deep local hyperthermia for cancer therapy: external ... · deep local hyperthermia for cancer...

[CANCER RESEARCH (SUPPL.) 44, 4736s-4744s, October 1984]

Deep Local Hyperthermia for Cancer Therapy: ExternalElectromagnetic and Ultrasound Techniques1

Augustine Y. Cheung and Ali Neyzari

Department of Electrical Engineering and Computer Science, George Washington University, Washington, DC 20052, and Cheung Associates, Inc.,Beltsville, Maryland 20705

Abstract

External heating techniques for delivery of localized hyper-

thermia in patients are reviewed. This paper covers microwaves,radiofrequency, and ultrasound methods. Fundamental principlesgoverning tissue absorption, guidelines for applicator selectionand design, and restrictions of each heating approach are discussed. Innovative techniques utilizing multiple applicators toachieve better heating uniformity are also presented. The advantages and disadvantages of electromagnetic versus ultrasoundheating techniques are compared as a conclusion to this review.

Introduction

Elevated tumor temperature, or tumor hyperthermia, is amethod used in the treatment of cancer based on a considerableamount of good experimental data. In the early part of thiscentury, diseases such as arthritis, asthma, and multiple sclerosis and infectious diseases such as syphilis and gonorrheawere treated by hyperthermia (24).

At low-temperature hyperthermia (between 37Â°and 41.5Â°),

heat enhances cell growth and also may well enhance the growthand proliferation of tumors. At high-temperature hyperthermia(above 45Â°),heat begins to indiscriminately damage both normal

and cancer cells. Thus, to avoid both enhancement of the activegrowing edge of the tumor and damage to normal cells, we arelimited to a narrow therapeutic range.

This paper describes the 2 methods of external heating (EM2

and ultrasound) that have been or can be used locally to inducetemperature elevation for the treatment of cancer. As we shallsee, each method has advantages and disadvantages.

As we go deeper inside the tissue, the number of humantumors that can be treated with hyperthermia increases. Therefore, depth of penetration of the heating beam is an importantconsideration in hyperthermia systems. Another important factoris the noninvasiveness of the technique. Metastasis, caused bydelivering heat invasively, might increase with disruption of bloodvessels and mechanical probing of the tumor. EM and ultrasoundare the 2 main methods that are potentially useful for noninvasiveheating (17).

Localization is also a factor of consideration in hyperthermia.In treating known or suspected multiple tumors with whole-bodyhyperthermia, temperatures above 42Â° are hazardous due to

difficulty in quick and precise control and physiological stress(24). Consequently, producing localized deep heating withoutexcessive surface heating by means of external EM and ultrasound techniques is the primary subject of this paper.

Heat-producing Modalities

Most of the heat-producing methods are divided into 2 major

modalities: (a) ohmic heating, which is produced by electricalcurrents generated from radiofrequency sources and by electricalwaves generated from microwave sources; and (b) mechanicalfriction, which is caused by an ultrasound wave shaking themolecules.

EM and ultrasound beams follow the general laws of wavesas they propagate through the body (14).

Because each heat-producing modality has its own physical

properties and because the anatomical site of the lesion and thesize and depth of the tumor vary, one or several methods mayhave specific applications or limitations in a given topographicalarea (22).

EM Techniques

Heat can be generated in tissue by different kinds of interactionbetween EM fields and biological systems. One such way is byrotating polar molecules; the friction associated with the rotationof the atoms and molecules causes heat generation when time-

varying EM fields are applied. Another kind of interaction isoscillation of free electrons and ions. In this way, collisionsbetween electrons and ions with immobile atoms and moleculeswithin the tissues produce heat. At microwave frequencies andradiofrequencies, the internal electric field E is primarily responsible for transferring energy into tissue as heat. At microwavefrequencies (300 MHz to 30 GHz), the rotation of water molecules dominates all interactions; therefore, water-containing tis

sues like skin and muscle are usually good microwave absorbers(8).

