0159_hyperthermia 15.pdf

8/14/2019 0159_HYPERTHERMIA 15.pdf

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15Hyperthermia

Car los A. PerezB a h .n a n E m a m i

G ilbert NussbaumStephen Sap areto

R A T I O N A L E F O R C L I N IC A L U S E O F H E A TThe effect of heat on malignant tumors w as first reported byHippocrates. In 1856 Busch8 described the disappearanceof a soft tissue sarcoma following high fever m a patientwith erysipelas. Later, Coley14 induced fever by injectingbacterial toxins, and W estermark18~ used localized hyper-thermia to produce tumor regression in patients. W a r re n1~reported 32 patients with advanced cancer of various typestreated with a combination of heat. induced with pyrog enicsubstances, and x-ray therapy. Twenty-nine of these patientsimproved for 1 to 6 m onths.In the past 10 years interest has been rekindled in theclinical application of this modality because numerouspapers have indicated that there may be a significant advan-tage to the use of heat alone or combined with irradiationand cytotoxic drugs to enhance the killing of tumorcells.22"2~4~156 The clinical use of heat has been hamperedby a lack of ad equate equipment to d eliver effective heat indeep-seated lesions and of thermometry techniques thatprovide reliable informanon on heat distribution in targettissues. However, significant t~rogress has been m ade.About 30% to 50% of patients with solid tumors haverecurrences at the primary site. Many of these patients haveregional lymph node recurrences. Both failure patternscould be improved if effective radiation sensinzers aredeveloped.n viiro and it: vivo experiments strongly suggest thatheat may be more damaging to tumors than to normal tis-sues for several reasons: (1) hypoxic ceils may have anincreased sensitivity to heat (they a re at least as thermosen-sitive as oxygenated cells;23 (2) metabolically deprivedtumor ceils with reduced pH are more heat sensitive; (3)heat affects ceils in "S" phase, w hich are known to be resis-tam to irradiation: and (4) blood flow in the tumor is re-duced.2a23*s Heat causes a greater degree of m itotic delaythan irradiation, and this factor may affect the distribution ofcells in the cell cycle after heat or x-rays. 2 ~ ~ *The heat sensitivity of hypoxic cells is complicated bythe possible association of low oxygen tension with nu-

trient deficiency or reduced pH. As Dew ey and colleagues2spointed out, the response of the tumor may be affected byphysiologic changes associated with lowering of the bloodflow and oxygen tension produced by the hyperthermia.H a h n~ has demonstrated in vitro the additive or syner-gistic cell killing effect of a com bination of heat and a vari-etT of chem otherapeutic agents. Further, the cyxotoxic ef-fects of hypoxic sensitizers alone or combined withirradiation can be enhanced by heatOvergaard and Overgaard~a~ observed in a mousemam mary carcinoma treated with 27 MH z microwaves thatthe central portion of the tumor was more severely dam-aged than the periphery. This supports the use of combinedirradiation and heat, hyperthermia being especially effec-tive against centrally located hypoxlc ceils and irradiationeliminating the tumor cells in the periphery of the tumor,where heat w ould be less effective. In experiments done ona transplanted mammary carcinoma, Overgaard reported nocures with 1600 cGy (single dose), 22% with heat alone(43C, 60 minutes), and 77% wh en the two m odalities withthe same factors were applied.Localized or regional hyperthermia may b e an effectiveadjuvant in tumor control when combined with irradiation.An area in which hyperthermia may be quite useful, per-haps alone at high temperatures (45C) or at 43C com-bined with moderate doses of irradiation (3000 to 4000cGy) is the treatment o f patients with recurrences followingdefinitive radiation therapy (6000 to 7000 cGy). Likewise,since grow ing tissues are more sensitive to irradiation khanmature organs, it may be possible that a combination ofhyperthermia with cytotoxic agents .or the combination ofthese modalities with low doses of irradiation may be ef-fective in the treatment of pediatric neoplasias, which willresult in decreased grow th disturbances.Who le-body hyperthermia has been used for the treat-ment of disseminated disease, alone or with chemothera-peutic agents,lxx2*a~2 It may have potential value not only inthe treatment of overt m etastatic disease but perh aps lateras an adjuvant , combined w ith chemotherapy for the treat-ment of micrometastasis.

317


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318 Principles and Practice of Radiatkon OncologyBIOLOGIC ASPECTS OF HYPER~EI-IERMIADespite the publication of mare: reports on biomolecularmechanisms by which heat ki~ls ceils, no consensus hasbeen reached. Three maior m~ chanisms for the heat inacu-vanon of cei ls have been pr . ,posed:1. Cellular membrane dg, mage, with changes in its perme-ability, composition, or fluidity, ultimately leading to thedeath of the cell.vs Heat eff{cts on membrane fluidityhave been implicat.ed by the observed interaction of heatwith membrane-vnodifying drugs; both alcohols9"~ andlocal anesthetic5ls6 have been shown to cause ~ncreasedsensitiwtv to beat. Cress2I. in a study of several in vitrocell lines, ha.s shown an inverse relationship betweencholesterol to phospholipid ratio and heat sensitivity,while Anderson1 observed a direct correlation betweencholesterol to phospholipid ratio and adaptation of cellsto growth at temperatures from 32 to 41 C.2. Dam a.ge in lysosomes of the cellular cytoplasm, as sug-gested by Overgaard.n~ Disintegration of these lyso-som e vesicles and damage by the released digestive en-zymes might be the cause of cellular death. Reports ofbiochemical evidence of increased lysosomal enzyme

activity in heated ce ls~,~a~ lend support to thishypothesis.3. Thermal dam age to prote ins , suggested by Tomasovicand associates~6s and Roti Roti.~: They have both re-ported an increased, nonspecific attachment of nonhis-tone nuclear proteins to DNA following heat; however,this phenomenon shows only limited correlation to heatkilling and more likely is important in preventing repairof radiation dam age,a~ as discussed later. Other investi-gations implicate heat effects on a number of proteinfunctions, such as DNA ,s~a~s RiNA,~v9 and protein*~ syn-thesis, and respiration,nAs show n in Figure 15-1, CHO cells exposed for various

times to temperatures ranging from 41.5 to 46C are killedappearcells to heat exposure be- and 43C. This can be more readily seen in anhe logarithm of l/D0 (Fig. 15-2), whereeduce survival by 1/e on the

1~-1. Survival curves for asynchronous Chinese hamster

lO10-I

10-4

\ _ N\4~D% k osynchronous~43.5 k42 5C

~x 46+5o c10-5 t t I ~ I0 2 ~ 400 500 600 7Time of immers ion (min)

exponential portion of the curve as a fun ction of the inverseof temperature.T h e r m a D o s eThe analysis of cell killing by heat provides the followinginformation: (1) Above 43C the points fall on a straightline. indicative of cell killing by a single mechanism in thisrange of tem peratures. (2) Below 43C, this m echanism isaltered such that the rate of chang e in cell killing as a func-t ion of temp erature increases (see discussion o n therm oto-lerance). (3) The slopes of these lines indicate that above43C a 1 increase in te, gnperature will reduce by a factor oftwo the time o f heating required to achieve the same effect;below 43C an increase in temperature of 1 C w ili require areduction of time by a factor of four to obtain the sameresult.This relat ionship can be d escribed m athematicalJy as:

(t~ ) = R( T I - T a)t2R = 0.5 for T > 43C

where R = 0.17 for T < 43CThe "t" and "T" represent time and temperature, respec-tively, for equivalent treatments. The validity of this rela-tionship has been demonstrated for a number of celllines~52~ and in fact is also observed in vwo as shown inFigure 15-3. This graph is similar to an Arrheniu.s plot andFIGURE 15-2. An Arrhenius plot of heat inactivation with theinverse of the Do values taken from the maxim um slopes obtainedat various temperatures as a function of the inverse of tempe raturefor various published in vitro data. (Henle KJ, Dethlefsen LA. AnnNY Acad Sci 335:234, 9806~)

i I I

io

g t o - ~

//

/:

I0 i85 ~ .175 3.16~ + . I+55 ~ .145 3.13,5 :~ .1~5 ~ ,115l iT [x O "3 )


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T IME T EMPERAT URE RELAT IONOF SOLID TUMORS IN VIVO

I I I I4] 4 2 4 5 aaTE M P E R A TURE C 45 46

MGURE 15-3. Time-temperature relation required to cure mur-le= tumors an vavo obtained by various investigators. The timesca]e is in relative units owing to the different hea t sensitivities ofthe tumors. (Streffer C ed]: Cancer Therapy by Hyperthermia andRadiation, p 49. Munich, Urban & Schw arzenberg, 1978)shows both a change in response at 43C and an R value of0.5 above 43C. the same as observed in vitro.Field4~ has also compiled a summary of published dataon in vivo thermal response of both tumor and normaltissues and has shown that for 15 biologic systems the re la-tionship described in Equation 1 is valid both above andbelow the break temp erature. Ahh ough the relationship be-tween t ime and temperature shown in the equation is val idin the majority of the cellular and animal model systemsstudied, it does not indicate that these systems all show thesame sensitivity to heat. In fact, orders of magn itude differ-ences in actual cell survival have been sho wn fo r differentcell lines from the sam e heat exposure.I~The observation that Equation 1 is valid for all in vivonorm al tissues as well as almost all tumors tested suggeststhat l[ may be used to equate thermal doses at differenttemperatures to express the same thermal effect. Such amethod, which converts a thermal exposure to an equiva-lent exposure at an arbitrarily chosen reference tempera-ture of 43C, has been reported by Sapareto and Dewey.14This method may be used to construct a nomogram (Fig.15-4), which may b e used to determine an equivalent ther-mal exposure t ime between any two temperatures by con-version, to the reference temp erature.This concept has been shown to be a good prognosticindicator by Dewhirst and co-workers2 for spontaneoustumor treatment in dogs and cats when the thermal dosecalculated for the coolest part of the treated tumo r is used(Fig. 15-5). These results indicate that equivalent minutesexposure was the best predictor of long-term tumor re-sponse. A number of factors still must be evaluated andtheir importance resolved before general acceptance of thisconcept is warranted. These factors include: (1) the tem-perature of the transition or breakpoint, (2) the R valuebelow the breakpoint , (3) the effect of step-dow n h eating,(4) the effect of thermotolerance, (5) the effect of the in-teraction and irradiation on Equation 1, and (6) the impor-tance of blood flow an d other physiologic factors.Intrinsic differences in survival between norma andmalignant cells have been suggested or reported by a num -ber of investigators. In early in vivo studies Overgaardla3observed that exposures over the range of 41.5 to 43.5Ccaused little histologic damage in normal mouse tissue but

