You are on page 1of 36

15

Hyperthermia
Carlos A. Perez Bah .nan Emami Gilbert Nussbaum Stephen Sapareto

trient deficiency or reduced pH. As Dewey and colleagues2s pointed out, the response of the tumor may be affected by The effect of heat on malignant tumors was first reported by physiologic changes associated with lowering of the blood Hippocrates. In 1856 Busch8 described the disappearance flow and oxygen tension produced by the hyperthermia. Hahn~ has demonstrated in vitro the additive or synerof a soft tissue sarcoma following high fever m a patient 14 with erysipelas. Later, Coley induced fever by injecting gistic cell killing effect of a combination of heat and a varibacterial toxins, and Westermark18~ used localized hyper- etT of chemotherapeutic agents. Further, the cyxotoxic efthermia to produce tumor regression in patients. Warren1~ fects of hypoxic sensitizers alone or combined with reported 32 patients with advanced cancer of various types irradiation can be enhanced by heat Overgaard and Overgaard~a~ observed in a mouse treated with a combination of heat. induced with pyrogenic substances, and x-ray therapy. Twenty-nine of these patients mammary carcinoma treated with 27 MHz microwaves that improved for 1 to 6 months. the central portion of the tumor was more severely damIn the past 10 years interest has been rekindled in the aged than the periphery. This supports the use of combined clinical application of this modality because numerous irradiation and heat, hyperthermia being especially effective against centrally located hypoxlc ceils and irradiation papers have indicated that there may be a significant advantage to the use of heat alone or combined with irradiation eliminating the tumor cells in the periphery of the tumor, and cytotoxic drugs to enhance the killing of tumor where heat would be less effective. In experiments done on cells.22"2~4~156 The clinical use of heat has been hampered a transplanted mammary carcinoma, Overgaard reported no by a lack of adequate equipment to deliver effective heat in cures with 1600 cGy (single dose), 22% with heat alone deep-seated lesions and of thermometry techniques that (43C, 60 minutes), and 77% when the two modalities with provide reliable informanon on heat distribution in target the same factors were applied. tissues. However, significant t~rogress has been made. Localized or regional hyperthermia may be an effective About 30% to 50% of patients with solid tumors have adjuvant in tumor control when combined with irradiation. recurrences at the primary site. Many of these patients have An area in which hyperthermia may be quite useful, perregional lymph node recurrences. Both failure patterns haps alone at high temperatures (45C) or at 43C comcould be improved if effective radiation sensinzers are bined with moderate doses of irradiation (3000 to 4000 developed. cGy) is the treatment of patients with recurrences following !n viiro and it: vivo experiments strongly suggest that definitive radiation therapy (6000 to 7000 cGy). Likewise, heat may be more damaging to tumors than to normal tissince growing tissues are more sensitive to irradiation khan sues for several reasons: (1) hypoxic ceils may have an mature organs, it may be possible that a combination of increased sensitivity to heat (they are at least as thermosenhyperthermia with cytotoxic agents .or the combination of sitive as oxygenated cells;23 (2) metabolically deprived these modalities with low doses of irradiation may be eftumor ceils with reduced pH are more heat sensitive; (3) fective in the treatment of pediatric neoplasias, which will heat affects ceils in "S" phase, which are known to be resisresult in decreased growth disturbances. tam to irradiation: and (4) blood flow in the tumor is reWhole-body hyperthermia has been used for the treatduced.2a23*s Heat causes a greater degree of mitotic delay ment of disseminated disease, alone or with chemotherathan irradiation, and this factor may affect the distribution of peutic agents,lxx2*a~2 It may have potential value not only in 2~~* cells in the cell cycle after heat or x-rays. the treatment of overt metastatic disease but perhaps later The heat sensitivity of hypoxic cells is complicated by as an adjuvant, combined with chemotherapy for the treatthe possible association of low oxygen tension with nu- ment of micrometastasis. RATIONALE FOR CLINICAL USE OF HEAT

317

318

Principles and Practice of Radiatkon Oncology

BIOLOGIC ASPECTS OF HYPER~EI-IERMIA

exponential portion of the curve as a function of the inverse of temperature. Therma! Dose The analysis of cell killing by heat provides the following information: (1) Above 43C the points fall on a straight line. indicative of cell killing by a single mechanism in this range of temperatures. (2) Below 43C, this mechanism is altered such that the rate of change in cell killing as a function of temperature increases (see discussion on thermotolerance). (3) The slopes of these lines indicate that above 43C a 1 increase in te, gnperature will reduce by a factor of two the time of heating required to achieve the same effect; below 43C an increase in temperature of 1 C wili require a reduction of time by a factor of four to obtain the same result. This relationship can be described mathematicalJy as:

Despite the publication of mare: reports on biomolecular mechanisms by which heat ki~ls ceils, no consensus has been reached. Three maior m~chanisms for the heat inacuvanon of ceils have been pr .,posed: 1. Cellular membrane dg, mage, with changes in its permeability, composition, or fluidity, ultimately leading to the death of the cell.!vs Heat eff{cts on membrane fluidity have been implicat.ed by the observed interaction of heat with membrane-vnodifying drugs; both alcohols9"~ and local anesthetic5ls6 have been shown to cause ~ncreased sensitiwtv to beat. Cress2I. in a study of several in vitro cell lines, ha.s shown an inverse relationship between cholesterol to phospholipid ratio and heat sensitivity, while Anderson1 observed a direct correlation between cholesterol to phospholipid ratio and adaptation of cells to growth at temperatures from 32 to 41 C. 2. Dama.ge in lysosomes of the cellular cytoplasm, as suggested by Overgaard.n~ Disintegration of these lysosome vesicles and damage by the released digestive enzymes might be the cause of cellular death. Reports of biochemical evidence of increased lysosomal enzyme activity in heated ce!ls~,~a~ lend support to this hypothesis. 3. Thermal damage to proteins, suggested by Tomasovic and associates~6s and Roti Roti.~: They have both reported an increased, nonspecific attachment of nonhistone nuclear proteins to DNA following heat; however, this phenomenon shows only limited correlation to heat killing and more likely is important in preventing repair of radiation damage,a~ as discussed later. Other investigations implicate heat effects on a number of protein functions, such as DNA,s~a~s RiNA,~v9 and protein*~ synthesis, and respiration,n As shown in Figure 15-1, CHO cells exposed for various times to temperatures ranging from 41.5 to 46C are killed at an exponential rate. The shapes of the curves appear similar to those representing cell survival as a function of ionizing radiation dose. In addition, there is a marked increase in the sensitivity of the cells to heat exposure between 42 and 43C. This can be more readily seen in an Arrhenius plot of the logarithm of l/D0 (Fig. 15-2), where Do is the time required to reduce survival by 1/e on the HGI.IRE 1~-1. Survival curves for asynchronous Chinese hamster ovary ceils as a function of time at indicated temperatures. (Dewey WC, Hopwood LE, Saparto SA, et al: Radiology 123:463. 197723)
lO
10-I

