Electromagnetic Heating for Cancer Treatment - American Chemical

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Electromagnetic Heating for Cancer Treatment Chung-Kwang Chou Department of Radiation Research, City of Hope National Medical Center, Duarte, CA 91010

Biologists have demonstrated the cancer-killing ability of hyper thermia in combination with radiation and chemotherapy; however, clinicians have found it difficult to raise and keep the tumor tempera ture at therapeutic levels. During the past two decades, significant progress has been made in heat delivery, temperature monitoring, and thermal dosimetry. When electromagneticfieldsare used, the energy deposition is a complex function of the frequency, intensity, and polarization of the appliedfield,of the geometry and size of the applicator, and of the dielectric properties, geometry, size, and depth of the tumor. Final temperatures in exposed tissues are dependent not only on energy deposition but also on blood flow and thermal conductivity of tissues. Treatment effectiveness depends on how well the tumor is heated.

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since the beginning of human history (7). The heat sources used were natural: sunshine,fire,and hot water. The earliest recorded use of heat for cancer therapy was 5000 years ago when an Egyptian physician used aflamingwooden drill to treat a breast tumor (7). The heating achieved with natural sources was generally only superficial. Because changes in the vasomotor tone of the blood vessels in the skin aid in the maintenance of constant temperature in deep tissues, the usefulness of heat in therapy was limited until relatively recently. Diathermy ("through heat" in Greek) beEOPLE HAVE USED HEAT FOR THERAPY

0065~2393/95/0250-0287$12.00/0 ©1995 American Chemical Society

In Electromagnetic Fields; Blank, M.; Advances in Chemistry; American Chemical Society: Washington, DC, 1995.


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came available only in the early 20th century, and it made the heating of deep tissues possible. More on the history of medical applications of electromagnetic (EM) energy can be found in references 2 and 3. During the past two decades, interest in the use of hyperthermia in combination with other forms of therapy has increased significantly (4-9). Currently, hyperthermia is still an experimental treatment in the United States, and it is usually applied only to patients with advanced disease. Heating methods include whole-body heating by hot wax, hot air, a hot-water suit, or infrared radiation; and partial-body heating by radio-frequency E M fields (including microwaves), ultrasound, and heated blood or fluid perfusion. Clinical and experimental results from various countries have indicated a promising future for hyperthermia. However, the foremost problem is the generation and control of elevated temperatures in tumors. Some reports have shown (10, 11) a synergistic effect of heat and radiotherapy or of heat and chemotherapy. The effective temperature range of hyperthermia treatments is very small: 41-45 °C. A t lower temperatures, the effect is minimal. A t temperatures higher than 45 °C, normal cells are damaged. Temperatures in tumors are usually higher than those in normal surrounding tissues during hyperthermia treatment because of a difference in blood flow. In addition, tumors are generally believed to be more sensitive to heat than normal surrounding tissues. This property is explained by the hypoxic, acidic, and poor nutritional state of tumor cells (12). The synergism of radiation and hyperthermia is accomplished by thermal killing of hypoxic and S-phase (DNA synthesis) cells that are resistive to radiation. Hyperthermia has been used in combination with chemotherapy because heating increases membrane permeability and the potency of some drugs. When E M methods are used, energy deposition in tissues is a complex function of the frequency, intensity, and polarization of the applied fields, the geometry and size of the applicator, and the dielectric property, geometry, size, and depth of the tumor (75, 14). The material, thickness, and construction of a surface-cooling bolus between the applicator and the body also influence the amount of energy absorption. The final temperatures are dependent not only on energy deposition but also on tissue blood flow and thermal conduction. Because of the narrow effective temperature range, the tumor response rate is highly dependent on how much of the tumor is heated to a therapeutic level. In this chapter, the biophysics of E M heating will be reviewed, and then the methods of E M heating will be discussed.