50

5OO I000=

Chapter 15 HyperthermiaT

5 00

5 O

- IO5

319

FIGUR E 154. Nomogram for equivalent-minute calculacion of43C (t4~). (Sapareto SA. Dewey W C: IntJ Radiat Oncol Biol P hyst0:787, 1984~ 4 )

0.400.300.20.0.10

Total Fail7 4-34 Ea 435 o ;~ 35 EQ 43 ICl)a vs a Logrank p = .006. Wllcoxonb v$ 0 LogranK P =.014, Wilcoxon o = .022

0 15 30 45 60 75 90 105 120T i m e a f te r t re a tm e n t (we e k s )

FIGUR 15-5. Response duration as a function of minimumvalue obtained on the first heat treatment. The response d urationincreased significantly when greater than or equal to 35 Eq4~ (d)was obtained compared with no heat [XRT alone (a)] or less thanor equa to Eq~ (b). Tumors with intermediate heat dose values 14to 34 Eq4~ (c)] fell between the two extremes. (Dewhirst MW, SimDA, Sapareto SA. et al: Cancer Res 44:43, 198426)

resulted in severe damage to mammary carcinoma. How-ever, possible temp erature differences between tum or andadjacent normal tissue complicate these studies. Giovan-ella, investigating both mouse cellss~ and human cells invitro,s" found that ceils derived from normal tissues wereless heat sensitive than are malignant cells. In his humanstudies he found this to be true when he compared mela-noma, colon carcinoma, malignant neuroepithelial, and fi-brosarcoma cells each with norm al cells of comp arable his-tologic type. However, these results were based on thenumber of attached ceils 3 to 7 days after treatment and thusmay indicate the heat sensitivity of attachment rather thanproliferative ability. In addition, clonogenic studies have


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320 Principles and Pract ice of Radi~a tion Oncologyshown that normal tissue-derived ceils in culture are lesssensitive to heat than are maligrxant ceils either tissue de-rived or transformed in vitro.93~9 In con trast. Harisiadis62noted that rat hepatoma ceils were less sensitive to heat(42 to 45C) than were normal rat liver cells Evidencedoes not clearly show that all malignant cells are intrinsi-cally more h eat sensitive ".nan are norm al cells.THERMOTOLERANC,E AND STEP-DOWN I-IEATINGIt frequently has b;een reported that mammalian ceils aresubstantiallv mo re_, resistant to heat following a p rior heatexposure.6(Hen.~m68 reported that cells initially exposed to45C became resistant to subsequent exposure to 45C ifallowed a 10- ~o 20-hour period at 37C between treatments(Fig. 15-6).Thermotolerance is a transient phenomenon and thusdoes n ot represent a selection of genetically resistant cells.Such selection, shown only for pig kidney cells63 and more

FIGURE 15-6. The development of thermotolerance inasynchronous CHO ceils at various times after an initial heat doseof 45C for 17.5 m inutes. The top abscissa shows the scale for theinitial heat treatment; the bottom absciss~ shows the duration ofthe second heat dose at 45C.6~ This phenomenon, termed tber-motolerance, also is observed during continuous heat exposure attemperatures below 43C. Evidence suggests that these two re-sponses represent the same biologic mechanism. (Spiro IJ, Raa-phorst GP, Saparato SA, et at: Int J Radiat Oncol Biol Phys [inpress]x55)1000 10 20min.ot 450IZSmin. (4511)+T(37EI)+T(450) :-:

10-1

10-5

ra=12hr

10-40 20 40 60HYPERTHERMIA, min. at 45 8O

recently for Chinese hamster cells.6~ occurs at too low afrequency to account for this phenomenon.The mechanism for thermotolerance is not known:however, protein or RNA synthesis must occur before ther-motolerance can develop.84 Studies have suggested that thechange in slope observed in an Arrhenius plot below 43Cis indeed due to thermotolerance, as was previously sug-gested,x~3 Both Henle6s and Li and colleagues9a have indi-cated that prior exposure to temperature above 43C imme-diately eliminates the break in the Arrhenius plot for ceilssubsequently exposed to temperatures from 41 to 45C.This phenomenon has been termed step-down beating.Also. Li and colleagues9~ have shown that thermotoleranceis inhibited for several hours immediately following expo-sure to 45C.

H E A T S H O C K P R O T E I N SThe pheno meno n of thermotolerance appears to be closelyrelated to the induction of a class of proteins pol},,pepddesof molecular weights in the range of 25r. to 110K dal-tons.8295~62 These "heat shock proteins" kave been wellcharacterized as a gene transcription phenomenon ,n Dro-sophila m elanogasteta:; however, their function is un-known. A good correlation exists between the increasedinduction and degradation of these constitutive proteinsand the induction and decay of thermotolerance (Fig.15-7), whether induced by heat shock or o ther toxic stressphenomena.96

HEAT INTERACTION WITH IRRADIATIONAND CHEMOTHE.RAPYInvestigations of the interaction of heat and irradiation havereceived as much attention as studies on the effects of heatalone and several good reviews on this subject are avail-able.=~a8a~ A num ber of observations suggest that the com-bination of heat and irradiation is of potential benefit incancer therapy. The first and most generally observed phe-nomenon is that heat radiosensitizes cells.Z~4~a4-4 Most re-ports observe that the maximum increase in the slope of theradiation survival curves is 25% and that ceils in S pha se aremore radiosensitized by heat than are cells in G~ .~4~The cau se of this radiosensitizati on has not been firmlyestablished; howev er, it is believed that the accum ulation ofnon-histone proteins, which bind to DNA following heat

F I G U R E 15-7. Correlation be-tween heat shock protein synthe-sis (A) and thermotolerance (B)for Chinese hamster ovary cells.(Subjeck JR, Scianda JJ, Chao CF,et aI: BrJ Cancer 45:127, 1982~62)lOCi

B

H S P 6 8

t t ~ t t I 10-5= t J = ~ ~ I I I I I I I6 6 10 ~2 14 16 ~ 4 1~ 4 6 8 10 12 14 16 18 ~ ~ 4TIME A~ER HEAT (H) TIME A F TE R H E A T S H OC K (H )


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treatment, prevents the cell from repairing radiation dam-age. This hypothesis is supported by several observations.First, the interaction between heating and subsequent radi-auorf exposure persists for about t2 hours between treat-ments. This coincides with the return to normal of DNA-to-non-histone protein ratios.I3 Second. the ability forenzymatic repair of irradiation-induced thymine damage isinhibited when chromatin is heated but not when only theenzyme is heated,lsI Third, there is a linear increase both inthe amount of no n-histone protein at tached to DN A and inthe inhibition of micrococcal nuclease digestion of chro-matin into fundamental nucleosomal structures which sug-gests that access to the sites between nucleosomal struc-tures is blocked3s2An other factor of possible clinical relevance is the factthat cells in G~ are less sensitive to heat than are cells in Sphase, while the opposite is true for cellular sensitivity toirradiation (Fig. 15-8). However, this effect may not be ap-parem,if the lethal effect of one modalitv is much greaterthan that of the other,e since Westra~s4 noted that the mag-nitude of the difference in sensitivity between G1 and Sphase is reduced as the severity of the heat exposuredecreases.Timing of Irradiation and Heat AdministrationOne m ust carefully consider the sequence of app lication inorder to combine heat and irradiation effectively. Li andco-workers94 reported little difference in survival of CHOcells for either order o f treatment when heat and irradiationwere adm inistered with minim al separation. How ever, theirresults may d epend on m any factors, such as pH,46 tempera-ture. and duration of exposure.86 A nu mber of studies haveshown that in general heat-induced radiosensitization is

I R G U R 15-8. The variation in the survival of CHO cells follow-ing exposures to either heat (45.5C for 6, 10, or 15 minutes) orirradiation (600 cGy). (Westra A, Dewey WC: Int J Ra diat OncolBiol Phys 19:467, 1971ls4)

Ho urs after plating m itotic cells

Chapter 15 Hyperthermia 321maximum when the two modalities are given simulta-neously (Fig. 15-9),~21A42"~sv However. simultaneous administration is not necessarily the best proto col for therapeutictreatments because tumor cure will improve only if cyto-toxicity to tumor cells is enhanced to a greater extent thanthe effect on norm al ceils.Dewey and co leagues25 and Sapareto and associates~have show n that when h eat and irradiation are administeredtogether to cells in vitro there is a greater cell kill thanwhen h eat is delivered more than 30 m inutes before or afterirradiation.Dewey and co-workers2~ have hypothesized that if heatis delivered 3 hours before irradiation, ceils with a low pHwill have minimal ability to repair heat damage and there-fore mav be greatly sensitized to the effects of subsequentirradiat ion. Hil l and Denekam p.7 Field,42 and Overgaarstrongly su ggest that wh en there is preferential (selective)heating of the tumor in relation to the normal tissues, theoptimal time for administration of the two modalities issimultaneous. However, when the temperature in thetumor and the normal tissues ts the same there may be atherapeutic gain only if heat is delivered four hours orlonger after irradiation (Fig. 15-10).The interaction between heat and irradiation does notshow the same t ime-temperature relat ionship as does h eatalone. This is borne out by both in vitro and in vivo studies.83A44 When heat doses at various temperatures adjustedto achieve the same amount of cell killing are combinedwith a radiation exposure, the survival of ceils for the com -bined treatment is not the same at all temperatures. Maxi-mal effectiveness is seen near 42.5C, suggesting that theremay be an optimal temperature for combined modalitytreatment.Mittal and associates~s carried out experiments intransplanted R IF-1 fibrosarcoma in the flank of C3H m~ ce.Tumors were treated with fractionated x-rays (400 cGytwice weekly X 0) alone or in combination with heat (RFcurrents, 43C, twice weekly). Heat treatments were d eliv-ered before, in conjunction with, or after the fractionatedradiation therapy. Animals treated with irradiation alone orwith the heat an d irradiation delivered with sequential frac-tionation (all heat sessions given befo re or after irradiation)exhibited a 20% cure rate. In anim als treated w ith "simulta-

