Application of electromagnetic energy in cancer treatment

IEEE TRANSACTIONS ON INSTRUMENTATION AND MEASUREMENT, VOL. 31, NO. 4. DECEMBER 1988 547 Application of Electromagnetic Energy in Cancer Treatment Abstract-While biologists have demonstrated the cancer killing ability of hyperthermia in combination with radiation and chemotherapy both in vitro and in vivo, clinicians find that it is difficult to raise and to keep the temperature of tumors at therapeutic levels. During the last decade, there has been significant progress in the method of heat delivery, temperature monitoring, and thermal dosimetry. In this presentation, radiofrequency (RF) and microwave heating techniques are reviewed. Examples of heating patterns of various applicators are shown to illustrate the complex energy deposition of RF and microwave energy in tissues. I. INTRODUCTION ISTORICALLY, the treatment of cancer with hyperthermia can be traced back to 3000 B.C. when smoldering sticks of wood were inserted in tumors. At the end of the 19th century, Coley's toxin was introduced to patients to produce whole body hyperthermia which resulted in tumor regression. Since then, sporadic reports using heat to treat cancers have appeared in Western journals. During the last decade, especially in recent years, the interest in using hyperthermia and/or in combination with other forms of therapy has increased tremendously. Currently, hyperthermia is an experimental treatment and usually applied to late stage patients. Heating methods include whole body heating using hot wax, hot air, hot water suits, infrared, or partial body heating utilizing radiofrequency (RF), microwave, ultrasound, hot blood, or fluid perfusion. Clinical and experimental results from various countries have indicated a promising future for hyperthermia, however, the main problem is the generation and control of heat in tumors. Numerous reports show how various animal or human tumors can be successfully treated by heat alone. Also, there are many publications emphasizing the synergistic effects of heat and radiotherapy or heat and chemotherapy. The effective temperature range of hyperthermia is very small, 42.5-44°C. At lower temperatures, the effect is very minimum. At temperatures higher than 44"C, the normal cells are damaged. Due to the difference in blood flow in normal and tumor tissues, tumor temperatures are usually higher than surrounding tissue temperatures during hyperthermia treatment. In addition, it is generally believed that tumors are more sensitive to heat. This is H Manuscript received April 20, 1988; revised August 5 , 1988. This work was supported in part by NCI under Grant CA33572. The author is with the Department of Radiation Research, City of Hope National Medical Center, Duarte, CA 91010. IEEE Log Number 8824016. explained by the hypoxic, acidic, and poor nutritional state of tumor cells. The synergism of radiation and hyperthermia is accomplished by the thermal killing of hypoxic and S-phase cells which are resistive to radiation. Since heating increases the membrane permeability and the potency of some drugs, hyperthermia has been used in combination with chemotherapy. The temperature rise in tumors and tissues is determined by the energy deposited and the physiological responses of the patient. When electromagnetic methods are used, the energy deposition is a complex function of frequency, intensity, polarization of the applied fields, geometry, and size of applicator as well as the dielectric property, geometry, size, and depth of the tumor. The final temperature elevations are not only dependent on the energy deposition but also on blood flow and thermal conduction in tissues. In present hyperthermia research, thermal dosimetry and treatment planning with microwave and RF waves is far from adequate. Further clinical applications cannot fully proceed without the prerequisite knowledge of how heat is to be delivered in various clinical situations. The development of advanced hyperthermia equipment and techniques will allow successful treatment of cancers that are resistant to other methods of therapy. 11. BASIC METHODS The cooling mechanism of superficial tissue circulation has made it difficult to heat deep tissue by conductive heating. Diathermy using microwaves, RF waves, and ultrasound is necessary to bring electromagnetic or acoustic energies to tissue beneath the subcutaneous fat layers. Microwaves occupy the electromagnetic frequency band between 300 MHz and 300 GHz. The most commonly used frequencies for hyperthermia are 4 3 3 , 9 15, and 2450 MHz. They are the designated ISM (industrial, scientific, and medical) frequencies in the U.S. and Europe (433 MHz in Europe only). Frequencies higher than 2450 MHz have no practical value due to their limited penetrations. While RF by definition is between 3 kHz and 300 GHz, generally it means frequencies below microwave range in hyperthermia. The RF frequencies of 13.56 and 27.12 MHz have been widely used in diathermy and now in hyperthermia. The other ISM frequency is 40.68 MHz, which has not been used extensively for tissue heating. Operating frequencies other than these are not allowed by the Federal Communication