In general, materials that interact with an EM field via theinteractions mentioned above are classified as lossy dielectricsand are described by a property of material called permittivity,designated by Â«.Permittivity involves a complex number forsinusoidal steady state fields and can be expressed as

Â«= eo(i' - Je") (A)

1Presented at the Workshop Conference on Hyperthermia in Cancer Treatment,

March 19 to 21,1984, Tucson, AZ.2The abbreviation used is: EM, electromagnetic.

where (0 Â¡sthe permittivity of free space (F/m) and (Â«'- Ji") isthe relative permittivity, with Â«'as the real part and Â«"as the

imaginary part, both of which are unitless. From Equation A, wesee that the relative permittivity is (/<0 = <r; it is called thedielectric constant. Tissue can be characterized by e' and a, theconductivity (Siemens m~1) that is given by a = we0e",where w

is the angular frequency. Note that the permittivity of tissue Â¡sastrong function of frequency.

The concept of plane wave propagation in a lossy dielectric isoften used to describe wave phenomena in tissues. Therefore,although this concept does not actually occur physically, it is

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Deep Local Hyperthermia by External Techniques

nevertheless an important tool in understanding the basic salientcharacteristics of EM waves in tissue (9).

Frequency and Depth of Penetration

The use of higher frequencies results in a decreased depth ofpenetration. As Chart 1 shows, as the frequency decreases, thedepth of penetration of the plane wave in muscle tissue increases. By drawing a vertical line at any point on the depthaxes, we would see that, for the same depth of penetration, theuse of a lower frequency results in higher power absorption. Bydrawing a horizontal line at any point on the power axes, wewould see that, for the same power absorbed, use of a lowerfrequency results in a higher depth of penetration. Power absorbed P is given by

@"(mmhos/cm)

100

= VÃ¯ (W/m3) (B)

where Â£is the magnitude of electric field (V/m) and <r, theconductivity, is in (S/m). P is the same as the specific absorptionrate. Penetration depth D is defined by

where a, the absorption coefficient, is given by

and reduced wave length XÂ«Â«is given by

+1 C")

where X0 is the free-space wave length which is always greater

than AÂ«Â«(8).Chart 2 shows penetration depth D and power absorption P

as a function of frequency for muscle and fat tissue. At anyfrequency, this graph shows penetration depth in fat is higherthan that in muscle, but conductivity a of muscle is higher thanthat of fat. Despite better penetration, the lower frequency is not

FBEQI1PMCV. MHÂ»

DEPTH IN MUSCLE cm

Chart 1. Power absorption in muscle by plane wave versus depth of penetrationat different frequencies (9).

2 4 6 10" 2 4 6 10

Chart 2. Frequency dependence of D (plane-wave depth of penetration) and <r(conductivity) for EM waves in muscle and fat tissues (5).

necessarily desirable since as given by Equation B and Chart 2,a, the primary factor governing absorption, decreases with decreasing frequency (8).

Frequency Selection

Because depth of penetration is a function of frequency, thento heat tumors at various depths, it is more desirable to have agenerator covering the entire range of frequencies. However,this is not practical because of the radiation hazards as well asrestraint on decreased absorption with lowering frequency.Therefore, EM generators other than those of the officially designated industrial, scientific, and medical band are generallyprohibited for operating on a patient in a regular hospital room;a special shielding room is required for any frequencies otherthan the above mentioned. For hyperthermia, the EM generatorsthat are commercially available operate at the ISM band frequencies of 13.56, 27.12, 40.68, 915, and 2450 MHz. A frequency of433 MHz is also authorized in Europe. For hyperthermia, thepower range also varies normally within the range of 10 to 500watts for a single applicator at microwave frequencies (915 and2450 MHz).

EM Applicators

Experimental studies strongly suggest that hyperthermia isuseful in the treatment of cancer. One of the most important anddifficult parts of this treatment is the delivery of well-controlled

heat into the body, a complex biological system.One of the most significant problems facing application of EM

energy is the proper design and selection of the applicators thatdirect deep penetration of EM energy into the patient. Indeed,the success of hyperthermic treatment appears to be strongly

OCTOBER 1984 4737s



A. Y. Cheung and A. Neyzari

related to the capability of the applicator(s) to focus energyeffectively into a tumor (6). Factors like reliable, simple, and safeequipment; power output (reproducibility) and surface cooling;localization of the treatment area; knowledge of minimum tumorand maximum normal tissue temperature to avoid temperaturerise in the surrounding healthy tissue; and acceptable heatingduration are critical in the applicator selection and design processes (3). They provide uniform, reliable, and safe heating of thetumor volume.