Biophysics ofEM Heating Dielectric Properties. The dielectric constant and conductivity of tissue (75) make propagation of E M waves in tissue different from that in free space. In general, biological tissues can be classified into two major categories. Tissues of one category have a high water content (muscle, skin, kidney, and liver tissues), which results in higher dielectric constants and conductivity than



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those of groups with low water content, such as fat and bone. Brain, lung, and bone-marrow tissues contain intermediate amounts of water and have dielectric constants and conductivities that fall between the values for the other two groups. Dielectric properties are frequency-dependent. With an increase in frequency, the dielectric constant decreases and the conductivity increases. N u merical dielectric data of various tissues have been published (15-17). The action of E M fields on tissues produces two types of effects that determine their dielectric properties: the oscillation of free charges on ions and the rotation of polar molecules at the frequency of the applied field (16). Freecharge motion loss is due to the electric resistance of the medium. The rotation of polar molecules generates displacement current in the medium with an associated dielectric loss due to viscosity. These two effects, which produce heat in the medium, are the basis of E M energy absorption. Bioheat Equation. The rate of temperature rise, d(AT)/dt, in tissue heated with E M energy is related to the rate of energy absorption (W ), metabolic heating rate (W ), and power dissipation by thermal conduction (W ) and blood flow (Wh) as expressed in the following bioheat equation: A

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^=iL^ «- . In many tumors, blood flow is vigorous at the periphery and sluggish in the center. Because the blood vessels in tumors are often fully open during ordi nary conditions (19% in many cases no further vasodilation occurs during the heat treatment (Figure 2). After steady-state conditions are reached, the final temperature of the tumor is higher than that of the surrounding normal tissue. The shaded area in Figure 1 indicates the range of temperature rises in tumors. The lower boundary is for the periphery of the tumor and the upper is for the center, in which no blood flow exists. The rate of energy absorption W must be sufficiently high so that the therapeutic level of temperature can be maintained over a major portion of the treatment period. If too low a power is used, the duration and the level of tem perature elevation will not, respectively, be long enough and high enough for any benefit. With too high a power level, the temperature of the normal tissue may not be maintained at a safe level by vasodilation. h

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Methods ofEM Heating Microwaves occupy the E M frequency band between 300 M H z and 300 G H z , with respective wavelengths in air between 1 m and 1 mm. The most commonly used frequencies in hyperthermia are 433, 915, and 2450 M H z . They are designated I S M (industrial, scientific, and medical) frequencies in the United States and Europe (433 M H z only in Europe). Frequencies higher than 2450 M H z have no practical value as a result of their limited depth of penetration. A t lower frequencies, penetration is deeper, but the applicator must be larger and focusing is difficult. A compromise must be made. Although radio-frequency (RF) energy, by International Telecommunication Union definition, lies between 3 H z and 3000 G H z , generally foi hyperthermia it means frequencies below the microwave range. The frequencies of 13.56 and 27.12 M H z have been widely used in diathermy and are now used in hyperthermia. Another I S M frequency is 40.68 M H z , but it has not been used extensively for tissue heating. Use of other frequencies is not allowed by the Federal Communication Commission unless the treatment is administered in a shielded room to minimize interference with the communication network. In addition, stray E M radiation during treatments must be monitored. Safety standards recommended by the American National Standards Institute and the Institute of Electrical and Electronics Engineers, Inc. (20) and by the American Conference of Government Industrial Hygienists (21) are to be followed to ensure the safety of operators. Local Heating. External The cooling mechanism of superficial tissues makes deep heating difficult by conductive methods. Two R F methods have been used to provide subcutaneous heating. First, tissues can be placed between two capacitor plates and heated by displacement currents. This method is simple, but overheating of fat, which is caused by the perpendicular electric field, remains a major problem for obese patients. Because of large differences in dielectric properties and specific heats of fat and muscle, the rate of temperature rise in planar-tissue models is about 17 times greater in fat than in muscle (22, 23). In addition, blood flow is significantly less in fat. Therefore, final temperatures in fat are much higher than those in muscle, and a water bolus is necessary to minimize heating of fat. The second R F method is inductive heating by magnetic fields that are generated by solenoidal loops or "pancake" magnetic coils to induce eddy currents in tissue. Because the induced electric fields are parallel to the tissue interface, heating is maximized in muscle rather than in fat. However, the heating pattern is generally toroidal with a null at the center of the coil (2). Fujita et al. (24) recently described a paired, aperture-type inductive applicator to produce deep heating in tissue models. In the range of microwave frequencies, energy is coupled into tissues by waveguides, dipoles, microstrips (antennas consist of a thin metallic conductor bonded to a thin grounded dielectric substrate), or other radiating devices. The shorter wavelengths of microwaves, as compared with longer wavelength RFs, provide the capability to direct and focus energy into tissues by direct radiation