Commission (FCC) unless 0018-9456/88/1200-0547$01.OO O 1988 IEEE 548 IEEE TRANSACTIONS ON INSTRUMENTATION AND MEASUREMENT, VOL. 31. NO. 4, DECEMBER 1988 the treatment is administered in a shielded room to minimize interferences with the communication network. In addition, the electromagnetic stray radiation during treatments must be monitored. Occupational safety standards recommended by the American National Standard Institute and the American Conference of Government Industrial Hygienists are to be complied with in order to protect the safety of the operators. The following heating methods have been used for diathermy in rehabilitation medicine for four decades. During the last ten years, these techniques have been modified and refined for heating tumors. Specific clinical applications are described in subsequent sections. A . Resistive Heating Tissues can be heated by alternating RF currents through the use of needle or plate electrodes. The operating frequency should be higher than 100 kHz to prevent excitation of nerve action potentials. B. Capacitative Heating Tissues can be heated by displacement currents generated between two capacitor plates. This method is simple, but the overheating of fat remains a major problem. In planar tissue models, the rate of temperature rise is about 17 times greater in fat than in muscle. In addition, the blood flow is significantly less in fat, so the final temperature is much higher than that in muscle. In Japan, the 8MHz Thermotron system uses a water-cooled bolus to minimize the heating of fat tissues. The sizes of the two electrodes are adjusted to control the heating patterns in patients. C. Inductive Heating Magnetic fields generated by solenoidal loops or “pancake” magnetic coils induce eddy currents in tissue. Since 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 in shape with a null at the center of the coil. D. Radiative Heating The previous three heating methods use frequencies in the RF band where a quasi-static condition applies. In the microwave frequency range, energy is coupled into tissues through waveguides, dipoles, or other radiating devices. The shorter wavelengths of microwaves, as compared to RF, provide the capability to direct and focus the energy into tissues by direct radiation from a small applicator. Loading an applicator with dielectric material can reduce the size of its aperture to provide more flexibility in controlling the amount of energy deposited at tumor sites. 111. CLINICIAL APPLICATIONS A . Interstitial Hyperthermia Interstitial techniques for radiation implants as primary or boost treatments have been practiced successfully by radiation oncologists for many years. When hyperthermia was known to be cytotoxic and synergistic with radiation, it was natural to consider the combination with conventional interstitial radioactive implantation. Other advantages of this technique include better control of heat distributions within the tumor as compared with external hyperthermia, and sparing normal tissue, especially the overlaying skin. 1) Local Current Fields (LCF) Techniques At the City of Hope National Medical Center an interstitial hyperthermia equipment utilizing 0.5-MHz RF currents was used for Phase I and I1 clinical trials. Most of the patients treated had advanced primary breast and cervix cancers which were considered uncontrollable by conventional methods. Complete response rate was high in primary carcinoma of the breast (12/13 patients, 92.3 percent), and less in primary carcinoma of the cervix (9/14, 64.2 percent) with follow-up times between 6 and 47 months. Overall complete response rate was 64.3 percent, 36/56 lesions. A number of technical improvements have occurred in the last few years in the development of the LCF unit. Multiple sensors can be built into a thermocouple probe so that measurements at up to 5 points can be made. The aggregate temperature information can give an excellent representation of the temperature distribution across a plane or volume of tissue. The present unit (Oncotherm LCF 2032) can record up to 32 temperature readings with 20 electrode pairs and simultaneously display these temperatures on a video terminal. Feedback control of RF power and current dwell time across the selected needle pairs can be adjusted by the computer, based on the temperature monitored by a reference sensor. Current research involves the refinement and clinical testing of a “multipoint feedback (MPF) system.” The MPF system takes into account the adjustments current dwell time across each needle pair, and theoretically it should provide for a more homogeneous temperature distribution than what can be achieved at the present. 