent thermal dose to the tumor or breast tissue treatment region in 120 to 240 minutes.

Fig. 27 shows an alternative embodiment in which applicator 100 is filled with a low loss medium such as water 1500 and a bag made of plastic or other non-conductive, water-proof material is wrapped around the mouth of the waveguide applicator to form a bolus 1010 that couples microwave energy into the breast tissue. The bolus 1010 may be pressed toward breast tissue, thereby compressing the breast to reduce blood flow in the treated area and reduce the thickness between the skin surface and the breast tumor or tissue being treated. The water may be distilled or deionized water, and may be cold or hot water to form a circulation against the breast tissue. The water may be circulated through the waveguide applicator 100 and around the breast 940 via tubing (not shown) connected in a manner well known in the art.

In addition to the microwave embodiments described above, applicants contemplate that any other type of focused energy embodiment may be used, including embodiments that employ focused electromagnetic energy, ultrasonic energy, radio frequency energy, laser energy, or other focused energy sources known to those skilled in the art. That is, any form of energy or combination of different forms of energy that can be focused to heat and ablate tissue in a region can be used in methods consistent with applicants' invention. Although the focused energy may be the primary heating source, it may also be used in conjunction with the introduction of a substance that increases or enhances the heating of the target area (tumor). The substance may be saline or a mixture of water and metal or other conductive substance such as a metallic surgical breast clip, which enables the substance to enhance the amount of heat delivered to the target area.

This is an alternative way of obtaining selective heating of the target area, since the introduced substance enhances the heating of the target area. Thus, applicants envision the use of a combination of unfocused energy and introduced substances such as saline or water and metal mixtures that will heat the target area sufficiently to destroy cancerous and/or benign diseased cells therein. Thus, the applicator used in such an embodiment may be an applicator that delivers unfocused energy. In such an embodiment, the use of an electric field probe is not necessary, since only unfocused energy is used according to the invention.

While the present invention has been particularly described, in conjunction with several preferred embodiments, it will be appreciated by those skilled in the art that many modifications and variations may be made to these embodiments without departing from the spirit and scope of the invention as defined by the appended claims. For example, although the thermotherapy system described above is directed to the treatment of breast cancer and benign breast lesions, the invention may be used to treat other types of cancer such as prostate cancer, liver cancer, lung cancer, and ovarian cancer, as well as benign lesions such as Benign Prostatic Hyperplasia (BPH). Likewise, the methods of improving safety disclosed herein may also be applied to microwave or radio-frequency hyperthermia treatments for treating other appendages or portions of the human body, such as legs, arms and torso.

It is also noted that the same is true for applicators using a greater or lesser number of antenna arrays or applicators using a single antenna. In addition, the methods disclosed herein may also be used in non-coherent multi-applicator treatment systems, where, of course, the use of an E-field focusing probe is not necessary. Where compression of the breast or other organ is not required or appropriate, the compression step of the method of the present invention may be eliminated. If a pressing step is not used, then absorbent pads and other metal shields may not be necessary. Certain methods and techniques disclosed herein may also be applied to ultrasound thermotherapy systems, particularly for use with feedback-controlled energy dosage. The methods of the invention can be used to enhance the effectiveness of radiation therapy or to deliver drugs of interest in thermosensitive liposomes and/or genes of interest. The invention can also be applied to high temperature heating systems for non-medical purposes such as industrial material or food heating.

Claims (30)

1. A device for heating cancerous or benign conditions of a body by selective irradiation of the body tissue with energy, said device comprising:

a) means for monitoring the temperature of the skin surface adjacent to the irradiated body tissue;

b) at least one energy applicator positioned proximate to a body site to be heated;

c) means for setting an initial power level delivered to each of the at least one energy applicators;

d) means for delivering energy to the at least one energy applicator for selectively irradiating body tissue with energy and heating at least one of cancerous and benign body lesions;

e) means for adjusting the power level delivered to each of the at least one energy applicators during selective illumination based on results from the means for monitoring skin temperature;

f) means for monitoring the energy delivered to the at least one energy applicator;

g) means for determining in real time the total energy delivered to the at least one energy applicator during the selective irradiation process; and

h) means for terminating energy delivery when a desired total energy dose has been delivered to the body tissue by the at least one energy applicator.

2. The apparatus of claim 1, wherein the energy is at least one of electromagnetic, ultrasound, radio frequency, and laser waves.

3. The apparatus of claim 1, wherein the body is a breast of one of a female patient and a male patient, and the breast is heated with a single applicator.

4. The apparatus of claim 3, wherein the means for monitoring the temperature of the area surrounding the breast tissue comprises a skin sensor placed on the surface of the breast to be heated.