In microwave diathermy (915 and 2450 MHz), spaced applicators are often used. However, because of the danger ofscattered radiation to the operators and the patient's body,

shielding is required (6). For a safe treatment with minimumleakage of radiation, an external direct contact applicator can beused where shielding is not required (6, 16). Based on officialsafety performance standards formulated by the United StatesBureau of Radiological Health, direct-contact applicators shouldbe able to induce hyperthermia in tissue at a rate exceeding 1Â°/min, thus raising the tissue temperature from 37Â°to 42Â°in less

than 5 min. At the same time, leakage exceeding the safety levelof 10 milliwatts/sq cm should not be found at 5 cm from theouter edge of the applicator in use (6, 23).

In designing EM applicators, the size of the applicator (radiator)must be an appreciable fraction of a wave length to be efficient.The wave length is given by

(C)

where f is the frequency and C is the speed of the waves in thebody, which is given by

o- Cl

where Ci is the speed of the waves in free space.A complication that must be considered for the waves is the

impedance mismatch between the source, the body, and thestructures in the body. The reflections between interfaces arerelated to the characteristic impedance Z,. In EM waves, thisvalue is Z, = 377 ii for air and Z2 = 50 ÃŽÃŽin the body. Thereflection power R at normal incidence for planar waves is givenby

z, - z

+ z,

and the transmitted power (7) is given by (14)

7 = 1 -fl

We know that the lower frequency (/) results in an increaseddepth of penetration (D), so that to have an applicator deliverdeep heating in muscle, the length of the radiator must be atleast one-half of the wave length (X) (13), and since wave lengthis related to the frequency by Equation C, a lower frequencyresults in a longer wave length, which leads to a large radiator.Using too long a radiator, however, is not a practical means ofproducing EM waves in regions of the patient's body. On the

other hand, it is usually desirable for one to use higher-frequency

microwaves, because it is easier to localize the radiator at highfrequencies; yet deep penetration cannot be achieved.

The design of microwave heating involves solutions to EM

problems such as near-field coupling (1). If an applicator that is

short compared to the wave length is used, since the near fieldis strong near the radiator but decays rapidly as its distancefrom the radiator increases and since the EM field produced inthe tissue is dominated by the near fields, then greatly increasedsurface heating occurs (9).

The following section includes a description of the differentkinds of EM direct-contact applicators (external), consisting of

capacitive, inductive, and radiative aperture applicators and alsomultiple applicators.

Capacitive Applicators

Capacitive applicators have been used widely in hyperthermiafor cancer patients. They are simple devices that operate at lowfrequencies (13.56 and 27.12 MHz). This type of applicatorconsists of 2 plates producing an electric field (Â£)that is perpendicular to the plates and causes deep heating (Chart 3). Parallelto the direction of the conduction current, electric field (E) isbasically perpendicular to the interfaces between the tissuelayers, such as fat and muscle. Due to differences in permittivity(Ã‰)of different tissues, interfaces between different tissues (e.g.,fat and muscle) in wave heating is a major concern (9). For anidealized geometry (parallel plate capacitor), the E field in the fat(E,) and muscle (Â£m)is constant. The boundary condition atjunction between fat and muscle requires that

i,Â£,= tmÂ£m (D)

where a and tm are the permittivities of fat and muscle. FromEquation B, power absorbed P (W/m3) at any point for fat and

muscle are given by (9,15)

P, =

Thus, the ratio of absorbed power in fat to muscle is given by

P, _ a, |Â£,|2P a \E I2

Therefore, from Equations D and E

|(m|2Pj_

PÂ»| i, |2

(E)

(F)

The following is a simple example that shows how excessives.c. fat heating occurs when the electric field is perpendicular to

Idealized geometryI i

Plate

Muscle

Charts. Capacitive applicator arrangement showing idealized parallel platecapacitor geometry (9).