(t~)
t2

= R(TI - Ta) R = 0.5 for T > 43C R = 0.17 for T < 43C

where

The "t" and "T" represent time and temperature, respectively, for equivalent treatments. The validity of this relationship has been demonstrated for a number of cell lines~52~ and in fact is also observed in vwo as shown in Figure 15-3. This graph is similar to an Arrheniu.s plot and
FIGURE 15-2. An Arrhenius plot of heat inactivation with the inverse of the Do values taken from the maximum slopes obtained at various temperatures as a function of the inverse of temperature for various published in vitro data. (Henle KJ, Dethlefsen LA. Ann NY Acad Sci 335:234, !9806~)
i0I I

ioo

/:
gto-~

\\4~D% _N
~43.5

k
k42 5C

(osynchronous)

/ /

10-4

~x 46+5oc t t I ~ I

10-5

Ioo

200 ~00 400 500 600 700 Time of immersion (min)

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

Chapter 15 Hyperthermia
TIME TEMPERATURE RELATION OF SOLID TUMORS IN VIVO

319

T 500

5O 50 - IO
I I

4]

42

aa 45 45 TEMPERATURE C

46 5OO I000=

MGURE 15-3. Time-temperature relation required to cure murle= tumors an vavo obtained by various investigators. The time sca]e is in relative units owing to the different heat sensitivities of the tumors. (Streffer C !ed]: Cancer Therapy by Hyperthermia and Radiation, p 49. Munich, Urban & Schwarzenberg, 1978)

shows both a change in response at 43C and an R value of 0.5 above 43C. the same as observed in vitro. Field4~ has also compiled a summary of published data on in vivo thermal response of both tumor and normal tissues and has shown that for 15 biologic systems the re lationship described in Equation 1 is valid both above and below the break temperature. Ahhough the relationship between time and temperature shown in the equation is valid in the majority of the cellular and animal model systems studied, it does not indicate that these systems all show the same sensitivity to heat. In fact, orders of magnitude differences in actual cell survival have been shown for different cell lines from the same heat exposure.I~ The observation that Equation 1 is valid for all in vivo normal tissues as well as almost all tumors tested suggests that l[ may be used to equate thermal doses at different temperatures to express the same thermal effect. Such a method, which converts a thermal exposure to an equivalent exposure at an arbitrarily chosen reference temperature of 43C, has been reported by Sapareto and Dewey.14 This method may be used to construct a nomogram (Fig. 15-4), which may be used to determine an equivalent thermal exposure time between any two temperatures by conversion, to the reference temperature. This concept has been shown to be a good prognostic indicator by Dewhirst and co-workers2 for spontaneous tumor treatment in dogs and cats when the thermal dose calculated for the coolest part of the treated tumor is used (Fig. 15-5). These results indicate that equivalent minutes exposure was the best predictor of long-term tumor response. A number of factors still must be evaluated and their importance resolved before general acceptance of this concept is warranted. These factors include: (1) the temperature of the transition or breakpoint, (2) the R value below the breakpoint, (3) the effect of step-down heating, (4) the effect of thermotolerance, (5) the effect of the interaction and irradiation on Equation 1, and (6) the importance of blood flow and other physiologic factors. Intrinsic differences in survival between norma! and malignant cells have been suggested or reported by a number of investigators. In early in vivo studies Overgaardla3 observed that exposures over the range of 41.5 to 43.5C caused little histologic damage in normal mouse tissue but

FIGURE 154. Nomogram for equivalent-minute calculacion of 43C (t4~). (Sapareto SA. Dewey WC: IntJ Radiat Oncol Biol Phys t0:787, 1984~4)
Total Fail 7 4-34 Ea 43 5 o ;~35 EQ 43 ICl) a vs a Logrank p = .006. Wllcoxon b v$ 0 LogranK P =.014, Wilcoxon o = .022

0.40 0.30 0.20. 0.10 0 15 30 45 60 75 90 105 120

Time after treatment (weeks)

FIGUR 15-5. Response duration as a function of minimum value obtained on the first heat treatment. The response duration increased significantly when greater than or equal to 35 Eq4~ (d) was obtained compared with no heat [XRT alone (a)] or less than or equa! to Eq~ (b). Tumors with intermediate heat dose values 14 to 34 Eq4~ (c)] fell between the two extremes. (Dewhirst MW, Sim DA, Sapareto SA. et al: Cancer Res 44:43, 198426) resulted in severe damage to mammary carcinoma. However, possible temperature differences between tumor and adjacent normal tissue complicate these studies. Giovanella, investigating both mouse cellss~ and human cells in vitro,s" found that ceils derived from normal tissues were less heat sensitive than are malignant cells. In his human studies he found this to be true when he compared melanoma, colon carcinoma, malignant neuroepithelial, and fibrosarcoma cells each with normal cells of comparable histologic type. However, these results were based on the number of attached ceils 3 to 7 days after treatment and thus may indicate the heat sensitivity of attachment rather than proliferative ability. In addition, clonogenic studies have

allowed a 10- ~o 20-hour period at 37C between treatments (Fig. 15-6). Thermotolerance is a transient phenomenon and thus HEAT SHOCK PROTEINS does not represent a selection of genetically resistant cells. 63 Such selection, shown only for pig kidney cells and more The phenomenon of thermotolerance appears to be closely related to the induction of a class of proteins pol},,pepddes of molecular weights in the range of 25r. to 110K dalFIGURE 15-6. The development of thermotolerance in tons.8295~62 These "heat shock proteins" kave been well asynchronous CHO ceils at various times after an initial heat dose characterized as a gene transcription phenomenon ,n Droof 45C for 17.5 minutes. The top abscissa shows the scale for the sophila melanogasteta:; however, their function is unknown. A good correlation exists between the increased initial heat treatment; the bottom absciss~ shows the duration of the second heat dose at 45C.6~ This phenomenon, termed tber- induction and degradation of these constitutive proteins motolerance, also is observed during continuous heat exposure at and the induction and decay of thermotolerance (Fig. temperatures below 43C. Evidence suggests that these two re15-7), whether induced by heat shock or other toxic stress sponses represent the same biologic mechanism. (Spiro IJ, Raa- phenomena.96
phorst GP, Saparato SA, et at: Int J Radiat Oncol Biol Phys [in press]x55)
1000 10 20min.ot 450 IZSmin. (4511)+T(37EI)+T(450) :-:
10-1

recently for Chinese hamster cells.6~ occurs at too low a frequency to account for this phenomenon. The mechanism for thermotolerance is not known: however, protein or RNA synthesis must occur before thermotolerance can develop.84 Studies have suggested that the change in slope observed in an Arrhenius plot below 43C is indeed due to thermotolerance, as was previously suggested,x~3 Both Henle6s and Li and colleagues9a have indicated that prior exposure to temperature above 43C immeTHERMOTOLERANC,E AND STEP-DOWN I-IEATING diately eliminates the break in the Arrhenius plot for ceils subsequently exposed to temperatures from 41 to 45C. It frequently has b;een reported that mammalian ceils are This phenomenon has been termed step-down beating. substantiallv more_, resistant to heat following a prior heat Also. Li and colleagues9~ have shown that thermotolerance 68 exposure.6(Hen.~m reported that cells initially exposed to is inhibited for several hours immediately following expo45C became resistant to subsequent exposure to 45C if sure to 45C.