FIGURE 15-9. The variation in survival of asynchronous CHOceils as a function of the sequence of irradiation (400 cGy) an dheat (42.5C for 17.5 minutes [ or 40 m inutes [~]). (Sapareto SA,Raaphorst GP. Dewey WC: Int J Radiat Oncol Bio Phys 5:343,1979TM)~ x xA [Asynchronous CHO

~ 500 cGy; 42.5C (17.5 or 4 0 rain)

10-z .... ,~,......... ifII 9 7 ~ 3 ,o ,~o 0 ~o eo 3 5 7 9Hrs before &(X --~ A) (min) Hrs after G(& -+ X


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322 Principles and Practice of Radiation OncologyX-raysHeat before He at after

Tumor

Skin

I I I I I I I I I I I I5 4 5 2 1 o ] 2 5 4. 5 6Time between x-rays and he at (hours)Thermal enhancement ratio as a function of theIGURE 15-10.time interval between heat and irradiation. The solid line repre-sents skin data of Stewart and Denekamp.156 = TER values forfibrosarcoma at 20-day regrowth delay, that is, at the same x-ray

dose as that used for skin. (Stewar~ FA, Denekamp J: Br J Radio]51:307, 1978ls7)

Table 15-1Hyperthermia and Interaction With Drugs1. Drugs with no temperature threshold effect..ThiotepaNitrosourea group: BCNU. CCN U

Cisplatin(Probably suitable for systemic hyperrhermia)2. Drugs with a temperature threshold effect, about 43C. before a

major potentiation is observed:BleomycmAdriamycinActinomycin-D(Probably suitable for local hyperthermia)

3. Drugs not normally cytotoxic at 3 7C but that cause considerablecell kill above a threshold temperazure:AlcoholsAmphotericin-BCysteamineAET (2-amino-ethyl-isothiourea)-- Cysteiffe

neous" combination of both modalities (heat delivered thesame day as irradiation, immediately after x-ray exposure),the cure rate was 70%.

Thermo-Chemotherapy

promise in combination with other conventional moctali-ties, such as irradiation or chemothera_j~ thermo-chemo-therapy is far from being understoo~Hahn and col-leagues66~ have reported on the inter~ei~n of heat with avariety of cy~otoxic agents. The type of drug, dose. tempera-ture, and time of administration of the agents are all impor-tant factors in determining cell kill by combinati on of theseagents.59.~00Three types of drug interactions have been categorized(Table 15-1).~ The first are drugs that show an increase ineffectiveness with increased temperature, even those below42C. Examples of these drugs are several of the alkylatingagents, such as nitrosoureas.~ The second category of drugsseem to show increased effectiveness only above a thresh-old temperature value; for example, bleomycin~ shows athreshold for interaction with heat at about 43C. The thirdcategory are those drugs that are normally not considered ofany value therapeutically at 37C but that show significantkilling ability at elevated temperatures. Amphotericin-B, apolyene antibiotic, is in this category.Agents in the first category would be effective for usewith whole-body heating, in which temperatures cannotexceed 42 C. The second category of drugs would be use-ful for local hyperthermia, in which heat treatments areexpected to exceed 43C. Drugs in the third category mightaiso be classified in the previous two categories, most likelythe second category; however, it is a class of drugs that maybe diliicult to find, since they would fail conventionalscreening attempts at 36C.Although many drugs show increased effectivenesswhen combined with hyperthermia, the great variety inmechanism of drug killing precludes the idea that heat anddrug interaction is a simple unilateral phenomenon. In fact,

in the case of Adriamycin6 and actinomycin D.29 As heatingduration increases, cells in culture become highly resistantto killing by either drug. This may be caused by heat-in-duced alteration in drug transport into the cell.4 ~Thus, although enhanced d rug effectiveness is clearly adesirable effect on cancer chemotherapy, the subject ofthermo-chemotherapy has barely been touched on; it is tobe hoped that thermo-chemotherapy wil one day provideimproved cancer control and increased understanding ofdrug m echanisms of act ions.PHYSIOLOGIC MECHANISMS IN HYPERTHERMIA~ [icrovasculature of Normal TissueThere is great variation in the microcirculation of differenttissues such as striated muscle, skin, and so on. Nevezxhe-less, there is regularity in distribution within a specific tis-sue.s~ In a typical "model" all exchanges between bloodand parenchymal cells take place at the capillary level (mi-crocirculation). True capillaries in normal tissues have adiameter close to that of an erythrocyte (7 to 10 microns)and walls consisting of three layers: endothelium, base-ment membrane and pericytes, and adventitia.

Microvasculature of TumorsIn general, at an early stage of tumor development thetumor cells probably survive and proliferate using energyand nutrients supplied through the hosts blood vessels. Asthe tumor g rows, host vessels are occasionally incorporatedinto the tumor m ass. As the demand for nu trients and oxy-gen exceeds the sup ply capacity of the host vessels, a newvascularization in the tumor begins (formation of "buds"and, by confluence, "sprouts"). It has been suggested thatcertain humoral factors are important for the initiation ofthis process (e.g., tumor ang~og enesis factor [TAF] and en -dothelial proliferating factor [EP F]). The capillaries formedby random fusion of sprouts are tortuous, elongated, anddilated and lack basement m embrane2z The flow of blood


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through such a coarse capillaw netw ork is sluggish. A greatproportion of tumor blood does not exchange with blood inthe general circulation (stasis). This intermittent circula-tion periods of sr.asis followed bv resumption of bloodflow--is probably a "normal" feature of the intravasculartransport system o f neoplastic tissues,s6,lv4 Another charac-teristic of tumor vascular network is the abundance of la-cuna-l ike sinusoids and chann els that do not drain prop erly,leading to stasis and thrombosis. The histologic patternsand functional status of vascular networks in malignanttumors vary depending on the type, age, and size of thetumor.176 Rub in and Casarettl~s classified tum or vasculariza-tion into three categories: (1) peripheral. (2) peripheralwith penetrating vessels, and (3) central. The proportion oftumor space occupied by vasculature decreases as thetumor grows.5~167 ~8 TannockI6~ has suggested that thelonger turnover time of endothelial cells--their slower pro-liferation relative to that of neoplastic cells--accounts for{he decline in vascular density. Reduced vascular densitytogether with the sluggish perfusion of blood through the

Table 15-2Vascular Changes Caused by Hyperthermia 43 C for 1 hour)

Blood FlowTissues Control HeatedSkinNormal 7.82 + 0.76 29.13 --+ 3.39Near tumor 14.39 x 3.37 64.61 _ 8.38MuscleNormal 4.97 + 0.55 14.61 _ 1,75Near tumor 10.26 ___ 2,71 28.45 + 2.12

The values are means of more than 10 determinations standard error .The weights are net weight.(Song CW. Kang MS, Rhee JH, et ai: Radiology 137:795, 1980)

Chapter15 Hyperthermia 32capillaries may account for the decrease in total blooflOW.152,174

Effect of Hyperthermia on NormalTissue MicrocirculationIn studying the effect of hyperthermia on normal tissuvascular function, a distinction should be made betweenormal tissue adjacent to the tumor and normal tissue fafrom the tumor. Song an d associates~5~ have observed thathe blood flow of skin overlying the tumor and of muscnear the tumor is more than twice that of the skin andmuscle far from the tumor. They attribute this phenomenoto inflammatory processes near the tumors. There was asignificant increase in the blood flow in skin and muscboth near and far from the tumor upon h eating to 43C for hour~5s (Table 15-2). It is interesting to note that the manitude of increase was h igher in the norm al tissues adjacento the tumor than in the tissues far from the tumor. Thblood flow rate in both skin and muscle returned to normlevels within 2 hours after cessation of h eating.The dynamic changes of skin and muscle blood floware both time and temperature dependent (Fig. 15-tl). Asshown , the time that it takes the skin blood flow to reach itmaximum before declining for temperatures of 43, 44 ,and 45C are 120, 30, and 15 minutes, respectively. Notthat peak blood flows are different for various time-temperatures. Similar trends have also been observed in muscleblood flow.Effect of Hyperthermia on Tumor MicrocirculaHyperthermia at modest temperatures (up to 40C) hasbeen shown either to have no effect57a5 or to increasetumor blood flow.53s~7~ Bicher,5 Eddy,3~ Vaupel.~7~ andrich~ found significant decrease in tumor blood flow du ring the course of hyperthermia at tempera tures in the ther-apeutic range (42 to 45C). Song and associatesls~

120

100Skin Musc le

FIGURE 15-11. Changes in bloflow in the skin and muscle of normal leg of SD rat during heatingvarious temperatures for 12minutes. (Song CW: Cancer Re44(suppl):4721s, 984~)

Heating time ( m i n )


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324 Principles and Practice of Radiation OncologyTable 15-3Temperatures Causing Significant Reduction of Blood Flow in Various Tumors

TemperaturesAuthor (Reference) Tumor Animal o C )Song et al?5 Walker carcinoma 256 Rat 43.5Emami et al ~s BA-11 t2 rhabdomyosarcoma R a t 42.5Endrich et a1.40 BA-1112 rhabdomyosarcoma Rat 40.0Reinhold et al x36 BA-1112 rhabdomyosarcoma Rat 42.5Von Ardenne et al . DS carcinosarcoma Rat 41.0Vaupel et al.IV3 DS carcinosarcoma Rat 42.0Dickson et at.a 7 Yoshida sarcoma Rat 42.0Song et al.~ 3 SCK mamm ary tumor Mouse 40.5Sutton et al.1 6 s Ependymoblastoma Mouse 41.0Bicher et al.s Mammary adenocarcinoma Mouse 41.0Eddy et al .~ Squamous cell carcinoma Hamster 41.0

noticed no significant change m tumor blood flow inWalker rat tumors during heating at 43C but observed asignificant decrease in tumor blood flow after terminationof hyperthermia at 45C.Emami and colleagues3s reported that hyperthermia atmodest temperatures (40 to 41C) caused either nochange or a slight increase in tumor blood flow in a rattumor. At higher tem peratures there was a temperature-de-pendent reduction in the tumor blood flow after heating.The vascular damage was irreversible after heating at 43 to 45C.Eddy and co-workers34 reported that tumors heatedtwice at 42C for 30 minutes, with heating periods sepa-rated by different time intervals, had complete cessation ofblood flow at the end of the second heating when it wasgiven 1 hour after the first heating. When the intervat be-tween heating w as increased to 5 or 24 hou rs, the effect ofthe second heating was significantly lessened.Table 15-3 summarizes the results on effect of hyper-

thermia on tum or blood flow reported by several invest iga-toi:s. It should be stressed that the temperatures at whichblood flow is reduced or vascular damage is induced aregenerally lower than those causing the sam e phenom ena inmost n orm al tissues.In most animal tumors blood perfusion deteriorateswhen heated for 30 to 60 minutes at 41 to 43C. On theother hand, blood flow in the skin and muscle of SD ratsincreased by a factor of 8 to 10 during h eating at 43C, andskin blood flow of W ister rats increased as much as 20 timesat 43C.3~.1~2 R elative changes of blood flow as function oftemperature are shown in Figure 15-12.The effect of hyperthermia on the m icrocirculation wasaccentuated when additional treatments were combinedwith hyperthermia. Eddy and associates~4 combined hy-perthermia (42C for 30 minutes) with irradiation (2000cGy) and found that the changes in tum or circulat ion w eremore prominent than those caused by heat alone. Bloodflow ceased com pletely wh en hyp erthermia and irradiationitantly, whereas such a response did notrradiation and heatinghen irradiation was g~ven after heat. Theeffect on the heat-induced change in1~ observedthio-D-glucose or misonidazole combined with mo d.