the fat-muscle interface and how this condition may be pre

vented. The values needed for this calculation for frequency27.12 MHz are given as

a, = 0.012<', = 20

t", = 7.23

S/m am = 0.61 S/mi'm = 113

t"m = 405.82

â€” a 0.020*

From Equation A,

and

Therefore

Â«m= KÃ•f'mâ€”Jt'm)

- J("m\2 I113-J405.82I2

From Equation F,

I20-J7.23I2

= (0.02) (392) = 7.84

392

which means that power absorbed in fat is greater than powerabsorbed in muscle (P, > Pm). From Equation D,

Ei <mEm (t

or

Ifrl2392

which means that Â£field in fat is greater than Â£field in muscle.Thus, if E, > Â£m,then P,>Pm, where the fat-overheating problem

occurs. The above calculation is based on the condition that theÂ£field is perpendicular to the fat-muscle interface. To prevent

fat overheating near the interface, the Â£field should be parallelto the fat-muscle interface. The boundary condition requiresE, = Â£m.Therefore, from Equation E,

portion of a patient. These simple applicators, which are nowcommercially available with the name Magnetrode, operate at afixed frequency (13.56 MHz). No coupling medium is necessary.With Magnetrodes, high temperature has been achieved atdepths of 8 cm or more.

In the special case of a homogeneous dielectric placed coaxi-ally in a thin coil, the magnetic field concentrates in the edgevicinity of the coil, thus producing a null at the center, even inthe case of a lossless material. In the case of an inhomogeneousmedium (e.g., the human body), induced eddy currents do notflow symmetrically around the geometric center. Instead, manysmaller locally induced loops may be found in regions of differentconductivity (5). These local eddy-current loops may cause more

uniformity and deeper heating results (21).Three configurations of magnetic fields generated by induction

coils are illustrated in Chart 4 as follows: (a) pancake coil, wherethe coil is placed on the surface of the body and may consist ofone or more turns of a conductor in a planar or axial distributionand produces a magnetic field predominantly perpendicular tothe skin surface; (b) coaxial pair of coils, in which 2 single-turn

coils on a common axis can be placed on the anterior andposterior sides of the body region to be heated. The arrowsindicate the magnetic field lines that pass through the body. Thedotted circles indicate the path of representative eddy currentsin coronal planes of the body; (c) concentric coil. When one ormultiple-turn coils surround a portion of the patient's body,

magnetic field lines approximately parallel to the axis of thecylindrical volume are produced. Eddy currents associated withthe induced Â£field are also shown (20).

Radiative Aperture Applicators

This type of applicators is classified as a high-frequency appli

cator (microwave), which couples a propagating wave from theapplicator to the patient. They are well developed and cansatisfactorily heat tissue at depths of a few cm. Furthermore,because they are excited by wave guides, they do not producefat overheating problems since their Â£field is primarily tangentialto the fat-muscle interface (9).

Since the physical size of the applicator must be at least one-

half the wave length, at frequencies below microwave, the aperture applicators would be practically too large to use. However,as Chart 1 indicates, the penetration depth at microwave fre-

which means that power absorbed in fat is much less than thatin muscle, resulting in no fat burning (9).

In the capacitive heating technique, the current spread canalso cause excessive surface heating, which would require properly spacing the separation between plates and the tissue. Acirculated 0.9% NaCI solution bolus is very often used to controlthe surface temperature.

Inductive Applicators

In EM heating, inductive applicators are involved when, insteadof direct electric field coupling, the main source of power deposition is currents produced inductively in the tissue. Recently,Storm ef a/. (27) used a large loop induction coil surrounding a

(a) (b) (c)Chart 4. Three arrangements of current loops and the corresponding directions

of magnetic field lines. Eddy currents are also shown (20).

OCTOBER 1984 4739s




quencies is insufficient for heating deep-seated tumors. Furthermore, in operating a small-aperture applicator at low frequency(13.56 and 27.12 MHz), the production of radiation into the bodyis dominated by the near field, causing surface overheat. In adielectrically filled wave guide as the frequency is lowered, thesize of the aperture increases and a reduction of this size isdirectly proportional to the square root of the relative dielectric

constant t,, where t, = â€”.Therefore, by filling the empty spaceto

(air) of the wave guide applicator with commercially availablelossless dielectrics ranging from 1 to 150, the aperture size canbe reduced by a factor of up to 12 (5, 11, 13). Indeed, Sterzeref al. (26) have developed a large ridge-wave guide applicator

(27.12 MHz) loaded with deionized water (lossless dielectric withir = 81) that produces deep heating.