320 Principles and Practice of Radi~ation Oncology shown that normal tissue-derived ceils in culture are less sensitive to heat than are maligrxant ceils either tissue derived or transformed in vitro.93~9 In contrast. Harisiadis62 noted that rat hepatoma ceils were less sensitive to heat (42 to 45C) than were normal rat liver cells Evidence does not clearly show that all malignant cells are intrinsically more heat sensitive ".nan are normal cells.

HEAT INTERACTION WITH IRRADIATION AND CHEMOTHE.RAPY

ra=12hr

10-5

10-4

20 40 60 HYPERTHERMIA, min. at 45

8O

Investigations of the interaction of heat and irradiation have received as much attention as studies on the effects of heat alone and several good reviews on this subject are available.=~a8a~ A number of observations suggest that the combination of heat and irradiation is of potential benefit in cancer therapy. The first and most generally observed phenomenon is that heat radiosensitizes cells.Z~4~a4-4 Most reports observe that the maximum increase in the slope of the radiation survival curves is 25% and that ceils in S phase are more radiosensitized by heat than are cells in G~ .~4~ The cause of this radiosensitizati on has not been firmly established; however, it is believed that the accumulation of non-histone proteins, which bind to DNA following heat
B lOCi
HSP 68

FIGURE 15-7. Correlation between heat shock protein synthesis (A) and thermotolerance (B) for Chinese hamster ovary cells. (Subjeck JR, Scianda JJ, Chao CF, et aI: BrJ Cancer 45:127, 1982~62)

tt~tt

6 6 10 ~2 14 16 TIME A~ER HEAT (H)

~4

10-5= t J

=~

~IIII II

1~ 4 6 8 10 12 14 16 18 ~ ~4 TIME AFTER HEAT SHOCK (H)

Chapter 15 Hyperthermia 321

treatment, prevents the cell from repairing radiation dammaximum when the two modalities are given simultaage. This hypothesis is supported by several observations. neously (Fig. 15-9),~21A42"~sv However. simultaneous administration is not necessarily the best protocol for therapeutic First, the interaction between heating and subsequent raditreatments because tumor cure will improve only if cytoauorf exposure persists for about t2 hours between treatments. This coincides with the return to normal of DNAtoxicity to tumor cells is enhanced to a greater extent than to-non-histone protein ratios.I3 Second. the ability for the effect on normal ceils. enzymatic repair of irradiation-induced thymine damage is Dewey and co!leagues25 and Sapareto and associates~ inhibited when chromatin is heated but not when only the have shown that when heat and irradiation are administered enzyme is heated,lsI Third, there is a linear increase both in together to cells in vitro there is a greater cell kill than the amount of non-histone protein attached to DNA and in when heat is delivered more than 30 minutes before or after the inhibition of micrococcal nuclease digestion of chro- irradiation. matin into fundamental nucleosomal structures which sugDewey and co-workers2~ have hypothesized that if heat gests that access to the sites between nucleosomal strucis delivered 3 hours before irradiation, ceils with a low pH tures is blocked3s2 will have minimal ability to repair heat damage and thereAnother factor of possible clinical relevance is the fact fore mav be greatly sensitized to the effects of subsequent irradiation. Hill and Denekamp.7 Field,42 and Overgaard"~ that cells in G~ are less sensitive to heat than are cells in S phase, while the opposite is true for cellular sensitivity to strongly suggest that when there is preferential (selective) irradiation (Fig. 15-8). However, this effect may not be apheating of the tumor in relation to the normal tissues, the parem,if the lethal effect of one modalitv is much greater optimal time for administration of the two modalities is than that of the other,e since Westra~s4 noted that the mag-simultaneous. However, when the temperature in the tumor and the normal tissues ts the same there may be a nitude of the difference in sensitivity between G1 and S phase is reduced as the severity of the heat exposure therapeutic gain only if heat is delivered four hours or decreases. longer after irradiation (Fig. 15-10). The interaction between heat and irradiation does not show the same time-temperature relationship as does heat Timing of Irradiation and Heat Administration alone. This is borne out by both in vitro and in vivo studies.83A44 When heat doses at various temperatures adjusted One must carefully consider the sequence of application in to achieve the same amount of cell killing are combined order to combine heat and irradiation effectively. Li and with a radiation exposure, the survival of ceils for the comco-workers94 reported little difference in survival of CHO bined treatment is not the same at all temperatures. Maxicells for either order of treatment when heat and irradiation mal effectiveness is seen near 42.5C, suggesting that there were administered with minimal separation. However, their may be an optimal temperature for combined modality results may depend on many factors, such as pH,46 temperatreatment. ture. and duration of exposure.86 A number of studies have Mittal and associates~s carried out experiments in shown that in general heat-induced radiosensitization is transplanted RIF-1 fibrosarcoma in the flank of C3H m~ce. Tumors were treated with fractionated x-rays (400 cGy twice weekly X !0) alone or in combination with heat (RF currents, 43C, twice weekly). Heat treatments were delivIRGURE 15-8. The variation in the survival of CHO cells followered before, in conjunction with, or after the fractionated ing exposures to either heat (45.5C for 6, 10, or 15 minutes) or radiation therapy. Animals treated with irradiation alone or irradiation (600 cGy). (Westra A, Dewey WC: Int J Radiat Oncol with the heat and irradiation delivered with sequential fracls4) Biol Phys 19:467, 1971 tionation (all heat sessions given before or after irradiation) exhibited a 20% cure rate. In animals treated with "simultaFIGURE 15-9. The variation in survival of asynchronous CHO ceils as a function of the sequence of irradiation (400 cGy) and heat (42.5C for 17.5 minutes [] or 40 minutes [~]). (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 40 rain)

Hours after plating mitotic cells

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

322

Principles and Practice of Radiation Oncology Heat before X-rays Heat after

Table 15-1 Hyperthermia and Interaction With Drugs


1.