T umo r

3 8 39 40 41 42 43 44 45 46 47 4 8Temperature o C( ~H ea t ing f o r 30 40 Min }

FIGURE 15-12. Relative changes in blood flow in the skin andmuscle of SD rat and in various animal tumors at different tempera-tures. Note: Values in this figure are the relative changes of bloodflow as functions of temperature and are not the changes in abso-lute values of blood flow. (Song CW: Cancer Res 44(suppl):4721s,1984~4~)

alone. Hyperglycemia by itself can reduce or completelyabolish tumor blood flow?A pathologic study by Emami and colleagues37 con-firmed the physiologic findings described above: no spe-cific changes in microvasculature were observed with tem-peratures up to 40.5C. However, at 42C blood vesselsbecame dilated and were packed with red cel ls (stasis). Attherapeutic temperatures, massive hemorrhage, coagulativenecrosis, and rupture of blood vessels were evident. Thisstudy has shown that the vascular damage beco mes increas-ingly severe if a tumor is left in situ after termination ofhyperthermia. This phenomenon correlates well with thedelayed cell death that has been observed by Song andcolleaguesTMand Fajardo and associates.4~Effect of Hyperthermia on Intratumor pHThe pH of arterial blood is 7.4 and that of venous blood andinterstitial fluid is 7.35. Intracellular pH usually ranges be-tween 6.0 and 7.4 in different cells, averaging about 7.0.ss


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Recent studies have shown that there is no significant dif-ference between the intracellular pH of normal cell linesand that of their malignant coun terparts.7.Song and co-workersls3 and Bicher and colleagues~have shown that hyperthermia triggers an immediate andsignificant decrease of the pH in tumors. Song and co-workersls3 reported that the pH in SGK tumors of mice de-creased from 7.05 to 6.67 when the tumors were heated at45.5C for 30 minutes. When heating was terminated, thepH rose to 6.78 but decreased to 6.5 to 6.6 when the tum orswere reheated (Fig. 15-13).Recently, Ryu and associates139 observed that the lacticacid content in mouse tumors significantly increased uponheating. Streffer and colleagues161 also reported that hy-perthermia caused an increase in the amount of lactic acidas well as of fl-hydroxybutyric acid in mouse tumo rs. Thus,it appears that the lowering of tumor pH caused by hy-perthermia results from an increase in the acidic metabo-tires. Indications are that acidic conditions not only en-hance the heat killing but also inhibit repair of thermaldamagels~ and development of thermotolerance,s~l=

Role of Blood Flow in the Combined Use ofH y p e r t h e r m i a a n d O t h e r M o d a l i ti e sIndications are that the hypoxic cell fraction in a tumorincreases as a result of vascular dam age, despite the heat-induced death of previously hypoxic ceils. Song and co-workers~s4 found that the proportion of hypoxic ceils inSCK tumors was about 45%; it increased to about 95% at 5.hours after heating of the tumors at 43.5~C for 30 minutes.The pro portion of hyp oxic cells started to decrease thereaf-ter, probably because of the death as well as reoxygenationof hypoxic ceils, but the proportion of hypoxic cells 48 to72 hou rs after heating was still greater than that in the un-heated tumo rs. In contrast, partially hyp oxic norm al tissuesmay be better oxygenated by an increase in blood flow,causing an increase in radiosensitivity. These facts strongly

FIGUI~ 15-13. A histogram representation of tissue pH levelsobtained in C3H mammary tumors. A total of 96 determinationswere made at normal temperature; 108 measurements were madeafter 1 hour of 43C microwave h yperthermia. Mean values ofpHobtained in the control and 43C hyperthermia group w ere ~6.75and 6.2, respectively. (Bicher HI, Sandher TS, Hetzel FW: Int JRadiat On,vol Biol Phys 6:867, 19806)

~ 2O

10

o5. 6 7: 2

~ normothermia (n=96).... after 1 hour of 43~ hygerthermia (n=108)

I 610 6 .4 6 .8t issue g H

Chapter15 Hyperthermia 325suggest that the therapeutic gain m ay be greater if radiationtherapy is applied before hyperthermia rather than viceversa. Alternatively, Overgaard and N ielsen1= and Deweyahave hypothesized that hyperthermia may be used as anindependent modality and not as a radiosensitizer, thus se-quential timing would be insignificant.BASIC PRINCIPLES OF PHYSICSAND INSTRUMENTATIONThe primary goals of clinical hyperthermia must be trment accuracy, reproducibility, and safety of patients apersonnel. To attain these go als, it is necessary to assem bsuitable devices for the production and measurementelevated tem perature distributions at desired sites. It is anecessary that satisfactory thermal treatment planning clinical thermom etry facilitate effective use of the phyagents employed and permit the thermal state of the heattissue to be adequately described. Accordingly, instrumetation of clinical hyperthermia is concentrated in the lowing areas: (1) power depo sition, (2) thermom etry, (treatment planning, and (4) safety.Power DepositionThe physical agents employed for power deposition inlocal clinical hype rthermia are (1) electromag netic irradia-tion at very high and microwave frequencies (300 to 2450MHz), (2) electric and magnetic fields at radiofrequencies(0.1 to 27 MH z), and (3) uhrasound at frequencies from 0.3to 3 M Hz. The m ain characteristics of these moda lities aresumm arized in Table 15-4.For a given applied power, the temperature-versus-time curve during the very early stages of heating is astraight line. During this "early time" interval, typically 20to 30 seconds, the constant rate of rise of temperature isdirectly proportional to the absorbed power density(watts/cm3) at the point of interest. In muscle tissue anabsorbed power density of 0.060 watts/cm~ will produce aninitial rate of temperature increase of 1C per minute.While this simple proportionality of temperature elevationto time (for a given absorbed power density) disappears,heat transfer processes such as thermal conduction andblood flow-related convection becom e mo re important .Microwave Local Heating--External ApplicatorsTissue heating with m icrowaves may be induced both eternally with waveguide applicators or by interstitial or tracavitary coaxial antennas. The basic characteristics of mcrowave penetration in muscle for externally beam"plane waves" (which are approximated only when appcator aperture size is significantly greater than the wavlength of microwaves in muscle) are presented in Figu15-14. In the figure, intersection of the curves with thorizontal dashed lines yields the depths at wh ich the asorbed power density (watts/cm~) falls to 50% and 13;5%respectively, of its value at the surface. The 13.5% depth commonly referred to as the "penetration depth." Tab15-5 gives this quantity for a number of different frequecies, for both high (m uscle, skin) and low (fat, bone) w atcontent tissues. At all frequencies, microwave s are far mopenetrating in fat than in muscle. At 915 M Hz, for examp


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326 Principles and Practice of Radiation OncologyTable 15-4Physical Agents and Techniques for Local Hyperthermia

Microwaves RF Electric and Magnetic FieldsExternal (wave-guide Interstitial (coaxial Interstitial (needlecavities) antennas) External (plates, coil~) arrays)

FrequencT range 300-2450 M Hz 300-1000 M Hz 0.1-27 M Hz 0.1-1.0 M HzArea coverage 10-400 cm2. Implant volume 10-200 cm2. Implant volume(20-1000 cm3) (20-1000 cm3)Therapeutic depth Up to 3 cm (mu scle) -- Up to 8 cm (muscle) --Power required 20-300 W* 10-200 W 20-400 W* 10-200 WSuitable for Tumors in superficial Tumo rs in any Tumors in superficial Tumors in anyheating muscle; in muscle volume that can muscle or muscle volume that canbehind fat or bone be im planted behind fat (coils) be implantedUnsuitable for Deep-seated tumors T um or in vo lu me s T um ors in m usc le Tumors in volumesheating that cannot be behind fat (plates) that cannot besurgically surgicallyinvaded invaded

Single applicator or pair of plates.(Perez CA, Em ami B, Nussbaum GH: Front Radiat Ther Oncol 18:83, 1984)

ggtrasoundExternal (piezo.electriccrystal transducers)0.3-3.0 MHz5-75 cm2.Up to 6 cm (mu scle)10-100 W*Tum ors in muscle; inmuscle behind fat;deep-seated tumors(multiple beam s)Tumors behind (or near)bone or air cavities

lO0

~ - ~ o

% 2 5 4 5 6DEPTH (cm )F I G U R E 15-14. Variation of axial absorbed power density(watts/cm ~) with depth in a muscle-like medium, for incidentplane waves at a num ber of different frequencies. Values at depthare expressed as a percentage of value at surface. Intersection ofcurves with lower dashed line yields "penetration depths" for therespective frequencies (see also Table 15-5).

the penetration depth in fat is 17.7 cm , versus only 3.0 cm inmuscle. Both Figure 15-14 and Table 15-5 illustrate thatpenetration depth increases with decreasing frequency.Thus, the plane wave penetration depth in muscle, for ex-amp le, increases from 3.0 cm at 915 MH z to 3.9 cm at 300MHz to 6.7 cm at 100 MHz.The penetration depths listed in Table 15-5 refer to thedepths at which the absorbed power density (watts/cm3)drops to 13.5% of its value at the surface of the givenmedium.For waveguide applicators of clinically practical di-mensions (typically, comparable to microwave wave-lengths in muscle), the increase in penetration with de-creasing frequency is far less pronounced than is suggestedby the plane wave analysis tendered above. A detailed theo-

