History and Motivation
Facts about Cancer
Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormally transformed or mutated cells. If this spread is not controlled, death will eventually result. Cancer is caused by both external (chemicals, radiation, and viruses) and internal (hormones, immune response dysfunction, and inherited gene deficiencies) factors. Causal factors may act together or in sequence to initiate or promote carcinogenesis.
About 2.6 million new cancer cases are expected to be diagnosed in 2000. This year about 552,200 Americans are expected to die of cancerómore than 1,500 people a day. Cancer is the second leading cause of death in the US, exceeded only by heart disease. In the US, 1 of every 4 deaths is from cancer.
Breast cancer is a malignant tumor that has developed from cells of the breast. Breast cancer is the most common cancer among women, excluding non-melanoma skin cancers. The American Cancer Society estimates that in 2000 182,800 new cases of invasive breast cancer (Stages I-IV) will be diagnosed among women in the United States, producing in 2000, 41,200 deaths. Breast cancer is the second leading cause of cancer death in women, exceeded only by lung cancer.
There are many treatment options for women with breast cancer including surgical removal of the entire breast or lump, radiotherapy and various chemotherapy and hormone treatments. If a cancer comes back after treatment it is called a recurrence. Nearly one third of these breast cancer recurrences are on the chest wall. This chestwall recurrence of breast carcinoma is quite deadly with only 25 to 30% of the patients surviving out to five years . An interesting fact about chestwall recurrence is the large range in survival. Two years is the median survival following recurrence but it ranges from a few months to 30 years . Successful treatment of chestwall recurrence thus has the potential to add years to a patientís life as well as significantly improve the patients' quality of life
Hyperthermia as Cancer Treatment
Hyperthermia is the use of elevated tissue temperature for the treatment of cancer. Hyperthermia therapy consists of elevating tissue temperature to the range 41 to 45° C, for an hour. When used alone, it is thought that protein denaturation is the main cause of hyperthermic cell . Heat is also thought to affect cells in the following ways: heat can alter the structure of plasma membranes (blood vessel walls) and impair many membrane-related functions that can lead to cell death. Heat also damages mitrochrondria and inhibits glycolysis and respiration. Heat can also inhibit the synthesis and repair of damage to DNA, proteins, RNA, and heat damages polysomes and microsomes.
While hyperthermia used alone is effective (when temperatures and thermal doses are sufficiently high) heat is most commonly used as an adjuvant treatment. The two types of cancer treatments most commonly used with hyperthermia are chemotherapy and radiotherapy. Chemotherapy is the use of drugs to kill the cancer cells. These drugs, through various methods, disable the reproductive abilities of cancerous cells. Radiation therapy is the use of x-rays, gamma-rays and electrons as ionizing agents that interact with biologic material to produce highly reactive free radicals, which result in biologic damage . The main effect of radiotherapy is to block the cellís ability to reproduce. Radiation and heat interact in more than a simply additive way. This synergistic interaction of heat and radiation is interpreted as a heat-induced sensitization of cells to radiation, termed heat radiosensitization or thermal radiosensitization . This synergistic interaction is attributed to the hyperthermic effect of preventing the repair of radiation-induced DNA strand breaks and the excision of damaged bases . It is believed that these effects are caused by (1) heat-induced inactivation of DNA repair enzymes and/or (2) alteration of the chromatin structure due to protein denaturation and aggregation, which causes decreased accessibility of the damaged sites to the repair machinery. It has also been shown that mild hyperthermia, when given concurrently with low-dose-rate irradiation can remove the low-dose-rate sparing effect. There has also been no evidence that radiation results in an enhancement of heat lesions, i.e. no radiation-induced heat sensitization takes place .
Hyperthermia with chemotherapy has not been studied as extensively as combinations with radiation, but some strong rationales exist for its use. Hyperthermia enhances the cell-killing effect of a number of chemotherapeutic agents, such as, cyclophosphamide, melphalan, cisplatin and doxorubicin. Perhaps the most obvious effect is, that if heat is localized to the tumor volume, the flow of blood to that area is increased in response to the elevated temperature as the body attempts to cool the area with increased blood flow and thereby increase the concentration of therapeutic chemicals delivered to the tumor relative to the rest of the body at a cooler temperature. Heat also causes blood vessel walls, inside the tumor, to become more permeable (leaky) causing drugs to leak into the heated tumor at a higher rate. The increased chemotherapeutic effect at elevated temperatures can be caused by, altered pharmacokinetics or pharmacodynamics, increased DNA damage, decreased DNA repair, reduced oxygen radical detoxification, and increased membrane damage . In addition, concentrations of agents that are not normally toxic at normal body temperature can become cytotoxic above 39° C and in some cases; hyperthermia may partially overcome some types of drug resistance .