Tumor

Drugs with no temperature threshold effect.. Thiotepa Nitrosourea group: BCNU. CCNU Cisplatin (Probably suitable for systemic hyperrhermia)

Skin

IIIIIIIIIIII 5 4 5 2 1 o ] 2 5 4. 5 6 Time between x-rays and heat (hours) FIGURE 15-10. Thermal enhancement ratio as a function of the time interval between heat and irradiation. The solid line represents skin data of Stewart and Denekamp.156 = TER values for fibrosarcoma 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)

2. Drugs with a temperature threshold effect, about 43C. before a major potentiation is observed: Bleomycm Adriamycin Actinomycin-D (Probably suitable for local hyperthermia) 3. Drugs not normally cytotoxic at 3 7C but that cause considerable cell kill above a threshold temperazure: Alcohols Amphotericin-B Cysteamine AET (2-amino-ethyl-isothiourea) -- Cysteiffe

neous" combination of both modalities (heat delivered the same day as irradiation, immediately after x-ray exposure), the cure rate was 70%. Thermo-Chemotherapy ~though hyperthermia currently shows its greatest clinical promise in combination with other conventional moctalities, such as irradiation or chemothera_j~ thermo-chemotherapy is far from being understoo~Hahn and colleagues66~ have reported on the inter~ei~n of heat with a variety of cy~otoxic agents. The type of drug, dose. temperature, and time of administration of the agents are all important factors in determining cell kill by combinati on of these agents.59.~00 Three types of drug interactions have been categorized (Table 15-1).~ The first are drugs that show an increase in effectiveness with increased temperature, even those below 42C. Examples of these drugs are several of the alkylating agents, such as nitrosoureas.~ The second category of drugs seem to show increased effectiveness only above a threshold temperature value; for example, bleomycin~ shows a threshold for interaction with heat at about 43C. The third category are those drugs that are normally not considered of any value therapeutically at 37C but that show significant killing ability at elevated temperatures. Amphotericin-B, a polyene antibiotic, is in this category. Agents in the first category would be effective for use with whole-body heating, in which temperatures cannot exceed 42 C. The second category of drugs would be useful for local hyperthermia, in which heat treatments are expected to exceed 43C. Drugs in the third category might aiso be classified in the previous two categories, most likely the second category; however, it is a class of drugs that may be diliicult to find, since they would fail conventional screening attempts at 36C. Although many drugs show increased effectiveness when combined with hyperthermia, the great variety in mechanism of drug killing precludes the idea that heat and drug interaction is a simple unilateral phenomenon. In fact, instances have shown that heat can enhance drug resistance

in the case of Adriamycin6 and actinomycin D.29 As heating duration increases, cells in culture become highly resistant to killing by either drug. This may be caused by heat-induced alteration in drug transport into the cell.4~ Thus, although enhanced drug effectiveness is clearly a desirable effect on cancer chemotherapy, the subject of thermo-chemotherapy has barely been touched on; it is to be hoped that thermo-chemotherapy wil! one day provide improved cancer control and increased understanding of drug mechanisms of actions.
PHYSIOLOGIC MECHANISMS IN HYPERTHERMIA ~,[icrovasculature of Normal Tissue There is great variation in the microcirculation of different tissues such as striated muscle, skin, and so on. Nevezxheless, there is regularity in distribution within a specific tissue.s~ In a typical "model" all exchanges between blood and parenchymal cells take place at the capillary level (microcirculation). True capillaries in normal tissues have a diameter close to that of an erythrocyte (7 to 10 microns) and walls consisting of three layers: endothelium, basement membrane and pericytes, and adventitia. Microvasculature of Tumors

In general, at an early stage of tumor development the tumor cells probably survive and proliferate using energy and nutrients supplied through the hosts blood vessels. As the tumor grows, host vessels are occasionally incorporated into the tumor mass. As the demand for nutrients and oxygen exceeds the supply capacity of the host vessels, a new vascularization in the tumor begins (formation of "buds" and, by confluence, "sprouts"). It has been suggested that certain humoral factors are important for the initiation of this process (e.g., tumor ang~ogenesis factor [TAF] and endothelial proliferating factor [EPF]). The capillaries formed by random fusion of sprouts are tortuous, elongated, and dilated and lack basement membrane2z The flow of blood

Chapter 15 Hyperthermia

323

through such a coarse capillaw network is sluggish. A great proportion of tumor blood does not exchange with blood in the general circulation (stasis). This intermittent circulation periods of sr.asis followed bv resumption of blood flow--is probably a "normal" feature of the intravascular transport system of neoplastic tissues,s6,lv4 Another characteristic of tumor vascular network is the abundance of lacuna-like sinusoids and channels that do not drain properly, leading to stasis and thrombosis. The histologic patterns and functional status of vascular networks in malignant tumors vary depending on the type, age, and size of the tumor.176 Rubin and Casarettl~s classified tumor vascularization into three categories: (1) peripheral. (2) peripheral with penetrating vessels, and (3) central. The proportion of tumor space occupied by vasculature decreases as the tumor grows.5~167!~8 TannockI6~ has suggested that the longer turnover time of endothelial cells--their slower proliferation relative to that of neoplastic cells--accounts for {he decline in vascular density. Reduced vascular density together with the sluggish perfusion of blood through the

capillaries may account for the decrease in total blood


flOW.152,174

Effect of Hyperthermia on Normal Tissue Microcirculation

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


Blood Flow Tissues Control Heated

In studying the effect of hyperthermia on normal tissue vascular function, a distinction should be made between normal tissue adjacent to the tumor and normal tissue far from the tumor. Song and associates~5~ have observed that the blood flow of skin overlying the tumor and of muscle near the tumor is more than twice that of the skin and muscle far from the tumor. They attribute this phenomenon to inflammatory processes near the tumors. There was a significant increase in the blood flow in skin and muscle both near and far from the tumor upon heating to 43C for 1 hour~5s (Table 15-2). It is interesting to note that the magnitude of increase was higher in the normal tissues adjacent to the tumor than in the tissues far from the tumor. The blood flow rate in both skin and muscle returned to normal levels within 2 hours after cessation of heating. The dynamic changes of skin and muscle blood flow are both time and temperature dependent (Fig. 15-tl). As shown, the time that it takes the skin blood flow to reach its maximum before declining for temperatures of 43, 44, and 45C are 120, 30, and 15 minutes, respectively. Note that peak blood flows are different for various time-temperatures. Similar trends have also been observed in muscle blood flow.
Effect of Hyperthermia on Tumor Microcirculation

Skin Normal Near tumor Muscle Normal Near tumor

7.82 + 0.76 14.39 x 3.37 4.97 + 0.55 10.26 ___ 2,71

29.13 --+ 3.39 64.61 _ 8.38 14.61 _ 1,75 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)

Hyperthermia at modest temperatures (up to 40C) has been shown either to have no effect57a5 or to increase tumor blood flow.53s~7~ Bicher,5 Eddy,3~ Vaupel.~7~ and Endrich~ found significant decrease in tumor blood flow during the course of hyperthermia at temperatures in the therapeutic range (42 to 45C). Song and associatesls~
FIGURE 15-11. Changes in blood flow in the skin and muscle of normal leg of SD rat during heating at various temperatures for 120 minutes. (Song CW: Cancer Res. 44(suppl):4721s, !984~)

120

Skin
100

Muscle

Heating time (min)

324

Principles and Practice of Radiation Oncology Table 15-3 Temperatures Causing Significant Reduction of Blood Flow in Various Tumors Author (Reference) Temperatures (o C)

Tumor

Animal

Song et al?5 Emami et al ~s Endrich et a1.40 Reinhold et al x36 Von Ardenne et al.m Vaupel et al.IV3 Dickson et at.a7 Song et al.~3 Sutton et al.16s Bicher et al.s Eddy et al.~