Table 15-5Plane Wave Penetration of Microwaves in HomogeneousMedia of High and Low Water Content

Penetration Depth (cm)Frequency (MHz)

2450 1.7 11.2915 3.0 17.7433 3.6 26.2300 3.9 32.1100 6.7 60.4* H--High water content (muscle, skin).f L--Low water content (fat, bone).

retical analysis o f the problem conducted by Turner17 hasshow n that over the frequency ran ge 300 to 1000 MHz, thechange in penetration depth is very modest. Measurementsof power deposition from a variety of applicators employedfor local hyperthermia in the Mallinckrodt Institu,. :~ of R adi-ology H yperthermia Treatment Center suggest that the in-crease in penetration (e.g., in muscle) at 300 MH z over thatat 915 MHz is minimal for all but the largest applicators.89While it has been suggested that for microwaves frequen-cies close to 300 MH z m ay provide near optimum differen-tial power absorption between malignant and normal tis-sue,75 the existence of this phenomenon has not beenconvincingly demonstrated. Because of these reasons andFCC regulations, 915 MHz is used in the vast maiority ofclinical applications of local external microwavehyperthermia.Thermotherapeutic Field SizeFie ld s i ze a lso cr it i ca l ly governs the vo lum e of t i s sue thatcan be h eated sat i s factor i ly wi th a g iven app l icator . Fromfundam enta l cons iderat ions , i t i s un l ike ly that usefu l thera-peut ic heat ing a t a given depth can be exten ded to regions


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in which the absorbed power den sity is less than 50% of themaxim um at that depth or in an area enclosed by the curvedelineating 50% of the maximum specific absorption rate,For m tcrowave applicators emp loyed in ci inical hyperther-mia, the thermotherapeutic field size is considerablysmaller than the area of the applicator aperture. This isillustrated in Figure 15-15A for an 8 X 8 cm2 applicatoroperating at 915 MHz in the TEl0 mode; according to the50% criterion defined above, the therapeutically useful areaof this applicator is only 23% (E g = 0.23) of the geometricarea of 64 cm2. The small lateral heating efficiency indi-cated above is characteristic of man y single antenna app li-cators. We have been able to obtain m uch larger therapeuticfields from such ap plicators (i.e., much h igher values of Eg)by driving them with more than one antenna,s9Figure 15-15B shows the iso-power density curves (at 1cm depth) for the same 8 8 cm 2 applicator, now fittedwith three antennas (placed as shown) driven 180 out ofphase. It is seen that the therapeutically u seful heating areahas been more than doubled (Eg = 0.51). Figure 15-16shows the so-power density plots for a 12 X 12 cm 2 appli-cator ":iven with four antennas, symmetrically placed. Forthis applicator, the thermotherapeutic field size is morethan 80% of the aperture size of 144 cm 2. The use of m ulti-pie antenna applicators described in Figures 15-15 and15-16 has significantly reduced temperature non-uniform ityacross the areas treated with local hyp erthermia.Interface EffectsIn tissues with different dielectric properties (due to vary-ing w ater content, for example) electromag netic irradiationat VHF and microwave frequencies can undergo significantreflections at interfaces betw een the d ifferent tissue types.When such irradiation propagating through a tissue of lowwater content (e.g., fat) is incident on an interface with atissue of high water content (e.g., muscle) of sufficient

FIGURE 15-15. (A) Relative iso-power density curves for 8 X 8c m 2 applicator with a single antenna. (B) R elative iso-power den-sity curves for 8 8 cm a applicator with three antennas, driven 180degrees out of phase, under the sam e experimental conditions asA. App licator is fully loaded with, = 6 dielectric power and oper-ates at 915 MH z. Applicator-p, hantom coup ling is through 1 cmdeionized water. Measure,-nents are made at a depth of 1 cm in:,~.uscle phantom.

A n t e n n o

A

8 X 8 applicatorwith 1 antennaRate o f tempe raturerise 2.5C/rain. at100% area1 cm de pth

Antenno

B

A n t e n n ~

A n t e n n a

8 x 8 applicatorwith 3 antennasRate of tem peraturerise 2.7C/m in. at100% area1 c m de pth

A n t .

Chapter 15 Hyperthermia 32750

70 7( ~

FIGUR E 15-16. R elative iso-power density curves for 12 X 12 cmapplicator with four antennas symmetrically placed. The applicatoris fully loaded with ~ = 6 dielectric power and operates at 915 MHzApplicator-phantom coupling is through 1 cm deionized water.Measurem ents are made at a depth of 1 cm in muscle phantom .

thickness, the reflected wave is nearly 180 out of phasewith the incident wave. thereby produ6ing a standing wavewith an intensity minimum (a "cold spot") near the inter-face. If the wave is propagating in a tissue of high watercontent (e.g., muscle) and is incident on a tissue of lowwater content (e.g., bone), the reflected wave is in phasewith the incident wave, thereby producing a standing wavewith an intensity maximum (i.e., a "hot spot") near theinterface. R eflections at interfaces between m uscle and airare even more prono unced than those at muscle-fat or mus-cle-bone interfaces. Th e significant reflections indicated attissue interfaces of clinical interest establish cold spots inthe vicimty of fat-muscle interfaces and hot spots in theimmediate region of muscle-bone and especially muscle-air interfaces.Coupling of External ApplicatorsReducti on of electromagnetic leakage intensities in the im -med iate vicinity of the applicator-patient interface is also ofconsiderable importance in local hyperthermia from thepoint of view of both patient safety and system operatingefficiency. We have found that by coupling applicator topatient surface (across mr gaps) with bags of deionizedwater, we can reduce the average microwave leakage to lessthan 2 mW/cm2 (at 5 cm from applicator) in most applica-tions.113 It is also noted that for such coupling configura-tions, the efficiency of power transfer from applicator totissue is far greater than that obtained for coupling across airgaps.naImproved coupling of microwave applicators to tissuesurfaces of extreme curvature can be effected through theuse of multi-element applicators in which the mechanicalcoupling of component elements to one another is non-rigid. Moreover, through independent control of power toindividual elements or to groups of elements within themulti-element array, patient-appropriate shaping of lateraspecific absorption rate distributions may also be carriedout. In our clinic we h ave employed a six-element conform -able "soft" applicator for applications of local microwavehyperthermia to the lateral chest wal , an area of pro-nounced curvature2e Fitted with an antenna of specia de-sign and operating at 915 MHz, individual elements arefabricated with non -conducting walls and fi l led with deion-ized water, which can be circulated if desired. As show n inFigure 15-17, the therapeutically useful heating area of a


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328 Principles and Practice of Radiation Oncologysingle element of the six-element applicator is 79% of theaperture area of 11.6 cma. For a two-element array, 81% ofthe 3.4 8.1 cm2 area is therapeutically useful,s9Microwave Local HeatingmInterstitial AntennasMicrowave interstitial heating is typically produced withcoaxial antennas operating at frequencies of 300 to 1000MHz. A cross-sectional view of one type of antenna em-ployed for this purpose is shown in Figure 15-18. As dis-cussed by Wong an d colleagues~ss this antenna is madefrom either standard or custom -made braided 50 ohm coax-ial cable. At the junction, the tuner condu ctor is soldered tothe outer conductor of an extension section whose length ish, (see Fig. 15-18). At an operating frequency of 915 M Hz,ha is approximately 3.5 cm. Loose e nds of the braided cableare soldered at the juncnon an d at the top to prevent futurefraying. Epoxy is used at the junction to strengthen theconnection between the two pieces of cable. The antenna isinserted into an insulating catheter so that the distance fromthe tissue-air interface to the junction is hb, with the value ofhb dictated by the depth and dimensions of the tumor.The an tennas are usually placed in plastic catheters in-serted to hold the iridium-192 sources used fo r brachyther-apy. Hence, the volume heated by an application of inter-stitial hyperthermia is usually the implant volume (e.g., 20to 1000 cm3). The heating pattern of a coaxial antennaoperating at microwave frequencies is ellipsoidal, coinci-dent with the antenna axis (Fig. 15-19). Both the longitu-FIGUIIE 15-17. Iso-SAR curves for a single element and a pair ofelements of a six-element conformable applicator. Note that theuseful heating area is about 80% of the ape rture area in both cases.(Leybovich L, Nussbaum GH [submitted for publication]sg )

s o S i n g l e e l e m e n t

~ 3.4 X 3.4era2fu l ly Iooded (=81)915rn Hzcoupling: direct contoctdepth: lcm. muscle phantomE C = 0 . 7 9E c = 0.81

Tw o- e l e m e n t a r roy3.4 X 8.1 cm 2

dinal and transverse (perpendicular to the antenna) extentof the therapeutically significant power absorption from agiven antenna will depend on the length of the exposedinner conductor and on the frequency of operation. Wehave employed single junction coaxial antennas operatingat 915 MHz. for which the length of the exposed innerconductor is approximately 4 cm. The therapeutic heatingpotential of an array of four such antennas, placed paralleland intersecting the corners of a square of side 2 cm, isshown in Figure 15-20. Figure 15-20A depicts the specificabsorption, rate distribution in a plane perpendicular to theantennas and passing through the antenna junctions. Thedistribution is normalized to its maximum value at thecenter of the array. Nearly 85% of the 4 cm 2 area bounded bythe antennas lies within the 50% iso-specific absorption ratecurve, indicating that lateral (i.e., transverse) he ating in thisplane is likely to be therapeutically satisfactory. Figure15-20B sho ws the relative specific absorption rate distribu-tion along the central axis of the array for phantoms of 12cm and 6 cm, respectively. The "longitudinal heatinglength." as defined by the separation of the points denoting50% of the m aximum specific absorption rate in eac~ case,drops from 5.3 cm to 3.2 cm as coverage by the ph antom ofthe port ion of the antennas below the junction drops from 8cm to 2 cm.Measurement of specific absorption rate (W/kg) distri-butions produced in phantom s by a variety of antenna arraysand operating conditions has provided valuable insight intomethods for producing improved therapeutic heatingacross the entire treatment volume. To this end we haveemployed bolus material, independent control of power tocomponent subvolumes, and repositioning of antennaswithin respective catheters in clinical applications of inter-stitial hyperthermia. Figure 15-21 illustrates the use of a l ofthese techniques in the treatment of a bulky, renal cellcarcinoma in the posterior fiank.TMA major problem with the design of m~crowave an-tennas is the so-called dead space at the distal end of theantenna. The physical significance of this proce,s is thatwhen attempts have been m ade to increase the length of theantenna by increasing the length of the exposed inner con-ductor, the dead sp ace becomes proport ionally longer. Theclinical significance is that in certain situations (e.g., treat-ing brain tumors with interstitial thermo-radiotherapy), thevolume of implant must be significantly longer than tumorvolume at the expense of normal tissue. Some modifica-tions of basic antenna design have been carried out in order