Applicator Bolus Tumor TissueChart 5. Transmission of EM radiation from an applicator to a tumor in hyper-

thermia system using a bolus.

Bolus

In EM hyperthermia, a tissue-equivalent bolus is often used to

improve the coupling between the applicator and the patient(Chart 5). Application of bolus has the following advantages.

Smooth Transmission from Applicators into Tissue. Lack ofuniformity of the deposited energy and loss in the couplingcoefficient of energy in the heated area due to the curvature ofthe body surface require use of bolus.

Skin Cooling to Avoid Surface Heating. With single applicators, maximum heating always occurs near the surface. Therefore, unless treating very superficial skin, deionized water isoften circulated into the bolus to act as a cooling agent againstthe skin.

Safer Treatment by Reducing the Amount of Leakage fromthe Applicator. Deionized water bolus greatly reduces theamount of leakage from the applicator.

Maintenance of the Body Surface at a Fixed Distance fromthe Applicator for Each Session of the Treatment. Microwavebolus can be used as a spacer to ensure proper placement ofthe applicator.

With a proper frequency, a well-designed applicator, and use

of a bolus, EM hyperthermia induction systems can deposituniform heating into the tissue at the depth of a few cm, but thedepth of heating can be greatly increased by using 2 or moreapplicators rather than a single one.

Multiple-Applicator Technique

This technique can be incorporated into hyperthermia treatment to improve the depth of heating in tissue. In regions ofextreme curvature (e.g., breasts, head, neck, and limbs), it ispossible to generate deep hyperthermia by superposing severalbeams. With a capacitive applicator, by placing more than onepair of capacitive plates in a "cross-fire" arrangement, heating

from all the pairs adds in the center, where deep tissue heatingis desired. Less superficial heating may be achieved with thisarrangement (11).

Phased Array. An array of radiation designed to create constructive interference at the focus is called phased array. In amultiple-element array arrangement (with N elements), depending on whether or not the elements are excited in phase, theheating at the focus can be A/2 or only N greater than that

expected from a single applicator. However, in reality, it is hard

44 -43Â°-

42'-

41Â°-

Applicators

Tissue

volume

Scm

Chart 6. Distribution of heat induced by means of 2 conformai applicators facingeach other across the heated area in the thigh muscles of an anesthetized dog.Graph represents temperature readings at various points of thermocouples. Insertion along the distances between applicators (19).

to design a phase array radiating into a lossy inhomogeneousdielectric (human tissue) (6).

Radiative aperture applicators have been used in arrays toobtain improved heating patterns. Cheung ef al. (7) used 2applicators at 2450 MHz to obtain more uniform heating. Men-

decki ef al. (19) used a single conformai applicator at 2450 MHz.The heat induced in the tissue was not uniform, and the therapeutic temperature range was limited to 1.5 to 2 cm below thesurface level (cutaneous or s.c. heating). To improve deep heating, they used 2 conformai applicators facing each other acrossthe heated area. As illustrated in Chart 6, perfectly uniformheating in tissue with a thickness of 5 cm is achieved. Guerquin-Kern ef al. (12) used two 2450-MHz applicators perpendicular to

each other; an improved temperature field resulted from thesuperposition of the 2 intersecting beams.

In microwave hyperthermia, a single dielectrically loaded open-

ended waveguide, horn, or coaxial antenna is often used. Toavoid the disadvantage of the single applicator, phased array isused in layered lossy media with the focal point several cm awayfrom the radiating aperture. Gee ef al. (11) developed a theoryfor analyzing an arbitrary array designed for near-field focusingand for testing its predictions for a 4-element linear array against

experimental data. The focused linear array of 2450 MHz consists of 4 titanium dioxide-loaded horn antennas with apertures(2.0 x 1.4 cm). The experiments conducted with the 4-elementlinear array have successfully demonstrated that the near-field

focusing of an array can be accomplished by appropriate phasingof each antenna element for the desired focal point. This validatesthe theoretical model. Furthermore, Gee ef al. have obtained areasonable beam spot size (1.3 cm) that is amenable to electricscanning and achieved sufficient sidelobe suppression (as isevident by the 19-element hexagonal planar array) to ensure that

most of the EM energy can be confined and directed to theintended focal region.