Walker carcinoma 256 BA-11 t2 rhabdomyosarcoma BA-1112 rhabdomyosarcoma BA-1112 rhabdomyosarcoma DS carcinosarcoma DS carcinosarcoma Yoshida sarcoma SCK mammary tumor Ependymoblastoma Mammary adenocarcinoma Squamous cell carcinoma

Rat Rat Rat Rat Rat Rat Rat Mouse Mouse Mouse Hamster

43.5 42.5 40.0 42.5 41.0 42.0 42.0 40.5 41.0 41.0 41.0

noticed no significant change m tumor blood flow in Walker rat tumors during heating at 43C but observed a significant decrease in tumor blood flow after termination of hyperthermia at 45C. Emami and colleagues3s reported that hyperthermia at modest temperatures (40 to 41C) caused either no change or a slight increase in tumor blood flow in a rat tumor. At higher temperatures there was a temperature-dependent 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 heated twice at 42C for 30 minutes, with heating periods separated by different time intervals, had complete cessation of blood flow at the end of the second heating when it was given 1 hour after the first heating. When the intervat between heating was increased to 5 or 24 hours, the effect of the second heating was significantly lessened. Table 15-3 summarizes the results on effect of hyperthermia on tumor blood flow reported by several investigatoi:s. It should be stressed that the temperatures at which blood flow is reduced or vascular damage is induced are generally lower than those causing the same phenomena in most n ormal tissues. In most animal tumors blood perfusion deteriorates when heated for 30 to 60 minutes at 41 to 43C. On the other hand, blood flow in the skin and muscle of SD rats increased by a factor of 8 to 10 during heating at 43C, and skin blood flow of Wister rats increased as much as 20 times at 43C.3~.1~2 Relative changes of blood flow as function of temperature are shown in Figure 15-12. The effect of hyperthermia on the microcirculation was accentuated when additional treatments were combined with hyperthermia. Eddy and associates~4 combined hyperthermia (42C for 30 minutes) with irradiation (2000 cGy) and found that the changes in tumor circulation were more prominent than those caused by heat alone. Blood flow ceased completely when hyperthermia and irradiation were given concomitantly, whereas such a response did not Occur when the interval between irradiation and heating was increased or when irradiation was g~ven after heat. The addition of a chemotherapeutic agent such as Adriamycin did not have any effect on the heat-induced change in tumor blood flow. Reinhold and co-workers1~ observed that 5-thio-D-glucose or misonidazole combined with mod. est doses of hyperthermia exerted as detrimental an effect on tumor microc~rculation as did higher temperatures

Tumor

38 39 40 41 42 43 44 45 46 47 48 Temperature o C (~Heating for 30-40 Min }

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

alone. Hyperglycemia by itself can reduce or completely abolish tumor blood flow? A pathologic study by Emami and colleagues37 confirmed the physiologic findings described above: no specific changes in microvasculature were observed with temperatures up to 40.5C. However, at 42C blood vessels became dilated and were packed with red cells (stasis). At therapeutic temperatures, massive hemorrhage, coagulative necrosis, and rupture of blood vessels were evident. This study has shown that the vascular damage becomes increasingly severe if a tumor is left in situ after termination of hyperthermia. This phenomenon correlates well with the delayed cell death that has been observed by Song and colleaguesTM and Fajardo and associates.4~
Effect of Hyperthermia on Intratumor pH

The pH of arterial blood is 7.4 and that of venous blood and interstitial fluid is 7.35. Intracellular pH usually ranges between 6.0 and 7.4 in different cells, averaging about 7.0.ss

Chapter 15 Hyperthermia

325

Recent studies have shown that there is no significant difference between the intracellular pH of normal cell lines and that of their malignant counterparts.7. Song and co-workersls3 and Bicher and colleagues~ have shown that hyperthermia triggers an immediate and significant decrease of the pH in tumors. Song and coworkersls3 reported that the pH in SGK tumors of mice decreased from 7.05 to 6.67 when the tumors were heated at 45.5C for 30 minutes. When heating was terminated, the pH rose to 6.78 but decreased to 6.5 to 6.6 when the tumors were reheated (Fig. 15-13). Recently, Ryu and associates139 observed that the lactic acid content in mouse tumors significantly increased upon heating. Streffer and colleagues161 also reported that hyperthermia caused an increase in the amount of lactic acid as well as of fl-hydroxybutyric acid in mouse tumors. Thus, it appears that the lowering of tumor pH caused by hyperthermia results from an increase in the acidic metabotires. Indications are that acidic conditions not only enhance the heat killing but also inhibit repair of thermal damagels~ and development of thermotolerance,s~l=

suggest that the therapeutic gain may be greater if radiation therapy is applied before hyperthermia rather than vice versa. Alternatively, Overgaard and Nielsen1= and Deweya4 have hypothesized that hyperthermia may be used as an independent modality and not as a radiosensitizer, thus sequential timing would be insignificant.
BASIC PRINCIPLES OF PHYSICS AND INSTRUMENTATION

Role of Blood Flow in the Combined Use of Hyperthermia and Other Modalities
Indications are that the hypoxic cell fraction in a tumor increases as a result of vascular damage, despite the heatinduced death of previously hypoxic ceils. Song and coworkers~s4 found that the proportion of hypoxic ceils in SCK 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 proportion of hypoxic cells started to decrease thereafter, probably because of the death as well as reoxygenation of hypoxic ceils, but the proportion of hypoxic cells 48 to 72 hours after heating was still greater than that in the unheated tumors. In contrast, partially hypoxic normal tissues may 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 levels obtained in C3H mammary tumors. A total of 96 determinations were made at normal temperature; 108 measurements were made after 1 hour of 43C microwave hyperthermia. Mean values ofpH obtained in the control and 43C hyperthermia group were ~6.75 and 6.2, respectively. (Bicher HI, Sandher TS, Hetzel FW: Int J Radiat On,vol Biol Phys 6:867, 19806)

The primary goals of clinical hyperthermia must be treatment accuracy, reproducibility, and safety of patients and personnel. To attain these goals, it is necessary to assemble suitable devices for the production and measurement of elevated temperature distributions at desired sites. It is also necessary that satisfactory thermal treatment planning and clinical thermometry facilitate effective use of the physical agents employed and permit the thermal state of the heated tissue to be adequately described. Accordingly, instrumentation of clinical hyperthermia is concentrated in the following areas: (1) power deposition, (2) thermometry, (3) treatment planning, and (4) safety.
Power Deposition The physical agents employed for power deposition in local clinical hyperthermia are (1) electromagnetic irradiation at very high and microwave frequencies (300 to 2450 MHz), (2) electric and magnetic fields at radiofrequencies (0.1 to 27 MHz), and (3) uhrasound at frequencies from 0.3 to 3 MHz. The main characteristics of these modalities are summarized in Table 15-4. For a given applied power, the temperature-versustime curve during the very early stages of heating is a straight line. During this "early time" interval, typically 20 to 30 seconds, the constant rate of rise of temperature is directly proportional to the absorbed power density (watts/cm3) at the point of interest. In muscle tissue an absorbed power density of 0.060 watts/cm~ will produce an initial rate of temperature increase of 1C per minute. While this simple proportionality of temperature elevation to time (for a given absorbed power density) disappears, heat transfer processes such as thermal conduction and blood flow-related convection become more important.