2) Microwave Technique Small microwave antennas inserted into hollow tubings can produce satisfactory heating patterns with frequencies between 300-2450 MHz. A common frequency used in the United States is 915 MHz. A small coaxial antenna can irradiate a volume of approximate 60 cc. With a multinode coaxial antenna, the length of the heating pattern can be extended to about 10 cm in a 3 node antenna. Strohbehn et al. have calculated the isotherms for an array of antennas taking into account the absorbed power in tissues and relating it to the bio-heat equation. Assumptions with or without blood flow were included in the theoretical modelling. As in LCF hyperthermia, the degree of control of microwave power radiating from these antennas is important in order to achieve homogeneous heating. Multiple point feedback control would be important as well. At Dartmouth College, biomedical engineers have designed a 549 CHOU: EM ENERGY IN CANCER TREATMENT system which has the capability to split the power from the generator to the various antennas and modulate it according to the temperature measured. 3 ) Ferromagnetic Seed Implants Burton et al. used thermally self-regulating implants for the production of brain lesions. This technique is also applicable for delivering thermal energy to deep seated tumors. When exposed to magnetic fields, the implants absorb power and become heated but when a critical temperature (Curie point) is reached, 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 self-regulation of the implants and maintain a temperature close to the Curie point. Atkinson et al. showed that the rate of energy absorption by the implant is strongly dependent on the permeability of the material, the frequency of the magnetic field, the implant diameter, and the orientation of the implants with respect to the magnetic fields. Since the temperature of the tissues between the implants is dependent on thermal diffusion, the spacing between the implants must be small enough to achieve a therapeutic temperature. In animal studies the spacing was 1 mm or less. In areas with high blood flow, the spacing may need to be reduced. 4) Intracavitary/Intraluminal Hyperthermia Certain tumor sites at hollow visceras or cavities may be treated with these techniques: 1) gastrointestinal (esophagus, rectum), 2) gynecological (vaginal, cervix, uterus), 3) genitourinary (prostate, bladder), 4) pulmonary (trachea, bronchus), and 5 ) miscellaneous sites where it is technically feasible to insert such applicators. Clinical experience to date has been quite limited in the United States. Leybovich et al. presented their designs of intracavitary applicators for treating tracheal stoma cancers. These applicators permitted air flow and resulted in adequate heating patterns in phantoms. Wong et al. have performed phantom (tissue simulation) studies of the heating pattern of an intraluminal probe and treated a patient with recurrent adenocarcinoma of the bile duct through a percutaneous biliary drainage tube with combined microwave hyperthermia and radiation. Broschat et al. investigated the construction of an insulated dipole applicator for intracavitary hyperthermia, with potential application of treatment of prostate cancers. Mendecki et al. have reported the use of microwave applicators for localized hyperthermia for the treatment of cancers of the prostate. Third world countries, especially China, are pursuing this area of research because a large population of patients with cancers are suitable for such treatments. Li et al. reported the combined treatments with radiation and hyperthermia of 103 patients with esophageal cancers using intraluminal microwaves. Hao et al. reported 53 cases of carcinoma of the uterine cervix, 47 percent of whom were Stage IIb/IIIb. They were treated with intracavitary hy- perthermia alone, radiation alone, or combined hyperthermia and radiation. The best responses were observed in the combined group. B. Local External Hyperthermia Heating of small volumes of tumors usually up to 50 cm2 in area and up to 4 cm in depth located near the surface of the body can be achieved quite easily today. Perez and Meyer summarized the clinical experience with localized hyperthermia and irradiation. The majority of studies involve the use of microwaves, usually at 915 MHz. In most cases, skin cooling was employed if there was no evidence of superficial tumor. The average complete response rate with irradiation alone is 30 percent in comparison to 70 percent with irradiation and hyperthermia. Toxicities are mainly pain and thermal bums. Side effects of thermal blistering and bums were correlated with maximum temperatures attained during heat treatments. Engineering development has been mostly on the design of new microwave applicators. A number of applicators with various sizes operate over a frequency range of 300- 1000 MHz. Most of them are dielectrically loaded and with a water bolus for surface cooling. Low profile, lightweight microstrip applicators, which are easier to use clinically, have also been reported. To reduce the applicator size and weight, methods of using high permittivity dielectric material, electric wall boundary, and magnetic material have been applied. Although these applicators are only useful for treatment of tumors at a few centimeters below the skin, they are much more convenient than waveguide applicators in phased-array applications for treating deep-seated tumors. C. Regional Hyperthermia To heat deep-seated tumors noninvasively 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 temperature in tumors than normal organs. However, this temperature differential cannot be assured. Strohbehn used the term “dump