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from a small applicator. Engineering developments have focused on the design of new microwave applicators. A number of applicators of various sizes operate over a frequency range of 300-1000 M H z (25-28). Most of them are dielectrically loaded and have a water bolus for surface cooling. Low-profile, lightweight microstrip applicators, which are easier to use clinically, have also been reported (29, 30). Methods based on high-permittivity dielectric material, electric-wall boundary, and magnetic materials have been used to reduce applicator size and mass. These applicators are used, for the most part, for treatment of tumors a few centimeters below the skin. Pain and thermal burns usually are the major problems. Side effects of thermal blistering and burns are correlated with maximal temperatures attained during heat treatments. Intracavitary. Certain tumor sites in hollow viscera or cavities may be treated by intracavitary techniques. The advantages of intracavitary hyperthermia include (1) better energy deposition due to the proximity of an applicator to a tumor, and (2) the reduction of normal tissue exposure compared with externally induced hyperthermia. Clinical and research studies on hyperthermia and radiation or chemotherapy of esophagus, rectum, cervix, prostate, and bladder cancers have been performed. Microwaves and lower-frequency R F energy (2450-13.56 M H z ) have been used for intracavitary hyperthermia. The main problem is that tumor temperature is unknown. Most temperatures were measured on the surface of the applicators, which can be very different from those in the tumor. Furthermore, thermocouples or thermistors were used to measure temperatures by many investigators who did not know the perturbation problem caused by the metallic sensors (57). One solution to this problem is to measure tissue temperature in animals and then extrapolate to humans (32). Interstitial Heating. Resistive Heating. Tissues can be heated by alternating R F currents conducted through needle electrodes. The operating frequency should be higher than 100 kHz to prevent excitation of nerve action potentials. Interstitial techniques for radiation implants as primary or boost treatments have been practiced successfully by radiation oncologists for many years. When hyperthermia was learned to be cytotoxic and synergistic with radiation, it was natural to consider this combination with conventional interstitial radioactive implantation. Other advantages of this technique include better control of temperature distributions within the tumor compared with those of externally induced hyperthermia and sparing of normal tissue, especially the overlying skin (55). Microwave Technique. Small microwave antennas inserted into hollow plastic tubing can produce satisfactory heating patterns at frequencies between 300 and 2450 M H z (34-36). A common frequency used in the United States is 915 M H z . A small coaxial antenna can irradiate a volume of approximately 60 cm . With a multinode coaxial antenna, the extent of the heating pattern can be 3