Ultrasound Technique

Ultrasound is another method of producing deep heating inhyperthermia cancer therapy. This therapeutic modality has beenused for some years but, like the EM technique, has advantagesand disadvantages.

Vibration due to passage of ultrasound waves through tissuescauses the displacement of tissue molecules. Heating is produced as a result of the absorption of this ultrasound vibrationin the tissue. The speed of sound in tissue is considerably loweras compared to the velocity of EM wave propagation. Thisdifference in velocity and difference of the ultrasound and EMradiation results in vast differences between ultrasonic and EMheating. Because of the relatively low speed of sound in tissue(1.5 x 105 cm/sec), at frequencies between 1 and 10 MHz

(ultrasonic frequencies), the acoustical wave lengths (between1.5 to 0.15 mm) are much shorter than those in the EM range.This frequency range is still low enough to avoid high tissueabsorption and as a result provides deep penetration in tissue.

The propagation of ultrasound in the body is similar to that ofmicrowave beams. The acoustic impedance zÂ»is related to thevelocity of ultrasound V (speed of sound in region x in m/s) andthe average density P, (kg/m~3).

Because at ultrasound frequencies both speed of sound andaverage density are almost constant for most tissues (e.g. , water,brain, liver, muscle, and fat, but not bone), the acoustic impedance Zx is constant for different tissues. For this reason, theinternal reflections between fat and muscle are usually neglectedin ultrasound technique. However, propagation of ultrasoundwaves in bone and air is quite different from that of soft tissue;a great deal of reflection occurs at the interfaces of bone (or air)and tissue (2, 15). This is one of the disadvantages of ultrasoundtechnique.

Focusing

Because heating by plane-wave energy causes the intensity

and temperature to decay exponentially as the depth in tissueincreases (Chart 7, Curves A), deep heating is not achieved, andregardless of the wave length of the plane-wave energy, surface

heating occurs and injury is possible. Therefore, for selectivedeep-heat deposition in a limited region, focusing the energy isessential (17). As Chart 7, Curves B, shows, by focusing, higherintensity and temperature can be achieved at the desired pointof depth, and due to the small size of ultrasound energy wavelengths ultrasound waves can be focused easily into local regionsof tissue for producing controlled localized hyperthermia to heatdeep-seated tumors (17).

Insonation

Insonation, or irradiation with ultrasound, elevates the temperature in tissue and consists mainly of the following.

Transducer. Ultrasound is generated from a transducer (x-cutquartz crystals) which, when activated by a high-frequency volt

age, produces pressure waves that heat the tissue (4). A reasonable transducer size in ultrasound is several wave lengths indiameter, such as 8, 12, or 16 cm. Transducers with larger

Depth

(b)Depth

Chart 7. Intensity and temperature distribution patterns, with plane wave in ahomogeneous medium (Curves A) and with a focused radiation field (Curves B)(17).

diameters are used for deep tumors and operate at the lowerfrequencies (18).

Focusing Lens. Energy from the transducer can be focusedor concentrated into the tissue with a focusing lens. Differentsizes of lenses are available for different sizes of transducers.When selecting focusing lenses, factors such as good impedancematching and low-attenuation loss properties should be consid

ered.Degassed water or 0.9% NaCI solutions are used for acoust

ical coupling between the transducer and the body during inson-

ation(18).The attenuation coefficient of tissue increases approximately

linearly with frequency; i.e., the shorter the wave length in tissue,the greater is the attenuation. Therefore, when deep penetrationis needed for deep-tumor heating, a low frequency should be

selected. The size and shape of the focus are also determinedby wavelength. Therefore, a target as small as 1 mm can beselectively heated by ultrasound.