and pray” to describe the situation of putting large amounts of electromagnetic energy into the region, and hoping for satisfactory results. So far, the annular phased array systems (APAS) made by BSD Corporation (Salt Lake City, UT) and the Magnetrode made by Henry Medical Electronics, Inc. (Los Angeles, CA) have been evaluated by several institutions. The APAS consists of four sets of dual radiating apertures which operate in the transverse electromagnetic (TEM) mode over the frequency range of 50-110 MHz. The maximum power is 2 kW. The patient is placed inside the octagonal aperture. Distilled water bolus bags fill the air space within the aperture, and have the function of improving energy coupling, reducing stray radiation, and providing surface cooling. Due to FCC regulations, the system has to be operated inside a shielded room. 550 IEEE TRANSACTIONS ON INSTRUMENTATION AND MEASUREMENT, VOL. 31, NO. 4. DECEMBER 1988 In clinical evaluations, the safety, feasibility, and also the limitations of the use of APAS have been demonstrated for achieving therapeutic temperatures in the abdomen and pelvis. Treatment of the chest can cause severe heating in the head and neck region. In addition, the invasive thermometry current employed can puncture the lung or major vessels. Therefore, it has been concluded that more pilot studies are needed before this modality can be evaluated by a randomized clinical trial. The magnetic-loop applicators of the Magnetrode unit are self resonant, noncontact cylindrical coil with built-in impedance matching circuitry and operate at 13.56 MHz with a maximum power output of 1000 W. The RF current in the coil creates strong magnetic fields in parallel to the center axis of the coil where the body or limb of a patient is located. Since the magnitude of the induced eddy current is a function of the radius of the exposed object, there is no energy deposition at the center of the exposed tissue. However, Storm et al. have shown that in live dogs and humans the heating of tumors deep in the body was possible with no injury to surface tissue. This was apparently due to the redistribution of the thermal energy by blood flow. cident waves, various distinct SAR patterns were predicted. These patterns were verified experimentally by thermographic techniques. A patient with recurrent melanomas on a lower leg was subjected to a clinical trial. The heating pattern was the same as predicted on models. A therapeutic temperature of 43°C in the tumor was easily achieved. A miniature APAS called MAPA, was designed by Turner for treating cancers on the extremities. The MAPA deposits energy into tumors by an annular co-phase focusing of the E-field radiating from each of the 8 metallic strip radiators. The SAR patterns in a cylindrical phantom vary with the operating frequency and the position of the phantom. This system is being evaluated clinically at Duke University. IV. HEATINGPATTERNS For treatment planning, the heating patterns of a particular modality is needed before the treatment. The heating patterns can be predicted by numerical modeling. After the pattern is found, the next step is to use the heat transfer equation to calculate the temperature distribution. Numerous papers on mathematical modeling have been published. Numerical techniques, such as finite differences, D . Phased-Array Hyperthermia finite element, moment, and finite-difference time-domain An array of applicators with variations in phase, fre- methods, have been used for numerical modeling. For heating pattern measurements in phantoms heated quency amplitude, and orientation of the applied fields can add more dimensions to controlling the heating pat- by electromagnetic energy, the following method has been terns during the treatment. The APAS described by Turner described in detail in the literature. The absorption of radiates 16 RF fields in phase toward the patient. When electromagnetic energy in tissue is determined by many the electrical field in the tissue is increased by a factor of factors. Among them are amplitude, frequency, duration, N , the specific absorption rate (SAR) (and, therefore, the and polarization of applied fields; dielectric properties, temperature rise) is N 2 times higher. By changing the size, geometry, and depth of tissues; size and shape of phase and amplitude of the applied fields incident from applicator; as well as spacing or coupling between tissue different directions, the SAR pattern can be controlled. and the applicator. Therefore, in order to apply the penTheoretically it is possible to achieve the temperature el- etrating microwave or RF energy for tissue heating, meaevation at the tumor only. A few researchers have shown surements of energy absorption in tissues are required for theoretically and/or experimentally that the focusing ef- effective treatment in cancer hyperthermia. Phantom mafect can be achieved in models. A special issue on phase terials with dielectric properties similar to those of real arrays for hyperthermia treatment of cancer has been pub- tissues have been used for electromagnetic heating studlished in the IEEE TRANSACTIONS ON MICROWAVE THE- ies. Several nonperturbing temperature