FIGURE 15-18. Basic design ofinterstitial microwave antenna.(Lyons BE , Britt RH , StrohnbehnJW: IEEE Trans Biomed Eng31:54, t984)

~ACONNECTOR

1OAXIALFEEDLINENYLONCATHETER

INSULATOR

AIR


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FIGURE 15-19. Isotherms from a single antenin dog brain. (Lyons BE, Brit t RH. Strohnbehn JWIEEE Trans Biomed Eng 31:55, 1984)

to eliminate this "dead end" and to improve the thermaldistribution. A comparison of the specific absorption ratefor a conventional and a modified antenna are shown inFigure 15-22.Microwave Itltracavitary A p p l i c a t o r sIntracavitary applicators can be employed to deliver localhyperthermia to tumor sites in and adjacent to hollow vis-cera or cavities, for example, in gastrointestinal (esopha-gus, rectum), gynecologic (vagina, cervix, and uterus), andgenitourinary (prostate, bladder) systems. The design ofand specific absorption rate pat terns prod uced b y a hel icalintracavitary probe (that provides more uniform heatingthan probes of earlier vintage) are discussed by Luk andassociates.~ A photograph of one such probe is presentedin Figure 5-23. Clinical use of intracavitary heating probes,although cu rrently much less than that of interstitial probes,is increasing steadily.Local Heating With UltrasoundTissue heating with ultrasound may be carried out withexternal transducer applicators, appropriately coupled tothe tissue surface. These transducers can be focused or un-focused (Fig. 15-24A and B). E xcellent reviews by Fry andD u n n47 and Goss, Johnston, and Dunn 55 describe character-istics and properties of ultrasound in various media. For agiven frequency, ultrasound is significantly more penetrat-ing in fat than in muscle and far more penetrat ing in w aterthan in fat. For example, at 1 MHz penetration depths are3.8 cm in skeletal muscle, 10 cm in f~t, and 2000 cm indegassed, distilled water. The penetration of ultrasound inbone is extremely modest, with a penetration depth inhuman sku~l bone at 1 M Hz of only 0.3 cm. For frequenciesappropriate to clinical hyperthermia with ultrasound, pene-tration depths of ultrasound in both muscle and fat are in-versely proportional to frequency. At all frequencies of

15

o b1 2 c r n 6c m5.3cm 3.2cm

"Front " edge is 0.2cm beyond tip of antenno

FIGURE 15-20. (A) Relative distribution of specific absorptionrate (SAR, W/kg) for an array of four coaxial antennas operating a915 MHz. through a plane containing the antenna junctions. (B)Relative SAR distribution along the central axis of an array of fourcoaxial antennas operating at 915 MHz for phantoms of 12 cm (A)and 6 cm (B), respectively.

clinical relevance, the ultrasound absorption coefficient foskin may exceed that for underlying muscle by as m uch as afactor of two .55In contrast to microwaves, th~ penetration depth forultrasound at a given frequency (in a given type of tissue)and the frequency dependen ce of penetration depth are nota function of applicator size. This is because for all ultra-


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51

O00

L O N G I T U D I N A L ( c m )

o I 2 3

2 2 10

DEPTHo c m

25456


A

- 0 .5 1 9 M H z - M u s c l e - li k e p t a o ~ t o m - 5 0 w o r t s f o r o ~ e n , , i n u l ~ p o w r i n p u t1 0 c m t to ~ s d u c e r ~AR-GRAPHITE c o m p o ~ t e n e e d l e t h e r m o ~ : x ~ { ~1 5 c m h o t ~ i r~ I dB/cm/MHz - N u m b e r s o r e t , ~ m ~ e m f u r ee l e ~ o f io ~ s o f f ~ o ~ e m i n u t ei n d e g r e e s C

01-2-3-4-5-6-7-8-9-

B

. ;Depth. cm ~: .. .....:

6 5 4 3 2 1 0 1 2 3 4 5 6D i ame t e r , c m

B e e fin vitroTemperaturer ise

FIGURE 15-24. (A) Temperature elevations (C) withultrasound after 1 minute in muscle-like phantom agar-graphite composite (I dB/cm/MHz) 50 watts for 1 min-ute power input needle thermocou ple; 0.519 MH z, 10 cmtransducer, 15 cm ho using. (B) Tem perature distributionobtained in muscle mass in vitro using multiple ultra-sound beams (0.9 MHz frequency) focused at 6 cm incircular trajectory. (Cheung AY, Neyzari A: Cancer Res(suppl)44:4736s, 198412)

:rod its ,. .wua 2p total,_xeflectioi~ at tissue-air interfaces, ultra-sound-induced hyperthermia is not suited to therapeuticheating of lesions in the brain and chest wall because of thepresence of tile skull and ribs, respectively; it is also notsuited to heating of lesions in the thorax because of thepresence of air in the lungs.L o c a l H e a t in g w i th R a d i o f r e qu e n c y E l e ct r ic F i e ld sLocalized tissue heating with radiofrequency electric fieldsmay be carried out with both external and interstitial appli-cators. External applicators that may b e em ployed for thispurpose include pairs of conducting plates and both pan-cake and solenoidal coils. For interstitial heating with ra-diofrequency electric fields, electrical y connected arraysof metallic needles (e.g., stainless steel implant guides),defining electrode pairs in vivo, may be used. The tempera-

FIGURE 15-25. Radiofrequency heating. Three arrangements ofcurrent loops and the corresponding directions of magnetic fieldlines. Eddy currents are also shown. (a) Pancake coil induction.(b) Capacitive. (c) Concentric coil induction. (Cheung AY, Ney-zari A: Cancer Res (suppl)44:4736s, 1984~ 2)

a ) b ) c )


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332 Principles and Practice of Radiation Oncologyture elevations obtained in clinical hyperthermia with ra-diofrequency electric fields ma, y be produced through con -ductive, dielectric or inductive heating of the tissue ofinterest (Fig. 15-25).Cond uctive or resistive heating refers to heating withradiofrequency ion currents that are driven between pairs ofexternal or interstitial electrodes. The resulting power de-position is effected through collisions of moving ions withtissue molecules.With dielectric heating, power is deposited in tissuethrough the interaction of the electric fields produced be-tween plate electrode pairs with the rotational motion ofmo lecules within the tissue. In contrast to cond uctive heat-ing, which is best achieved with good electrical contactbetween plates and tissue, effective dielectric heating maybe produced with the plate electrodes physically removedfrom the respective tissue surfaces. Therefore, in situationsin which electrode plate-tissue coupling is poor, dielectricheating will often predominate over conductive heating.Inductive heating refers to heating of tissue with ra-diofrequency "eddy currents" induced (in the tissue) bythe radiofrequency magnetic fields produced in the tissueby the coil applicator employed.Wh atever the type of radiofrequency heating used, theelectric and magnetic fields referred to here are not asso-ciated with waves propagating through tissue. Therefore,the concepts of penetration depth, beam spreading, andreflection co efficients (central to the analysis of pow er de-position by microw aves and ultrasound) are irrelevant to ananalysis of power deposition by radiofrequency electricfields. The absorbed pow er densi ty distribution in ho mog e-neous tissue of a specific type, produced in a given applica-tion of conductive or dielectric heating, will depend verylittle on the frequency employed. In such an application,both axial and lateral distributions of absorbed power den-sity will be governed primarily by the ratio of the character-istic dimension of the electrodes to their separation. If thisratio is much greater than one, then the absorbed powerdensity distribution will be approximately uniform over theentire volume between the plates, except very near theedges of the region. As the electrode size-to-separationratio decreases, the distribution becomes increasingly non-uniform, with the higher absorbed power densities locatednearer the plates (the highest absorbed power density willusually be found adjacent to the edge of the smaller plateelectrode). The characteristics of the absorbed p ower d en-sity distributions sugg est that for plate electrodes of a givensize (e.g., diameter) heating at midplane depth will be-come less efficient as plate separation increases. Moreover,at a given tissue depth therapeutic field size wil also de-crease with increasing separation of plates of a givendiameter.Power deposition in inhomogeneous tissue by radio-frequen cy electric fields will be influenced critically by theresistive and dielectric properties of the component tissuetypes and also by the orientation of electric fields relative totissue interfaces within the medium . For example, for con-ductive heating in a tissue region containing fat and m uscle,in wh ich all the current driven between the plate electrodespasses through b oth the fat and m uscle slabs (in series), theratio of absorbed po wer den sity in fat to that in m uscle caneasily equal or exceed the ratio of resistivities in the twomedia. Since the fat to muscle resistivity ratio (e.g., for afrequency of 1 MHz) is n early 10, it is evident that therapeu-tic heating in the muscle slab will almost certainly be ac-complished by excessive heating in the overlying fatty tis-