In heating a deep-seated tumor by localized hyperthermia

using ultrasound technique, the longest wave length should beapproximately one-fifth of the dimension (thickness or diameter)

of the tumor (18). Chart 8 shows that in ultrasound techniquemost of the power is concentrated in the region (heating area)with the diameter S, where S is related to the wave length of theenergy X, the depth d (focal length of lens), and the diameter ofthe transducer D and is given by

S = 1.22 \d(cm)

Results from the above equation for a transducer 9 cm indiameter lead to the following (9). For any depth (focal length)smaller than 12 cm and frequently greater than 0.5 MHz, thediameter of the heating area is less than 0.5 cm, which wouldnot be practical for spot size. Ultrasonic power absorption perunit volume of tissue is a function of depth d and is given by

Wa = W<,exp(-2a.â€žd) (watt)

OCTOBER 1984 4741s




- Transducer

Focused Field

Chart 8. Schematic of focusing of energy from the transducer into the tumor(17).

where W0 is initial power incident at the tissue surface and amis the acoustic attenuation coefficient. Ultrasound intensity indepth d is also given by

' = T = TA A

(watt/sq cm)

or

/ = /oexp(-2aÂ«^) (watt/sq cm)

where I0 is the initial intensity and A is the cross-section of the7T-S

focused spot, given by A = -â€” (sq cm) (9,14).

When deep heating is needed, the smallest practical diameterof heating area S (focused spot) should be 0.5 cm; therefore, thearea is equal to

Thus

= 0.196 (sq cm)

/ = 5 Woexp(-2aÂ«<y) (watt/sq cm)

absorbed power per unit volume is given by

P = 2/0amexp(-2aÂ«^) (watt/cu cm)

Remark. For heating a fixed spot size (S = 0.5 cm) of homogeneous muscle with ultrasound at different frequencies, weshould consider the following. For a depth of 2 cm or less, afrequency of 2 MHz or higher is required. For a depth greaterthan 5 cm, a frequency of 1 MHz or less is required. Therefore,for a depth of 12 cm, the frequency of 0.5 MHz is optimal. If theinitial 3 cm of fat are followed by homogeneous muscle, then fordepths of 7 cm or more a frequency of less than 1 MHz isrequired (9).

Translocation

Translocation, or moving the heat source (or focal region), isimportant in the production of hyperthermia by ultrasound because of uniform temperature distribution. Tumors have lowerblood perfusion than do normal tissues, and the lowest appearsto be in their central regions (25). Because more heat can beremoved from a region with higher blood flow (2), depositingenergy evenly throughout the tumor would heat the central region

more and the tumor margin less, due to conduction and bloodperfusion. Since at low temperature heat may well enhance thegrowth and proliferation of a tumor, this situation would createserious problems. Therefore, to raise tumor temperature evenlyto the desired level in the entire tumor, translocation must beused, allowing deposition of enough heat at the periphery of thetumor. With a tumor larger than the heat source, stationary focusor pulsing stationary heat source on and off for production ofeffective hyperthermia is not adequate. Therefore, the heatsource (or focal region) must be moved over the entire tumor fordeposition of heat at different parts of a large tumor.

From the above thermophysical properties of normal tissueand tumors and the length of the trajectory, which depends onthe size of the tumor, the velocity of translocation can bedetermined. Since the generation of heat in tissue is a functionof both local intensity and duration of insonation, in order togenerate more heat in tumors by increasing the local intensitywithout possible focal damage to the tumor at focus, the durationof insonation needs to be decreased. This can be done byincreasing the translocation velocity (17).

Multiple Transducers

To deliver deep heating to large or vascular tumors, it may notbe possible to use a single transducer. By superposition of morethan one beam entering the tissue surface at different points,sufficient power and depth of penetration can be achieved (17).Phase arrays of transducer elements that are being activated insequence can produce a good deep temperature elevation. Twobeams can interface destructively, however, if they are out ofphase where they overlap. Consequently, the heat generationmay be lower in the overlap compared to that at the beamsthemselves.