probes are now ORY AND TECHNIQUES, May 1986. To determine the excitation phases of an array for heat- commercially available. They can be used to measure rate ing an inhomogeneous medium, the retro-focusing tech- of heating at various points in the phantom model. Hownique was applied by Loane et al. A small probe was first ever, this process is quite time consuming, and it is esinserted into a tumor. A signal was radiated fromlhe probe pecially difficult to know where to insert the temperature and received by the array of applicators outside the pa- probe, because the heating patterns can be very complitient. By reciprocity theory, conjugate fields were ra- cated. Guy has described a thermographic method for diated from the applicators and focused at the tumor. The rapid measurement of the rate of temperature rise (not technique was demonstrated experimentally in a water steady-state temperature) in tissue through the use of tank. A significant power increase at the desired focus phantom models of real tissue. This method uses a thermographic camera for recording RF induced temperature was observed. Guy et al. used a phased-array 915-MHz system for changes over an internal surface of the exposed object. heating deep and superficial tumors in cylindrical struc- The phantoms are composed of materials with dielectric tures such as the upper and lower limbs or neck. Theo- and geometric properties similar to the tissue structures retical analysis of SAR patterns was based on superposi- that they represent. Models are designed to separate along tion of four plane waves incident on a cylinder. By altering planes so that cross-sectional heating patterns can be meathe orientation of the electric fields and the phase of in- sured with the thermographic method. 55 1 CHOU: EM ENERGY IN CANCER TREATMENT BSD MA151 WATER BOLUS. PLANAR SLAB APPL 22 APPL 10 APPL 7 p.q Fl -k" APPLICATOR 12 AS A FUNCTION OF FREQUENCY 915 MHz 650 MHz 433 MHz 657 MHZ 189 MHz Fig. 1 Heating patterns of intracavitary applicators. TAG MED - TCA 434-1 434 MHZ SLAB * ii DIRECT CONTACT 0.8r.m SPACING Fig. 2. Heating patterns in bisected plane showing hot spots at the edges of a TAG-MED applicator when no spacing was between the applicator and model. This technique has been used to evaluate heating patterns of various RF and microwave applicators. Three selected examples are shown below to illustrate the complexity of heating pattern in tissues. 1) To treat cancers with hyperthermia in hollow viscera or cavities in the body, such as the esophagus, rectum, vagina, and bladder, intracavitary applicators have been designed and tested. The upper half of Fig. I shows that the heating patterns are different for different intracavitary applicators operated at the same 915 MHz. Applicator #22 shows that only one side of the phantom was heated, since the unheated side was shielded by a copper coil. This particular probe is suitable for treating diseases on one side of the cavity. The bottom of Fig. 1 indicates that with the same applicator (#12), the heating pattern varies as the operating frequency changes. 2) In Fig. 2, the heating pattern on the left was for a TAG-MED applicator (Boulder, CO) in direct contact with the fat surface. The two hot spots are in the fat with relatively slight heating in the muscle. When a 0.8 cm spacing is placed between the applicator and the phantom, the heating is greatly improved in the muscle region for electric fields either parallel or perpendicular to the inter- View publication stats Fig. 3. Heating patterns on the surface of a phantom exposed to microwaves at vanous frequencies using a BSD MA-151 applicator. face. Quantitative data are not shown in this figure but the data show that heating in the fat was six times higher if the 0.8 cm spacings were not in place. If the applicator is in direct contact with the patient this indicates that not only little heating in the muscle (or tumor) will be produced, but also that hot spots may cause burns in the patient. 3) Heating patterns of a small BSD applicator (3.8 X 5 cm) cooled by a water bolus are shown in Fig. 3 for operating frequencies of 930, 779, 657, and 581 MHz. Maximum heating was outside the rectangular aperture of the applicator for 779 and 657 MHz. Both 930 and 581 MHz produced heating in the center of the applicator. Unfamiliarity with these heating patterns can cause blisters outside the aperture area. V. CONCLUSION It is very important to the physician and the hyperthermia treatment team (physicist, engineer, and nurse, technologist, etc.) that the proper functions of any hyperthermia equipment be fully understood for the sake of safety to the patients and to the operators. In using electromagnetic heating, the applicators are critical components which come in close proximity or contact with the patients and can be the determining factor of effective and safe treatments or complications. Before an applicator is used, detailed heating patterns should be measured. Dosimetry data on phantom models will give physicians more insight into the heating capability of the applicator. REFERENCES Due to the page limitation, the 30 references are available upon request from the author.