There are three primary methods of heating tissue in hyperthermia: 1) frictional losses from molecular oscillations caused by an ultrasound pressure wave; 2) simple thermal conduction from areas of high temperature to areas of low temperature and 3) Resistive and dielectric losses from an applied electromagnetic field. Of these three, the present effort relies primarily on an applied EM field to induce heating of superficial tissue at a depth up to 1cm, and on deep and thermal conduction to heat slightly deeper and smooth the temperature distribution.
All living human tissue contains some amount of free charge. Free charges, which can interact with an external electromagnetic field. Tissues with high water content and thus a large percentage of polar molecules interact especially well. Blood, skin, muscle, internal organs and tumors all contain large percentages of water. At microwave frequencies above 100 MHz, human tissue can be considered as a lossy dielectric. The electrical properties of lossy human tissue may be characterized in terms of its dielectric constant and electrical conductivity. As an example, muscle has a dielectric constant of 51 and an electrical conductivity s of 1.21 while germanium, commonly used as a semiconductor, has a conductivity of 2.17. At 915MHz, dielectric losses in tissue predominate and heating results primarily from friction caused by polar water molecules that rotate and oscillate to maintain alignment with the time-varying electric field.
The amount of microwave energy absorbed by tissue is given by the absorbed power density, in watts per meter-cubed
where is the induced current density. The absorbed power density is also stated in terms of power absorbed per kilogram of tissue or specific absorption rate (SAR):
where r is the density of tissue in kilograms per meter cubed. The SAR pattern is the quality used most often to describe the heating properties of a particular hyperthermia applicator. In general the 50% SAR level is considered to be the extent of effective heating. The qualities inherent in an acceptable SAR pattern (see figure for an example) are, the 50% level extends to at least the dimensions of the applicator. The SAR distribution inside the 50% contour is relatively flat with no sharp peaks or valleys and rising smoothly everywhere to the maximum value.
Equipment and Techniques For Producing Hyperthermia in Superficial Tissues
The past two decades have seen considerable growth and development in electromagnetic techniques available for producing superficial hyperthermia. The microwave waveguide applicator is probably the most basic method for providing superficial hyperthermia by electromagnetic means, it consists of a rectangular waveguide excited by a monopole feed. The dimensions of the waveguide are selected so that a strong TE10 mode propagates at the chosen frequency. Because human tissues are in general layered with a high-resistance fat layer between low-resistance skin and muscle or tumor tissues, the TE10 mode is preferred because the electric field is oriented tangential to the skin surface. This tangential electric field minimizes overheating of the fat-muscle tissue interface because the high resistance fat appears in parallel to the low resistance muscle or tumor layer. While this design did produce some useful heating for a few limited clinical situations, the dimensions of the waveguide proved too large to conform adequately to the usually contoured treatment sites. The dimensions of the waveguide were reduced by loading the waveguide with high-dielectric material, reducing the wavelength in the guide and therefore the aperture size. The field pattern of these applicators has a maximum in the geometrical center and falls off to well below 50% of the maximum field at the waveguide edges. To reduce this central hot spot and to increase the field strength at the edges, a coupling bolus is used. A coupling bolus is a flexible bag attached to the waveguide face that circulates temperature-controlled de-ionized de-gassed water, or in some applications, silicone oil.
Variable-absorption bolus's have also been studied as a way to increase the homogeneity of the field pattern from a waveguide applicator. With this technique the de-ionized water bolus is compartmentalized and the different compartments can be filled with a more highly absorbing material such as saline solution. The compartments filled with saline will reduce the energy transmitted and in this way the central maximum can be reduced while the heating at the edges is not effected, resulting in a more uniform energy deposition in skin but at the cost of higher overall power .
To address the problem of standard waveguide applicatorís non-uniform field distributions, horn waveguide applicators were studied. Horn waveguide applicators utilize a flared opening to spread the radiated field and to obtain a better impedance match to the tissue. These applicators produced a more uniform field pattern with the 50% of maximum level being larger than the standard waveguide but still not equal to the horn perimeter.. While these horn applicators had a more uniform field pattern, they still suffered from being too large to effectively cover large regions of tissue over contoured treatment sites.
A common problem for both of these methods is the non-adjustability of the electromagnetic field pattern under the face of the applicator to tailor the field pattern for irregular tumor shapes. Thus the next logical step was to make an applicator consisting of several waveguides together in an array of radiating apertures. One such commercially available hyperthermia system is the Microtherm 1000 (Labthermics Technologies Inc, Champagne IL) which has an array of 16 waveguides and integral water bolus on a movable support arm (see fig. 1).