Microwave Local Heating--External Applicators


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

~ 2O

10

o 5.6 I , 610

6.4 tissue gH

6.8

7:2

Tissue heating with microwaves may be induced both externally with waveguide applicators or by interstitial or intracavitary coaxial antennas. The basic characteristics of microwave penetration in muscle for externally beamed "plane waves" (which are approximated only when applicator aperture size is significantly greater than the wavelength of microwaves in muscle) are presented in Figure 15-14. In the figure, intersection of the curves with the horizontal dashed lines yields the depths at which the absorbed power density (watts/cm~) falls to 50% and 13;5%, respectively, of its value at the surface. The 13.5% depth is commonly referred to as the "penetration depth." Table 15-5 gives this quantity for a number of different frequencies, for both high (muscle, skin) and low (fat, bone) water content tissues. At all frequencies, microwaves are far more penetrating in fat than in muscle. At 915 MHz, for example,

326

Principles and Practice of Radiation Oncology

Table 15-4 Physical Agents and Techniques for Local Hyperthermia


Microwaves External (wave-guide cavities) Interstitial (coaxial antennas) RF Electric and Magnetic Fields Interstitial (needle arrays) ggtrasound External (piezo.electric crystal transducers)

External (plates, coil~)

FrequencT range Area coverage Therapeutic depth Power required Suitable for heating Unsuitable for heating

300-2450 MHz 10-400 cm2. Up to 3 cm (muscle) 20-300 W* Tumors in superficial muscle; in muscle behind fat or bone Deep-seated tumors

300-1000 MHz Implant volume (20-1000 cm3) -10-200 W Tumors in any volume that can be implanted Tumor in volumes that cannot be surgically invaded

0.1-27 MHz 10-200 cm2. Up to 8 cm (muscle) 20-400 W* Tumors in superficial muscle or muscle behind fat (coils) Tumors in muscle behind fat (plates)

0.1-1.0 MHz Implant volume (20-1000 cm3) -10-200 W Tumors in any volume that can be implanted Tumors in volumes that cannot be surgically invaded

0.3-3.0 MHz 5-75 cm2. Up to 6 cm (muscle) 10-100 W* Tumors in muscle; in muscle behind fat; deep-seated tumors (multiple beams) Tumors behind (or near) bone or air cavities

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

lO0

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

~-~o
Frequency (MHz)

Penetration Depth (cm)

2450 915 433 300 100


* H--High water content (muscle, skin). f L--Low water content (fat, bone).

1.7 3.0 3.6 3.9 6.7

11.2 17.7 26.2 32.1 60.4

retical analysis of the problem conducted by Turner17 has FIGURE 15-14. Variation of axial absorbed power density shown that over the frequency range 300 to 1000 MHz, the (watts/cm~) with depth in a muscle-like medium, for incident change in penetration depth is very modest. Measurements plane waves at a number of different frequencies. Values at depth of power deposition from a variety of applicators employed for local hyperthermia in the Mallinckrodt Institu,. :~ of Radiare expressed as a percentage of value at surface. Intersection of curves with lower dashed line yields "penetration depths" for the ology Hyperthermia Treatment Center suggest that the inrespective frequencies (see also Table 15-5). crease in penetration (e.g., in muscle) at 300 MHz over that at 915 MHz is minimal for all but the largest applicators.89 While it has been suggested that for microwaves frequenthe penetration depth in fat is 17.7 cm, versus only 3.0 cm in cies close to 300 MHz may provide near optimum differenmuscle. Both Figure 15-14 and Table 15-5 illustrate that tial power absorption between malignant and normal tispenetration depth increases with decreasing frequency. sue,75 the existence of this phenomenon has not been Thus, the plane wave penetration depth in muscle, for exconvincingly demonstrated. Because of these reasons and ample, increases from 3.0 cm at 915 MHz to 3.9 cm at 300 FCC regulations, 915 MHz is used in the vast maiority of MHz to 6.7 cm at 100 MHz. clinical applications of local external microwave The penetration depths listed in Table 15-5 refer to the hyperthermia. depths at which the absorbed power density (watts/cm3) drops to 13.5% of its value at the surface of the given medium. Thermotherapeutic Field Size For waveguide applicators of clinically practical dimensions (typically, comparable to microwave waveField size also critically governs the volume of tissue that lengths in muscle), the increase in penetration with decan be heated satisfactorily with a given applicator. From creasing frequency is far less pronounced than is suggested fundamental considerations, it is unlikely that useful theraby the plane wave analysis tendered above. A detailed theopeutic heating at a given depth can be extended to regions

2 5 4 DEPTH (cm)

,5

Chapter 15 Hyperthermia

327

in which the absorbed power density is less than 50% of the maximum at that depth or in an area enclosed by the curve delineating 50% of the maximum specific absorption rate, For mtcrowave applicators employed in ciinical hyperthermia, the thermotherapeutic field size is considerably smaller than the area of the applicator aperture. This is illustrated in Figure 15-15A for an 8 X 8 cm2 applicator operating at 915 MHz in the TEl0 mode; according to the 50% criterion defined above, the therapeutically useful area of this applicator is only 23% (Eg = 0.23) of the geometric area of 64 cm2. The small lateral heating efficiency indicated above is characteristic of many single antenna applicators. We have been able to obtain much larger therapeutic fields from such applicators (i.e., much higher values of Eg) by driving them with more than one antenna,s9 Figure 15-15B shows the iso-power density curves (at 1 cm depth) for the same 8 8 cm2 applicator, now fitted with three antennas (placed as shown) driven 180 out of phase. It is seen that the therapeutically useful heating area has been more than doubled (Eg = 0.51). Figure 15-16 shows the !so-power density plots for a 12 X 12 cm2 applicator ":iven with four antennas, symmetrically placed. For this applicator, the thermotherapeutic field size is more than 80% of the aperture size of 144 cm2. The use of multipie antenna applicators described in Figures 15-15 and 15-16 has significantly reduced temperature non-uniformity across the areas treated with local hyperthermia.
Interface Effects

50 70 7( ~

Ant.

FIGURE 15-16. Relative iso-power density curves for 12 X 12 cm2 applicator with four antennas symmetrically placed. The applicator is fully loaded with ~ = 6 dielectric power and operates at 915 MHz. Applicator-phantom coupling is through 1 cm deionized water. Measurements are made at a depth of 1 cm in muscle phantom.

In tissues with different dielectric properties (due to varying water content, for example) electromagnetic irradiation at VHF and microwave frequencies can undergo significant reflections at interfaces between the different tissue types. When such irradiation propagating through a tissue of low water content (e.g., fat) is incident on an interface with a tissue of high water content (e.g., muscle) of sufficient

thickness, the reflected wave is nearly 180 out of phase with the incident wave. thereby produ6ing a standing wave with an intensity minimum (a "cold spot") near the interface. If the wave is propagating in a tissue of high water content (e.g., muscle) and is incident on a tissue of low water content (e.g., bone), the reflected wave is in phase with the incident wave, thereby producing a standing wave with an intensity maximum (i.e., a "hot spot") near the interface. Reflections at interfaces between muscle and air are even more pronounced than those at muscle-fat or muscle-bone interfaces. The significant reflections indicated at tissue interfaces of clinical interest establish cold spots in the vicimty of fat-muscle interfaces and hot spots in the immediate region of muscle-bone and especially muscleair interfaces.