sue. Radiofrequency electric fields approximately parallelto tissue (or media) interfaces can be produced in vivothrough conductive heating between properly placed inter-stitial electrodes or through inductive heating with coilsplaced near the tissue surface.Local hyperthermia with external radiofrequency ap-plicators is generally produced most effectively throughconductive or dielectric heating, employing pairs of plateelectrodes. The frequencies typically used in such applica-tions range from 0.1 to 27 MHz. Typical area coverage is 10to 200 cm2 (single pair of plates). Therapeutic depths inmuscle of up to 8 cm have been reported. The total powerrequired for therapeutic heating in a given applicationranges from 20 to 300 watts. Radiofrequency-induced hy-perthermia may also be produced through inductive heat-ing, employing pancake coils placed parallel to the tissuesurface. Frequencies employ ed typically range from 5 to 27MHz. Area coverage is typically from 10 to 400 cm2, an dtherapeutic depths of up to 4 cm may be obtained. ~n con-trast to conductive or dielectric "plate" heating, ind~,_.civeheating can raise temp eratures in m uscle behind fat or boneto therapeutic levels without producing unacceptably hightemperatures in the overlying fat or bone layers. This isbecause radiofrequency electric fields (driving the eddycurrents) induced in vivo will often be nearly parallel tofat-muscle or bone-muscle interfaces of clinical interest.Interstitial Heating with RadiofrequencyE l e ct r ic C u r r e n t sInterstitial heating with rad iofrequenc y electric fields is es-sentially resistive heating, produced by currents driven be-tween electrically conn ected arrays of needles (or betweenan intracavitary electrode and a needle array) (Fig. 15-26Aand B). Th us connected, the respective needle arrays con-stitute flat or curved electrodes in vivo. The slabs of tissuebetween respective pairs of adjacent arrays can be heatedsimultaneously, either by connecting alternate arrays toform a circuit with two "multiplane" electrodes (i.e., arrays1, 3, 5, etc., as one electrode; arrays 2, 4, 6, etc., as another)or by heating only one slab at any instant but sweepingrapidly back and forth (via electronic switching) throughsuccessive pairs of "single plane" electrodes. Either ofthese techniques will permit the entire implanted volumeto be heated in a single application. The frequencies usedin such applications are typically in the range 0.1 to 1".0MHz. The power required typically ranges from 10 to 200watts ...... ,,Regional Deep) HeatingThe basic physical characteristics of deep h eating have re-cently been reviewed by Cheung and Neyzari.l"- Descriptionof facilities and techniques for regional heating also havebeen published.~129Several systems for deep heating have been designed ata few institutions or are commercially available. Corry andBarlogie16 previously outlined the ch aracteristics of an idealregional hyperthermia system, which includes evaluabledepth of penetration with half penetration distances of t,pto 12 cm , field size from 20 cm to 30 cm , field locahzationto the tumor to minimize normal tissue toxicity and op~.i-mize therapeutic range, simple and safe patient machineinterface that is p referably noninvasive, not requiring con-


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E XT E R N A L AN D INTRACAVITARYRe c fum-P oste r io r W a ll(

Electrocie

INTERSTITIALAND INTRACAVtTARYVaginal Wal-Lateral Extension

E l e c t r o d e T h e r m o m e t e r ComponentE l e c t r o ~ i eFIGUILE 15-26. Radiofrequency current heating. Examples of in-terstitial and intracavitary technique s.

tact with the body surface and perm itting operation with anawake and alert patient and allowance for simple and accu-rate thermometry and dosimetry. These authors point outthat there is no system that can meet all of these criteria toprovide the optimal characteristics for regional hyper-thermia.The following system s are available for deep (regional)heating:1. Capacitive radiofrequency consists of the placement of

at least two electrodes at a distance from the skin, con-nected to an ap propriate generator that creates electro-mag netic fields between the two electrodes, causing ro-tation in isotropic molecules within the volume ofinterest,s7 Capacitive heating has been used by Japanesescientists and is apparently capable of he ating localizedvolumes at the depth of hum an body without superficialoverheating.16~ The Thermotron-8 (Yamamoto ViniterCo. Ltd., Japan) is in clinical use in a few centers71a66;however, mo re investigation is needed both from a phys-ics and clinical point of view to test its value in clinicalhypertherrnia.2. Resistive radiofrequency requires the con tact to the skinof the patient of two electrodes attached to a radiofre-quency generator that will produce electromagneticcurrents within the treatment volum e. Chilled water hasbeen used to cool the electrodes. Although the systemmay p ermit localization and m oderate size of the heatedvolume, according to Corry and Bar ogie~6 it is not opti-mal for deep heating.3. Induct ive radiofreque ncy, represented by the M agne-trode,~5 consists of a large circular coil, up to 30 inch es indiameter, which operates at 13.56 M Hz. This geomem cconfiguration makes no provision for physical localiza-tion of the magnetic fields to the area of the tumor.E xperiments on hom ogeneous or heterogeneous animaltissue phantoms sho wed that pow er at 400 to 500 watts

Chapter 15 Hyperthermia ~ 333resulted in preferential surface heating with ineffectivecentral heating.~25 Experiments by Storm and co-workers~6 in the live dog resulted in surface tissue tem-perature remaining within physiologically tolerablelevels and the central organs being heated to tempera-tures in the range of 42C; the authors pointed out thatstatic phantoms and dead animals are inadequatemodels to predict magnetic loop induction heating pat-terns since they do not accou nt for redistribution of heatby an intact circulatory system Gibbs49 has extensivelyevaluated the clinical applications of concentric coil(Magnetrode) operated at 13.56 MHz and the annularphased array. He has made spatial temperature measure-ments during clinical treatments with Magnetrode, andhis observations are consistent with theoretical predic-tions and phantom measurements: [emperatures fallwith increasing radial depth and ineffective heating indeep-seated tumor sites is observed.The mag netic induction coaxial electrode sys tem ocal-izes magnetic fields in relation to the tumor, resulting ina greater depth of penetration than with magnetic in-duction techniques. According to Corry~6 and Olesonnsthe only significant drawback is the necessity for skii~cooling. The field localization is better than that pro-vided by Magnetrode but not as good as that possiblyobtained with ultrasound.The annular phased array consists of a series of con-centrically arranged M W ap plicators operated in phase at50 to 00 MHz (BSD Corp., Salt Lake City, Utah).~4sa~9Several studies have reported its ability to deliver heathom ogeneously to d eep-seated structures in the thorax,abdomen, or pelvis. Gibbs and associates4s have de-scribed many of the characteristics of this device as we11as results in patients treated to abdomen and pelvis. Aclinical comparison study of the Magnetrode and theannular phased array system w as recently pub lished byGibbs.4 ~The ultrasound multi-transducer unit is a prototype em-ploying multiple focused, computer-coordinated ultra-sound transducers with capability for obtaining differentthermal configurations by selective motion of the trans-ducer. It was developed by Varian Associates (Palo Alto,California) and is under preliminary clinical evaluationat the M allinckrodt Institute of R adiology.~ 2 9A steered, focused ultrasound system has been de-signed by Leles5 who reported preliminary results.

Techniques of Regional HeatingThe techniques and preparation of patients to receive re-gional hyperthermia have been described.49a29 During thecourse of treatment, blood pressure, pulse, systemic tem-perature, and general condition of the patient should bemonitored continuously. ECG monitoring during thecourse of hyperthermia by taking a sam ple trace of lead IIevery 10 to 15 minutes is strongly recommended (radiofre-quency pow er supply m ust be off because i t interfers withan ECG device). During the course of hyperthermia, notonly the tumor temperature but the systemic temperaturemust be monitored continuously via the esophageal ther-mometer. Systemic temperature (core temperature) ofabove 40C may put the patient in danger of malignanthyperthermia. Care should be taken that core hyperthermiadoes not exceed 40.5C.


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334 Principles and Practice of Radiation OncologyTI-IERMOMETRYTemperature measurement in phantoms is an importantaspect of thermal treatment planning and will be discussedin the next sect ion. A t present , direct and continuous m om-tonng of temperatures in clinical applications of hyperther-mia constitutes the only truly reliable method of thermaltreatment verification. Clinical temperature probes shouldbe able to measure temperature to both an accuracy andprecision of 0.1 C. Therefore, reference thermom eters andother devices employed for calibration of such probesshould be able to establish temperature to within 0.02C byN ational Bureau of Standards (NBS) calibrated mercurv-in-glass thermom eters, N BS traceable highly stable therm istorprobes, and b y the use o f a variety of hydrated salt solutionsto establish several physico-chemical thermometric fixedpoints in the range of 30 to 50C. In clinical hyperthermiasubsurface therm om etry is currently carried out exclusivelywith invasive probes,ss

T h e r m o m e t e r sInvasive thermometers fall into three basic categories:electrically conducting, minimally conducting, and non-conducting (optical) probes. Standard thermistor and ther-mocouple sensors with metallic leads are conductingprobes; with a thermistor, the sensor is a semiconductorwhose resistance decreases with increasing temperature;with a thermocouple, the temperature sensor is the junctionbetween two dissimilar metals.R edistribution of charge across the junction leads to theestablishment of a potential difference whose value de-pends on the junction temperature. For a given pair ofmetals, the mathematical form of this temperature depen-dence is known. Thus, through measurement of resistance(thermistor) or voltage (thermocouple) and proper con-version of measured values to temperature, these devicescan be employed as accurate thermometers. In thermistorand thermocouple probes, the sensors may be exposed or,more typically, encased in 20- to 29-gauge plastic tubes orhypodermic needle sheaths.An example of a minimally conducting probe is thehigh resistivity thermistor with carbon impregnated plasticleads, developed by Bowman and now marketed by Vitekand BSD Medical Corporations. The sensor, a thermistorwhose resistance at a given temperature is much higherthan that of a "standard" thermistor, is encased in a Teflontube that can be inserted into a 16-gauge catheter.Non-conducting, "optical" probes employ sensorscomposed of gallium arsenide and a mixture of two rareearth phosphors, respectively. The "leads" of both opticalprobes are op tical fibers. Gallium arsenide is a sem iconduc-tor for which the "band gap" (the energy separation ofelectrons in the conduction and valence bands) is a knownfunction of temperature. The fraction of an incident beamof light (of a given wavelength) reflected or scattered bythe GaAs sensor will depend on the width of the band gapcompared with the energy of photons in the beam. Thegallium arsenide probe was developed by Christensen andis now marketed by Clini-Therm Corporation. In the rareearth bi-phosphor probe, developed by Wickersheim andmarketed by Luxtron Corporation, a pulse of incident lightexcites both phosphor materials, causing them to subse-quently fluoresce. The ratio of the intensities of a pair offluorescence emission lines one from each phosphor is

a known function of temperature. Therefore, for both typesof optical probes, analysis of the light returned from thesensor permits the temperature of the sensor to be accu-rately determined and establishes these probes as usefulthermometers. Both the GaAs and rare earth bi-phosphorprobes are encased in Teflon tubing and can be insertedinto 16- to 20-gauge catheters.While temperatures in electromagnetic fields can bereadily measured with minimally and non-conductingprobes, accurate measureme nt of temperature with invasiveprobes placed in ultrasound fields can also pose seriousproblems. Through the direct absorption of ultrasound byplastic or Teflon probe sheaths or catheters, temperatureartifacts of several degrees can easily be p~oduced. Asshown by the temperature decay curves (after power ~s shutoff) in Figure 15-27.8, the magn itude of ultrasound-inducedtemperature artifacts presen[ in measu remen ts with a Tef-lon-coated: gallium arsenide "optical" probe increases withincreasing diameter (decreasing gauge) of the Teflon orplastic catheters employed to house the thermometryprobe. Inaccuracies caused by such artifacts can be reducedby employing, for example, thermocoupie probes in hypo-derm ic needles, as is demonstrated by the lowest temp era-ture decay cu rve (0.2C artifact) in Figure 15-27B. In gen -