5. The apparatus of claim 4, wherein the means for monitoring the temperature of the region surrounding the skin surface of the breast tissue further comprises a temperature probe that can be inserted into the tissue region to be heated and uses the internal measured temperature to control the power delivered to the single applicator.

6. The apparatus of claim 4, further comprising means for compressing the breast toward the chest wall with a tubular cloth.

7. The apparatus according to claim 1, wherein the at least one applicator comprises a projectile containing a low loss medium attached to an end of the at least one applicator adjacent the body to be heated, wherein the low loss medium couples energy transferred from the applicator to the body tissue.

8. The apparatus of claim 7, wherein the low loss medium is one of distilled or deionized water.

9. The device of claim 1, further comprising means for post-conditioning the body tissue to be heated after the end of the energy transfer to the at least one applicator by one of passing a cooling gas through the body site to be heated and passing a warming gas through the body site.

10. The device according to claim 1, further comprising means for preconditioning the body tissue to be heated with means for passing a cooling gas through the body site to be heated or with means for passing a warming gas through the body site prior to delivering energy to the at least one applicator.

11. An apparatus for selective irradiation of breast tissue with energy to heat cancerous or benign breast lesions, said apparatus comprising:

a) means for monitoring the temperature of the skin surface surrounding the irradiated breast tissue;

b) a single energy applicator with energy feedback positioned adjacent the breast to be heated, the applicator having a waveguide with an aperture width and an aperture height, the applicator adapted to be positioned proximate to breast tissue to be irradiated such that the breast tissue is in close proximity to a midpoint of the aperture width and the aperture height;

c) means for delivering energy to the single energy applicator for selectively irradiating breast tissue with energy and heating at least one of cancerous and benign conditions of the breast;

d) means for adjusting the power level delivered to the single energy applicator during the selective irradiation process based on the monitored skin temperature;

e) means for determining in real time the total energy delivered to the single energy applicator during the selective irradiation process;

f) means for terminating energy delivery from said delivery means when a desired total energy dose has been delivered to said breast tissue by a single energy applicator.

12. The device of claim 11, wherein the total energy dose is a microwave dose of up to about 360 kilojoules.

13. The apparatus of claim 11 wherein the power delivered to the single energy applicator is up to about 200 watts of microwave power for about 30 minutes.

14. The apparatus of claim 11, wherein the means for monitoring the temperature of the skin surface surrounding the breast includes a skin sensor that measures skin temperature, and means for adjusting the level of power to the single applicator to maintain the measured skin temperature below about 41 ℃.

15. The apparatus of claim 14 wherein the measured temperature of the measuring means controls the power delivered to the single energy applicator to deliver an equivalent dose to the irradiated breast tissue in about 120 to 240 minutes.

16. The apparatus of claim 11 wherein said single energy applicator is sized to provide a gap between the applicator ends adjacent said breast to allow energy to be coupled to the breast through air.

17. The apparatus of claim 16, further comprising means for preconditioning the breast tissue to be heated with means for passing a cooling gas through the breast to be heated or means for passing a warming gas through the breast prior to delivering energy to the single applicator.

18. The apparatus of claim 16, further comprising means for post-conditioning the body tissue to be heated after the end of the energy transfer to the single applicator by one of passing a cooling gas through the breast to be heated and passing a warming gas through the breast site.

19. The apparatus of claim 11 wherein the single applicator further comprises a projectile containing a low loss medium attached to the end of the single applicator adjacent the breast to be heated, wherein the low loss medium couples energy transferred from the applicator to the breast.

20. The apparatus of claim 19, wherein the low loss medium is one of distilled water and deionized water.

21. The device of claim 11, further comprising means for preventing estrogen binding to estrogen receptors of breast cancer using tamoxifen or other antiestrogen drugs in combination with selective irradiation and directly killing cancer cells by heating.

22. An apparatus for heating cancerous or benign conditions of a body by selective irradiation of the body tissue with energy, the apparatus comprising:

a) means for monitoring the temperature of the skin surface adjacent to the irradiated body tissue;

b) at least one energy applicator positioned proximate to a body site to be heated;

c) means for setting an initial power level delivered to each of the at least one energy applicators;

d) means for delivering energy to the at least one energy applicator for selectively irradiating body tissue with the energy and heating at least one of cancerous and benign conditions of the body; and

e) means for adjusting the power level delivered to each of the at least one energy applicators during selective illumination and heating of the body based on the results of the means for monitoring skin surface temperature;

f) wherein the heat provided by the at least one energy applicator based on the results of the means for monitoring skin temperature heats the proteins of the body tissue to be heated, thereby promoting the production of protein inhibitors that inhibit the spread and growth of cancer and other related pathologies or diseases.