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extended to approximately 10 cm in a three-node antenna (57). Because most tumors seen in the clinic are large, a single microwave antenna cannot heat the entire tumor to a therapeutic temperature. Using an array of microwave antennas is thus necessary. A s in resistive R F hyperthermia, the degree of control of microwaves radiating from these antennas is important in achieving homogeneous heating. Because the antennas couple to each other, the spacing, phasing, and insertion depth affect the heating patterns of array applicators (38-40). Ferromagnetic Seed Implants. Burton et al. (41) used thermally selfregulating implants for producing brain lesions. This technique is also applicable for delivering thermal energy to deep-seated tumors. When exposed to R F magnetic fields (-100 kHz), the implants absorb energy and become heated. But at the Curie point temperature the implants become nonferromagnetic and no longer produce heat. The surrounding tissues are then heated by thermal conduction. The influence of blood flow and tissue inhomogeneities of the tumor, which may affect the temperature distribution, can be compensated by the selfregulation of the implants, so that maintaining a temperature close to that of the Curie point is possible (42). Another method that exposes magnetic fluid in a tumor to an RF magnetic field (0.3 to 80 MHz) has been shown (43) to be feasible for inducing selective heating. R e g i o n a l H e a t i n g . Electric Field. Heating deep-seated tumors is difficult. RF energy can be deposited into the center of the body, but a large region is affected. Differential increases of blood flow in the normal and tumor tissues may result in higher temperatures in the tumor than in normal organs. However, this temperature differential cannot be ensured. Strohbehn (44) used the term "dump and pray" to describe the situation of putting large amounts of E M energy into the region and hoping for satisfactory results. In Japan, an 8-MHz Thermotron system uses a capacitive electric field to heat deep tumors and a water-cooled bolus to minimize the heating of fat tissue (45). The sizes of the two electrodes are adjusted to control the heating patterns in patients. Most other electric field heating systems generate electric fields parallel to the body's surface. These include the annular phased-array systems (APAS) (46), the helix system (47), the coaxial transverse electromagnetic (TEM) system (48), the ring electrode (49), the segmented cylindrical array (50), the toroidal inductor (51), and the loosely coupled T E M system (52). The A P A S , made by the B S D Company (Salt Lake City, UT), radiates 16 R F fields in phase toward the patient. This array of applicators with variations in phase, frequency, amplitude, and orientation of the applied fields can add more dimensions to controlling the heating patterns during the treatment. A newer system with eight dipoles has been evaluated in the clinic (53). To determine the excitation phases of an array for heating an inhomogeneous medium, a retrofocusing technique is applied (54). A small probe is first inserted into a tumor. A signal is radiated by the probe and received by the array of applicators outside the patient. B y the reciprocity theory, conjugate fields are radiated from the applicators and focused on


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the tumor. The technique was demonstrated experimentally in a water tank. A significant increase in power level, at the desired focus, was observed. In general, superficial heating and hot spots in normal tissues are the limiting factors for effectiveness of existing treatments. Invasive techniques based on interstitial hyperthermia have been shown (33, 55, 56) to solve some of the deepheating problems. However, no completely adequate deep-heating system is available. Scanned ultrasound provides an alternative method (57). Magnetic Field. Magnetic fields heat tissue by induced eddy currents. The magnetic-loop applicators of the Magnetrode unit (Henry Radio, Los Angeles, C A ) are self-resonant, noncontact cylindrical coils with built-in impedancematching circuitry; they operate at 13.56 M H z and have a maximum output power o f 1000 W . The R F current in the coil creates strong magnetic fields that are parallel to the center axis of the coil in which the body or limb of a patient is located. Because the magnitude of the induced eddy current is a function of the radius of the exposed object, no energy deposits at the center of the exposed tissue. However, Storm et al. (58) showed that the heating of tumors deep in the body was possible as demonstrated in live dogs and humans, with no injury to surface tissue. This result was apparently due to the redistribution of the thermal energy by blood flow. Nevertheless, the Food and Drug Administration has forbidden use of the Magnetrode. Whole-Body Heating. During the past 20 years, hyperthermia was used primarily for treating localized tumors. However, tumors that are resistant to conventional therapy tend to be metastatic. For these patients, local and regional hyperthermia can only be palliative. For disseminated disease, wholebody hyperthermia (WBH) in conjunction with chemotherapy and radiation was studied by many groups (59-62). Methods of W B H include hot wax, hot water, water blanket, water suit, extracorporeally heated blood, and radiant heat. The high morbidity and labor-intensive methods associated with W B H have caused concerns. Except for the extracorporeal blood-heating technique, which requires extensive surgical procedures, all other methods depend on conduction of heat from the body surface to the core. The target core temperature is 41.8 °C; beyond that the brain and liver can be damaged (63). A t 41.8 °C, the metabolic rate is about double that at 37 °C, and with proper insulation, that increased metabolism can keep the body temperature elevated without additional heating. Because thermoreceptors are located cutaneously, the heating rate must be slow enough not to trigger pain or cause skin burns. The slowness of heat conduction methods causes inconvenience to patients, physicians, and the technical staff. Volumetric heating based on highly penetrating methods is a logical alternative. To heat the whole body uniformly with E M energy is impossible. However, to heat the body regionally is possible, and the blood flow will redistribute the heat to the whole body. In the past, applications of 434- and 468-MHz microwaves were explored (64) in Europe for W B H , but the results did not produce any significant impact. Several regional R F systems were attempted for W B H .