FIGURE 15-27. (A) Temperature decay curve with gallium-ar-senide probe, after power is shut off. (B) Reduction of artifactusing thermocouple probes in hypoderm ic needles.GALLIUM ARSENIDE PROBEDEPTH: 5cm PORK MUSCLEULTRASOUND FIELD, 2.SMHZ; ~0 W A T T S

1 4 G A . ( 2 . 1 r a m ) 6 . 2 oc*=

OFF30t l I I I I0 10 20 50 40 5 0 6 0TIM E ( sec )

THERMOCOUPLE: 29GA. HYPO. NEEDLEDEPTH: 3cm PORK MUSCLEULTRASOUND FIELD: 2.5MHZ~ 30 WATTS

I I I I t0 I0 20 30 40 50 60TIME


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era]., temperature m easurem ent in ultrasound fields is leastproblematic when conducting probes (thermistors or ther-mocouples) are employed and are placed either "bare" orin hypodermic needles directly into the tissue medium.Since the absence of catheters makes mapping along theprobe track relatively diiticult to effect, mu iti-sensor p robesare recommended for acquisition of the multiple-pointtemperature data de sired. Use of catheters fabricated frommaterials that only weakly absorb ultrasound would sub-stantially reduce temperature artifacts in ultrasound fields.As in the case of conducting probes in electromagneticfields, measurement errors can also be significantly re-duced by sam pling temperatures with the power turned off.Use of standard thermistors and thermocouples tomonitor temperatures in electromagnetic (microwave andradiofrequency) fields can often lead to substantial uncer-tainties in temperature determinations caused by noise in-duction in probe electronics or direct heating of the con-ducting probe sensors. The nature of field-induceddistortions of temperature information and of satisfactorycorrective techniques for determining actual tissue temper-ature are illustrated in Figure 15-28. The rapid decay oftemperature with time immediately following power shut-off, seen in the plot of the left of the figure, is a clearindication of the presence of field-induced probe heatingor noise. The actual tissue temperature just before powershutdown is determined through identification of the onsetof true tissue cooling on the cooling curve (the slowerdecay, typically 1 to 3C per minu te) and the projection ofthe tangent to the curve at this point to the instant of pow erremoval. From the cooling curve of the temperature-timeplot at the right of the figure, it is evident that no suchfield-induced artifacts are present. Therefore, the tem pera-rare indicated by the corresponding conducting probe maybe taken directly as actual tissue temperature. Em ploym emof the high resistivity (Bow man ) thermistors and in particu-

Chapter 15 Hyperthermia 335lar of the optical temperature probes effectively eliminatesthe field-induced artifacts mentioned above and permitsaccurate measurement of temperature, without correction,at all times (i.e., power on and off) during the heatingperiod.Non-invasive thermometry is currently the subiect ofconsiderable research in a number of laboratories and is notlikely to be commercially available in the near future. Tech-niques being evaluated include infrared thermography, mi-crowave thermography (radiometry), and ultrasound re-construction (to provide mappings of temperature-dependent ultrasound velocity or absorption). Although in-frared thermography is a commercially available tool fornon-invasive temperature measurement, it can provide in-formation only on surface temperatures.

Thermal Treatment PlanningIn principle, planning of the desired hyperthermia treat-ment may be carried out as in radiation therapy throughmeasurements in phantoms and calculations with modelsof tissue heating. To date, however, thermal modeling hasbeen of little value in predicting temperature distributionsproduced in a specific treatment of a given patient, partlybecause of problems with the mathematics of the processbut primarily because of the uncertainty in the values ofcritical patient-specific parameters (e.g., blood flow) andwith poorly defined, inappropriate boundary conditions.The fabrication of phantoms that are satisfactorily patientequivalent is far more d ifficult in hypertherm ia than in radi-ation therapy. For "patient equivalence" in hyperthermia,phantoms must be equivalent to the tissue of interest inboth power deposition and heat transfer in viva While theformer requirement m ay be satisfied without excessive dif-ficulty in most cases, the latter equivalence is usually pro-

37.0 40.0 43.0 40.0 43.0

~2C/min

power on

D o w e r of f

/

~,\1 mln. t i m e

I n c r e a s i n g

~2C/mm .

MGURE 15-28. Representative temperature-timeplots, expressed as strip chart recorder outputcurves, for two different conducting probes (e.g.,thermistors) in a microwave radiofrequency field.With the power on, the indicated temperatures atthe locations of the respective probe sensors in thegiven med ium are identical at 43C. Analysis of thedecay of temperature with time for both probes,after the power is shut off. identifies the actual tem-peratures at the two points in the medium to be40 C (left hand curve) and 43C (right hand curve),respectively.

t=ssue temp. = 4 0.0C t is s u e t e m p .


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336 Principles and Practice of Radiation Oncologyhibitively difficult to establish because of the problem ofsatisfactorily simulating convective heat transfer due toblood flow. Nevertheless, if properly used, phantoms thatare electromagnetically (or acoustically) equivalent to theclinical tissue of interest and also similar to the tissue withregard to static heat transfer (i.e., heat transfer due to ther-mal conduction) can facilitate the acquisition of valuableinformation of direct relevance to a specific, proposedtreatment. For electromagnetic energies (microwaves andradiofrequency fields) phantom material of value includedielectric liquids: sponges soaked in saline; mixtures of"superstuff," polyethylene powder, salt, and water; saline-formaldehyde gels; beef; and of course live animal tissue.In liquid phantoms mappings of electric (or acoustic) fieldsmay be readily made because of the ease with which theappropriate probes may be scanned across the phantomvolume. The field distributions obtained with a given ap-plicator can establish the characteristic performance of theapplicator in tissue with the sam e dielectric properties (andtopography) as the liquid phantom material. Absorbedpower density distributions may also be obtained frommeasurements of the initial slopes of temperature-timecurves at chosen points in sol id or gel phantoms. M easure-ment of absorbed power density distributions (watts/cm~)in such phantoms with site-specific or patient-specificgeometries can yield valuable information about the types,sizes, number, and p lacement of app licators well suited to aspecific, proposed application of clinical hyperthermia. In-formation obtained from m easurements of absorbed powerdensity and distributions of leakage intensity can also beused to improve the coupling of the applicators to the pa-tient surface, thereby reducing (e.g., for microwaves) bothleakage and field spreading across air gaps, for example.Finally, absorbed power density distributions obtainedfrom measurements in "patient-appropriate" phantoms canbe used as input data to calculations of temperature distri-butions employing thermal models.Temperature distributions obtained from measure-ments with a given applicator in liquid phantoms will sug-gest that the heating pro duced b y the applicator is far moreuniform than it is likely to be in tissue with similar dielec-tric properties. It shou ld also be ap preciated that the distri-bution of "static" state temperatures obtained from mea-surements in sol id and gel phantom s cannot be taken as anaccurate indication of the three-dimensional temperaturedistributions produced, with the same set-up and operationof applicators, in the corresponding living tissues, because

of the absence of heat dissipation retated to blood flow inthe phantoms.

QUALITY ASSURANCE INCLINICAL HYPERTI-IERMIAThe delivery of uniform treatment must be the principalgoal of a program of quality assurance and assessment inhyperthermia, t f sat isfactory comp liance w ith the tempera-ture-time specification in a particular clinical hyperthermiaprotocol is to result in the administration of approximatelyequivalent thermotherapy to all patients, the temperaturespecification itself will have to be sufficiently quantitativeand comprehensive as to unambiguously define the ther-mal state of the heated tissue, in general, both absorbedpower density (W/cm~) and local heat transfer (cal/sec-c m ~) will vary considerably over tissue volumes of clinicalinterest, making it extremely difficult to produce uniformtemperature distributions within the heated tissues. It isobvious that non-uniform three-dimensional temperaturedistributions cannot be described by specification of tem-perature at a single point. Correspondingly, production andmaintenance of equal temperatures at one point in each ofseveral tumors cannot be cited as proof that the thermalstates of the respective tumo rs are equivalent or even com -parable. To demonstrate that satisfactory compliance withhyperthermia protocol treatment specifications has in factbeen attained, the important characteristics of the treat-ments must be adequately described. A diagram of the set-up o f each treatment should be made, indicat ing clearly theanatomical location of the treatment site, the location andextent of tumor (tumor dimensions should be given), andthe location of applicators and thermometers (or ther-mometry catheters) within and around the tumor volume.Docum entation of the set-up for treatmen t of a tumor on thechest wall of a particular patient in our clinic is shown inFigure 15-29.n2 Additional requirements and proceduresfor effective quality assurance and assessment-in clinicalhyperthermia are discussed by N ussbaum.n2Practically speaking, it is recommended that before in-itiation of each treatment of every patient at least threetemperature probes (in plastic catheters) be implanted inthe tumor and one in the adjacent normal tissues close tothe tumor. Additional probes placed on tumor and normaltissue surfaces will also provide additional valuable infor-

F I G U R E 15-29. Documentation of the setup of a patientwith a minor on the left chest wall. Tumor dim ensions are6 8 x 3 cm The tum or border is indicated by a solidcurve. The estimated useful thermal field (10 10 cm 2) o fthe microwave applicator is bounded by a dotted curve.Five catheters are implanted in the tumor, one containing afour-sensor thermometry probe (sensors 9-12). Separationof successive catheters containing probes 8, 7, 9 to 12, and5 is 2 cm. The depth of the catheters beneath the tumorsurface is indicated in the lateral view. Sensors 2, 3, and 4are on the skin. (Nussbaum GH: Cancer Res44(suppl):4811s, 1984ha)

SUPERIOR

A P V IE W ~. LATERAL VIEW


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marion. For consistency, the following (but by no meansunique) distribution of subsurface probes is useful:1. One probe on central axis of the minor, at the greatestpossible depth2. Two probes, one on each side of the central axis of thetumor, at the greatest possi

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