Coupling of External Applicators


Reducti on of electromagnetic leakage intensities in the immediate vicinity of the applicator-patient interface is also of considerable importance in local hyperthermia from the point of view of both patient safety and system operating efficiency. We have found that by coupling applicator to patient surface (across mr gaps) with bags of deionized water, we can reduce the average microwave leakage to less than 2 mW/cm2 (at 5 cm from applicator) in most applications.113 It is also noted that for such coupling configurations, the efficiency of power transfer from applicator to tissue is far greater than that obtained for coupling across air gaps.na Improved coupling of microwave applicators to tissue surfaces of extreme curvature can be effected through the use of multi-element applicators in which the mechanical coupling of component elements to one another is nonrigid. Moreover, through independent control of power to individual elements or to groups of elements within the multi-element array, patient-appropriate shaping of latera! specific absorption rate distributions may also be carried out. In our clinic we have employed a six-element conformable "soft" applicator for applications of local microwave hyperthermia to the lateral chest wal!, an area of pronounced curvature2e Fitted with an antenna of specia! design and operating at 915 MHz, individual elements are fabricated with non-conducting walls and filled with deionized water, which can be circulated if desired. As shown in Figure 15-17, the therapeutically useful heating area of a

FIGURE 15-15. (A) Relative iso-power density curves for 8 X 8 cm2 applicator with a single antenna. (B) Relative iso-power density curves for 8 8 cma applicator with three antennas, driven 180 degrees out of phase, under the same experimental conditions as A. Applicator is fully loaded with, = 6 dielectric power and operates at 915 MHz. Applicator-p, hantom coupling is through 1 cm deionized water. Measure,-nents are made at a depth of 1 cm in :,~.uscle phantom.
8 X 8 applicator with 1 antenna
Antenno

Rate of temperature rise 2.5C/rain. at 100% area 1 cm depth

A
8 x 8 applicator with 3 antennas Rate of temperature rise 2.7C/min. at 100% area 1 cm depth

Antenn~ Antenno

Antenna

328

Principles and Practice of Radiation Oncology

dinal and transverse (perpendicular to the antenna) extent of the therapeutically significant power absorption from a given antenna will depend on the length of the exposed inner conductor and on the frequency of operation. We have employed single junction coaxial antennas operating Microwave Local HeatingmInterstitial Antennas at 915 MHz. for which the length of the exposed inner conductor is approximately 4 cm. The therapeutic heating Microwave interstitial heating is typically produced with potential of an array of four such antennas, placed parallel coaxial antennas operating at frequencies of 300 to 1000 and intersecting the corners of a square of side 2 cm, is shown in Figure 15-20. Figure 15-20A depicts the specific MHz. A cross-sectional view of one type of antenna employed for this purpose is shown in Figure 15-18. As dis- absorption, rate distribution in a plane perpendicular to the cussed by Wong and colleagues~ss this antenna is made antennas and passing through the antenna junctions. The distribution is normalized to its maximum value at the from either standard or custom-made braided 50 ohm coaxial cable. At the junction, the tuner conductor is soldered to center of the array. Nearly 85% of the 4 cm2 area bounded by the outer conductor of an extension section whose length is the antennas lies within the 50% iso-specific absorption rate curve, indicating that lateral (i.e., transverse) heating in this h, (see Fig. 15-18). At an operating frequency of 915 MHz, plane is likely to be therapeutically satisfactory. Figure ha is approximately 3.5 cm. Loose ends of the braided cable 15-20B shows the relative specific absorption rate distribuare soldered at the juncnon and at the top to prevent future fraying. Epoxy is used at the junction to strengthen the tion along the central axis of the array for phantoms of 12 cm and 6 cm, respectively. The "longitudinal heating connection between the two pieces of cable. The antenna is length." as defined by the separation of the points denoting inserted into an insulating catheter so that the distance from the tissue-air interface to the junction is hb, with the value of 50% of the maximum specific absorption rate in eac~ case, drops from 5.3 cm to 3.2 cm as coverage by the phantom of hb dictated by the depth and dimensions of the tumor. the portion of the antennas below the junction drops from 8 The antennas are usually placed in plastic catheters inserted to hold the iridium-192 sources used for brachythercm to 2 cm. apy. Hence, the volume heated by an application of interMeasurement of specific absorption rate (W/kg) distristitial hyperthermia is usually the implant volume (e.g., 20 butions produced in phantoms by a variety of antenna arrays to 1000 cm3). The heating pattern of a coaxial antenna and operating conditions has provided valuable insight into operating at microwave frequencies is ellipsoidal, coinci- methods for producing improved therapeutic heating dent with the antenna axis (Fig. 15-19). Both the longitu- across the entire treatment volume. To this end we have employed bolus material, independent control of power to component subvolumes, and repositioning of antennas FIGUIIE 15-17. Iso-SAR curves for a single element and a pair of within respective catheters in clinical applications of interstitial hyperthermia. Figure 15-21 illustrates the use of a!l of elements of a six-element conformable applicator. Note that the these techniques in the treatment of a bulky, renal cell useful heating area is about 80% of the aperture area in both cases. (Leybovich L, Nussbaum GH [submitted for publication]sg) carcinoma in the posterior fiank.TM A major problem with the design of m~crowave anso Single element tennas is the so-called dead space at the distal end of the 3.4 X 3.4era2 antenna. The physical significance of this proce,s is that fully Iooded (=81) 915rnHz when attempts have been made to increase the length of the coupling: direct contoct depth: lcm. muscle phantom antenna by increasing the length of the exposed inner con= E C 0.79 ductor, the dead space becomes proportionally longer. The clinical significance is that in certain situations (e.g., treating brain tumors with interstitial thermo-radiotherapy), the Two-element arroy volume of implant must be significantly longer than tumor 3.4 X 8.1 cm2 volume at the expense of normal tissue. Some modificaEc = 0.81 tions of basic antenna design have been carried out in order single element of the six-element applicator is 79% of the aperture area of 11.6 cma. For a two-element array, 81% of the 3.4 8.1 cm2 area is therapeutically useful,s9

~A CONNECTOR

NYLON CATHETER

AIR

FIGURE 15-18. Basic design of interstitial microwave antenna. (Lyons BE, Britt RH, Strohnbehn JW: IEEE Trans Biomed Eng 31:54, t984)