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The B S D dipole system and the helix system (47) require that the body be inserted into a tunnel applicator. The B S D system also requires a water bolus in contact with the patient to provide better energy coupling and skin cooling. For hour-long use the bolus is very heavy and uncomfortable. The R F electric field system, designed by the University of California at Los Angeles group (52), uses three electrode plates to heat deep-seated tumors in the torso. The patient lies on a table, and the top plate is swung over the abdomen to heat the thoracic region. No water bolus is needed, and there is no contact with the patient. It is very simple to use. After 2 years of extensive phantom and animal studies, it was found (65) to be a very promising system for regional hyperthermia and W B H .

Discussion In vitro, in vivo, and clinical studies have shown (66) that hyperthermia in conjunction with radiation and chemotherapy is effective for treating cancer. A summary of 25 nonrandomized studies, from 1980 to 1988, including 1556 superficial tumors treated with radiotherapy or radiation plus hyperthermia, shows that the average complete response rates were 34 and 64%, respectively. Clearly, hyperthermia is beneficial. However, two multi-institution, randomized phase III studies conducted in the United States, one published in 1991 (67) and the other to be published (68\ did not clearly show that hyperthermia in combination with radiation can improve tumor response when compared with radiation alone. Inadequate heat delivery is considered to be the reason for failure. In contrast, three randomized phase III trials recently conducted by European colleagues all showed positive results (69-71). Detailed reports are not yet available to discern the difference between the U.S. and European results. Significant progress has been made in the application of E M energy for clinical hyperthermia. Improvements in treatment equipment have been made based on medical demands, and the technological advances, in turn, have fillfilled many of the clinical requirements. Using a single piece of equipment to treat all clinical cases is impossible. After an evaluation of the location and vascularity of the tumor and adjacent tissues and the general physical condition of the patient, the hyperthermia practitioner should have the option of choosing the most appropriate equipment when hyperthermia treatment is warranted. Hyperthermia is a complicated technique and should be applied only by individuals well trained in the use of this modality (13). Because of the complexity involved in the coupling of E M energy to human tumors, careful heatingpattern studies should be performed for all exposure geometries and contingencies prior to treatment to ensure the best treatment conditions for the patient. Because high-energy radiotherapy cannot be repeated after the tumor has received a maximal dosage of ionizing radiation, the physician using hyperthermia must therefore try to reach the critical tumor temperatures in optimal conjunction with the radiotherapy. Anesthetizing or tranquilizing the patient may be necessary for an effective treatment. Accurate thermometry is particularly important in all phases of clinical hyperthermia, especially when the patient is anesthe-


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tized. The benefit of a good treatment outweighs minor risks. If there is no choice, it would be more beneficial for the patient to have an effective treatment with a few blisters rather than a safe but ineffective treatment. It is easier to treat the burns than the cancer.

Acknowledgments


This work was supported in part by National Cancer Institute Grants CA-33572 andCA-56116.

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