23. An apparatus for heating cancerous or benign conditions of a body by selective irradiation of the body tissue with energy, the apparatus comprising:

a) means for monitoring the temperature of a skin surface adjacent to body tissue to be irradiated;

b) at least one energy applicator positioned proximate to a body site to be heated;

c) means for setting an initial power level delivered to each of the at least one energy applicators;

d) means for delivering energy to at least one energy applicator for selectively irradiating body tissue with energy and heating at least one of cancerous and benign body lesions; and

e) means for adjusting the power level delivered to each of the at least one energy applicators during selective illumination based on the results of the means for monitoring skin surface temperature;

f) wherein heat provided by the at least one energy applicator based on the results of the means for monitoring skin temperature removes a protein responsible for its ability to self-repair when the heating damages a DNA molecule associated with the protein, thereby enhancing apoptosis of the cancer cells.

24. An apparatus for selectively irradiating body tissue with energy to reduce cellulite, cancerous or benign conditions of the body, the apparatus comprising:

a) means for injecting a material into a selected portion of the body prior to selective irradiation of body tissue with energy;

b) means for monitoring the temperature of the skin surface adjacent to the irradiated body tissue;

c) at least one energy applicator positioned proximate to a body site to be heated;

d) means for setting an initial power level delivered to each of the at least one energy applicators;

e) means for delivering energy to the at least one energy applicator for selectively irradiating body tissue with energy and reducing at least one of cancerous and benign conditions of the body;

f) means for adjusting the power level delivered to each of the at least one energy applicators during selective illumination of the body based on the results of the means for monitoring skin surface temperature;

g) means for monitoring the energy delivered to the at least one energy applicator;

h) means for determining in real time the total energy delivered to the at least one energy applicator during the selective irradiation process;

i) means for terminating energy delivery when a desired total energy dose has been delivered to the body tissue by the at least one energy applicator.

25. The device of claim 24, wherein the means for injecting injects one of a saline solution and a solution comprising a metal compound into the selected portion of the body.

26. The device of claim 25, further comprising means for applying sufficient pressure to the body after the heat is generated such that at least one of any bumps in the body region become smooth and the body region is shaped or formed.

27. An apparatus for selective irradiation of breast tissue with energy to heat cancerous or benign breast lesions, the apparatus comprising:

a) means for monitoring the temperature of a skin surface adjacent breast tissue to be irradiated;

b) at least one energy applicator positioned adjacent the breast to be heated;

c) means for setting an initial power level delivered to each of the at least one energy applicators;

d) means for delivering energy to at least one energy applicator for selectively irradiating breast tissue with energy; and

e) means for adjusting the power level delivered to each of the at least one energy applicators during selective irradiation of the breast based on the results of the means for monitoring skin surface temperature;

f) wherein the heat obtained by the at least one energy applicator based on the results of the means for monitoring skin temperature heats to destroy at least one of cancerous and benign breast lesions, and the resulting heat selectively destroys estrogen receptors, thereby preventing estrogen from binding to the at least one of cancerous and benign breast lesions.

28. An apparatus for selective irradiation of breast tissue with energy to heat cancerous or benign breast lesions, the apparatus comprising:

a) means for monitoring the temperature of the skin surface adjacent the irradiated breast tissue;

b) at least one energy applicator positioned proximate to the breast site;

c) means for setting an initial power level delivered to each of the at least one energy applicators;

d) means for delivering energy to at least one energy applicator for selectively irradiating breast tissue with energy; and

e) means for adjusting the power level delivered to each of the at least one energy applicators during selective irradiation of the breast based on the results of the means for monitoring skin surface temperature;

f) wherein the heat obtained by the at least one energy applicator based on the results of the means for monitoring skin temperature heats up to destroy at least one of cancerous and benign breast lesions, and the resulting heat selectively destroys estrogen receptors, such that the resulting heat is capable of employing a hormone replacement procedure without significant risk of breast cancer.

29. A device for heating cancerous or benign conditions of a body by selective irradiation of the body tissue with energy, the device comprising:

a) at least one energy applicator positioned proximate to a body site to be heated;

b) means for applying an analgesic to a site of the body to be heated by selective irradiation;

c) means for delivering energy to the at least one energy applicator for selectively irradiating body tissue with the energy and heating at least one of cancerous and benign body lesions;

d) means for monitoring the temperature of a skin surface adjacent body tissue to be irradiated during selective irradiation of said body tissue with energy;

e) means for adjusting the power level delivered to each of the at least one energy applicators during selective illumination based on the results of the means for monitoring skin surface temperature;

f) means for monitoring the energy delivered to the at least one energy applicator;

g) means for determining in real time the total energy delivered to the at least one energy applicator during the selective irradiation process; and

h) means for terminating energy delivery when a desired total energy dose has been delivered to the body tissue by the at least one energy applicator.

30. The system shown in fig. 5 or fig. 14.