Figure 1 The Microtherm 1000 hyperthermia applicator (Labthermics Technologies Inc, Champagne IL)
Figure 2 Close up of the extendable bolus of the Microtherm 1000
The Microtherm 1000 can treat an area of 13 by 13 cm wide by 1.5 cm deep. The Microtherm 1000 is currently the standard of care in electromagnetic superficial hyperthermia. This is the machine used at UCSF in treatments of superficial skin disease like chestwall recurrence of breast carcinoma. The advantages of this machine over single-waveguide methods are that it can cover a larger area than a single-aperture waveguide of identical size and that by adjusting the power to the various elements, the field pattern can be shaped somewhat to adjust for irregular tumor shapes. While this machine can cover more area, with improved heating uniformity, it still suffers from one of the same failings of the single waveguides-it can not conform around curved anatomy. While its 8cm thick water bolus helps it to conform somewhat to small curvature, it still can not treat surface disease which spreads around the ribcage. It is useful primarily on flat treatment sites.
Another heating approach makes use of an inductive-loop current sheet applicator, which is smaller and lighter in weight than typical waveguide applicators and can be connected together in hinged flexible arrays for contoured surfaces . While more compact than waveguide and horn applicators, these applicators require great care when used in arrays to avoid under or over heating the area between the adjacent apertures, especially when angled together over contoured surface.
Recently there has been considerable interest in using printed-circuit-board (PCB) based microwave radiators. Microwave patch, slot, and spiral radiators have been studied . It was found that many PCB-based microwave radiators have a large electric field component orientated normal to the fat-muscle interface. This strong normal field component falls off faster as a function of distance, from the applicator face, compared to the tangential component, suggesting the use of a thick water bolus to reduce the normal component in relation to the tangential component.
There is a commercially available Contact Flexible Microstrip Applicator (CFMA) which can treat an area of roughly 12.5 by 24 cm. While the CFMA has the ability to conform to contoured treatment sites, it is a single channel device. Thus there is no ability to shape the SAR pattern. If the field must be reduced in one area, to avoid overheating a nipple for example, the power and heating effectiveness must be reduced for the entire treatment site. Thus while this applicator can treat large areas involving contoured anatomy, there is no provision to adjust the heating pattern to accommodate patient specific anatomy or heterogeneous electrical and thermal tissue properties.
Arrays of microstrip spiral antennas have also been used. An array of 25 individually controlled spiral antennas built on a flexible PCB was studied by one group . It was found that the spiral antennas produced a sharply peaked gaussian pencil beam under the center of the spiral. A minimum 3cm thick water bolus was necessary to smooth the combined beam profile enough to achieve useful heating without cold areas between spiral elements. While this method, in general, was useful, the thick water bolus limited its use near complex contoured anatomy and increased setup complexity and the power required.
As a way of avoiding the problem of awkward and heavy water bolus structures, Ryan et. al. studied a dense array of overlapping spirals. This array produced a more spatially uniform field with a thinner water bolus. The draw back to this technique was that the large overlap of spirals needed for a uniform field severely restricted the size of the treatable area. It would seem that the microstrip spiral, with its sharply peaked central pencil beam radiation pattern was not ideally suited for hyperthermia treatments of large surface areas where homogeneity of the heating field is needed.
In summary, the currently available technology for heating superficial tissues can not cover a large enough treatment area, can not conform to curved treatment sites typically seen in the clinic and can not provide sufficient adjustment of heating pattern to cover irregularly shaped treatment sites.
From the previous evaluation of applicators, the following specifications were determined for an ideal large area superficial hyperthermia applicator:
The Conformal Microwave Array (CMA) described in this thesis has the potential to fulfill all the requirements of the above ideal applicator specifications for treating large area superficial hyperthermia. The CMA is an array of microstrip patch antennas etched into a very flexible two sided PCB (see fig 9-diagram of CMA). It is light in weight, extremely thin (9 mils), easy to use, and inexpensive to manufacture compared to previous applicators.
The main thrust of this thesis is to describe efforts to optimize the Conformal Microwave Array. Optimization is desired in the sense that we want to produce the highest uniform output power with the lowest possible input power. Specifically, the radiation efficiency (the ratio of power out to power in), and the uniformity or balance of output of individual antennas was improved. To achieve these goals, I have concentrated on applying microwave-engineering theory to the microstrip line network which extends from the coax-to-microstrip RF connector on the PCB edge and extends across the antenna array surface and splits to feed f the four sides of the radiating microstrip patch.
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