A good example of a combination of multiple transducers andtranslocation is Lele's (18) device, shown in Chart 9. With

steered, focused ultrasound, a spatially uniform level of hyperthermia restricted to the target volume and located at depth can

65432Diameter, cm

j i \ i l i i

Chart 9. Unitomi temperature distribution in beef muscle mass in vitro usingbeams focused at 6 cm depth at 0.9 MHz frequency in circular trajectories (18).




be achieved. This device is based on the conduction and bloodperfusion in tissue and tumors. Two well-focused beams are

moved in circular trajectories, one in the peripheral region of thetumor and the other close to the central region. In experimentation, such a technique resulted in excellent uniform temperaturedistribution at 2 to 7.5 cm of depth at a frequency of 0.9 MHz(18).

Pounds ef al. [from Hunt (14)] used another approach thatwas later followed by Fessenden ef al. (10) in which 6-planar, 7-cm-diameter PZT-4 discs mounted on a 90Â°spherical shell sector

with a 26-cm radius of curvature were utilized at 0.35 MHz toproduce therapeutic heating up to a depth of 15 cm.

Advantages and Disadvantages of EM and Ultrasound Techniques

EM Technique

Advantages. Since EM energy can propagate through air, inthis technique coupling is not required.

Due to the presence of air within and in the vicinity of areassuch as the lungs, stomach, bowel, bladder, rectum, and pelvis,the use of EM technique is suggested for cancer therapy inthese regions.

EM energy is not hindered by bones. Therefore, this techniquecan be used for treatment of cancer in the chest area and allportions of upper and lower extremities.

The preferred approach for brain tissue heating is microwavewith single or multiple external beams.

Microwave radiation can penetrate deeply into low-water-

containing tissue, like fat, and since the breast is composedlargely of fat, deep penetration for cancer therapy is possible.

Large volumes can be heated with multiple applicators orphase-array microwave.

Producing microwave power is relatively inexpensive as aresult of the commercialization of the microwave ovens.

Mechanisms of interactions of microwaves with biological tissue are reasonably understood. This allows a better design ofsafe and effective hyperthermia systems.

It is relatively simple to control the power output of a microwave generator.

Depending on the type of treatment, there are different methods of induction of hyperthermia by EM system. These arenoninvasive and invasive methods. Noninvasive methods canalso be divided into simple and multiple-applicator techniques. In

invasive methods, the objects can be either implanted in thebody or inserted into a body orifice.

Disadvantages. EM waves are absorbed by water-containing

tissues and cause excessive heat elevation due to both higherabsorption and lower heat dissipation. Thus, there are potentialhazards for the EM technique in hydrate tissues or in tissuesclose to the organs containing or surrounded by fluids, such asthe heart, stomach, and spinal cord.

Depth of dose is limited to a few cm by using a singleapplicator, particularly with microwaves.

The fat near the fat-muscle interface may overheat due to

large reflections. These reflections may generate standing wavesclose to the fat surface.

Focusing is difficult at low frequencies.Interaction with metal temperature-measuring devices is pos

sible.


There is a potential danger to patients using pacemakers.

Ultrasound

Advantages. Deep penetration of controlled beams up to 12cm is possible.

Tumors absorb ultrasound energy better than does normaltissue, as compared to EM energy.

Excellent focusing is possible because the wave lengths aresmall compared to the diameter of their source.

The acoustic impedance of most of the body fluids is close tothat of the soft tissue, and absorption in the fluids is lower thanthat in the tissues. Thus, there is no possibility of excessiveheating.

There are no significant reflections at the interfaces betweenfatty and muscle tissues.

The method is noninteractive with thermometry devices.Imaging and thermometry are possible with ultrasound.No special radio frequency-shielded room is required.

Disadvantages. There is high absorption in bone, causingbone heating.

Reflection between bone-tissue interfaces is large.

Reflected energy cannot be refocused within the soft tissue.Potential problems lie with cavities containing air. Acoustic

impedance mismatch between air and soft tissues is very high,and energy is completely reflected at air-tissue interfaces, be

cause there is no transmission through air cavities.Ultrasound is not suitable for lung, abdominal, or brain cancer

and also not recommended for deep heating in extremities.Coupling medium is required.

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1984;44:4736s-4744s. Cancer Res Augustine Y. Cheung and Ali Neyzari Electromagnetic and Ultrasound TechniquesDeep Local Hyperthermia for Cancer Therapy: External

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