COAXIAL FEEDLINE

INSULATOR

Chapter 15 Hyperthermia

329

FIGURE 15-19. Isotherms from a single antenna in dog brain. (Lyons BE, Britt RH. Strohnbehn JW: IEEE Trans Biomed Eng 31:55, 1984)

to eliminate this "dead end" and to improve the thermal distribution. A comparison of the specific absorption rate for a conventional and a modified antenna are shown in Figure 15-22. Microwave Itltracavitary Applicators Intracavitary applicators can be employed to deliver local hyperthermia to tumor sites in and adjacent to hollow viscera or cavities, for example, in gastrointestinal (esophagus, rectum), gynecologic (vagina, cervix, and uterus), and genitourinary (prostate, bladder) systems. The design of and specific absorption rate patterns produced by a helical intracavitary probe (that provides more uniform heating than probes of earlier vintage) are discussed by Luk and associates.~ A photograph of one such probe is presented in Figure !5-23. Clinical use of intracavitary heating probes, although currently much less than that of interstitial probes, is increasing steadily. Local Heating With Ultrasound Tissue heating with ultrasound may be carried out with external transducer applicators, appropriately coupled to the tissue surface. These transducers can be focused or unfocused (Fig. 15-24A and B). Excellent reviews by Fry and Dunn47 and Goss, Johnston, and Dunn55 describe characteristics and properties of ultrasound in various media. For a given frequency, ultrasound is significantly more penetrating in fat than in muscle and far more penetrating in water than in fat. For example, at 1 MHz penetration depths are 3.8 cm in skeletal muscle, 10 cm in f~t, and 2000 cm in degassed, distilled water. The penetration of ultrasound in bone is extremely modest, with a penetration depth in human sku~l bone at 1 MHz of only 0.3 cm. For frequencies appropriate to clinical hyperthermia with ultrasound, penetration depths of ultrasound in both muscle and fat are inversely proportional to frequency. At all frequencies of

15

o b 12crn 6cm 5.3cm 3.2cm

"Front" edge is 0.2cm beyond tip of antenno

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

clinical relevance, the ultrasound absorption coefficient for skin may exceed that for underlying muscle by as much as a factor of two .55 In contrast to microwaves, th~ penetration depth for ultrasound at a given frequency (in a given type of tissue) and the frequency dependence of penetration depth are not a function of applicator size. This is because for all ultra-

330

Principles and Practice of Radiation Oncology POSTERIOR


Pr.4 ~ P[5 Pr.6 Pr.4

MEDIAL
Pr.5 / Pr.6

14 15"16 6 II 12

FIGURE 15-21. Setup of microwave antennas and thermometers for treatmem of a bulky external protrusion of a large renal cell carcinoma. Each treatment session consisted of two successive applications of interstitial hyperthermia in which the junctions of all microwave antennas employed were positioned 4 cm and 8 cm. respectively, from the lateral edge of the tumor, as shown at right. (Nussbaum GH. Leybovich L. Emami B. et al: [submitted for publication]n4)

.
Pt I Power distribution (CTC) Ch. ] - Antennas Ch. 2- Antennas ,5-8 Ch.3- Antennas 9-12 Ch.4-Antennos

Pr.2

LATERAL
Position of antenna junctions I. First application Tr. Second application

PHANTOM

680MHz !

/
AIR
PHANTOM 1Omm

FIGURE 15-22. Intercomparison of conventional (below) and improved (above) interstitial microwave applicator, developed at Chalmers University of Technology. The specific absorption rate lines were measured by temperature probing using Bowman-type FIGURE 15-23. Helical intracavitary applicator, consisting of a thermistors in the initial phase of the heating. The measurements helical coil. plastic sleeve, and finger glove. The diameter of the were performed at 680 MHz with a delivered power of 20 W for the plastic sleeve is 2.1 cm; its length is 9.4 cm. (Luk KH, Jiang HB, improved and 10 W for the conventional applicator. The SAR Chou CK: Hyperthermic Oncology, vol 1. p 592. London. Taylor & values were then recalculated to the therapeutic levels 2 W and 1 Francis 1984)
XX~, respectively. (Courtesy of Yngve Hamnerius, Ph.D.)

sound transducers with dimensions of clinical relevance, the wavelengths of sound in clinical media are very much less than the above dimensions. This can be immediately appreciated from the fact that for water, muscle, and fat. the wavelength of ultrasound at ! MHz is only 0.16 cm. Therefore, regardless of the diameter of an ultrasound applicator employed in clinical hyperthermia, there is virtually no beam spreading and hence no loss of axial power density due to such dispersion. Compared with microwaves, ultrasound retains its collimation (i.e., surface beam width) far better in propagating through a clinical medium and consequently can more appropriately be thought of as a "beam." For ultrasound, the reduction of power density with increasing depth in a given tissue is caused predominantly by absorption in the tissue medium and reflection at interfaces between different tissues. Just as for electromagnetic irradiation, reflections of ultrasound at tissue interfaces can result in cold or hot spots in the vicinity of the interfaces, depending on whether the reflected wave is 180 degrees out of phase or in phase with the incident wave. Given the larger magnitude of the reflection coefficient at a muscle-bone interface, undesirable

cold spots could well be produced in the muscle tissue upstream of the interface, and a hot spot is likely to be produced in the first few millimeters of bone itself. Thus, both bone and air are serious impediments to :he propagation of ultrasound because of absorption and reflection, respectively. Tissue heating with ultrasound may be carried out with single or multiple beams. For single beam applications, ultrasound frequencies of 0.3 to 3 MHz typically are used. Typical area coverage is from 5 to 75 cm2. Therapeutic heating to depths of up to 6 cm in muscle is sometimes attainable, and power required ranges from 1 to 100 watts. Therapeutic heating to larger tissue volumes and a!so heattng at greater tissue depths may be obtained by employing a multiplicity of overlapping (or intersecting) ultrasonography beams. For multiple beam ultrasound, typical operating parameters are (1) frequency, 0.3 to 1.0 MHz; (2) ~,olume coverage, 20 to 500 cm3; (3) therapeutic depth, up t(; ~5 cm; and (4) power required, 30 to 200 watts. Ult, asound-induced hyperthermia is very well suited to therapeutic heating in homogeneous muscle and in muscle behind fat. However, due to its extremely high absorption rate in bone

Chapter 15 Hyperthermia 331


LONGITUDINAL (cm)

5
! 1 O 0 0

DEPTH o (cm)

5
4
2 2 1 0

5 6

- 0.519 MHz 10 cm tto~sducer 15 cm hot~ir~

- Muscle-like ptao~tom - 50 worts for o~e n,,inul~ power input ~AR-GRAPHITE compo~te needle thermo~:x~{~ I dB/cm/MHz - Numbers ore t,~m~emfure ele~ofio~s off~ o~e minute in degrees C

Depth. cm

~:"..

.....:

.,;
Beef in vitro Temperature rise

1234567896 543 21 0123456 Diameter, cm

FIGURE 15-24. (A) Temperature elevations (C) with ultrasound after 1 minute in muscle-like phantom agargraphite composite (I dB/cm/MHz) 50 watts for 1 minute power input needle thermocouple; 0.519 MHz, 10 cm transducer, 15 cm housing. (B) Temperature distribution obtained in muscle mass in vitro using multiple ultrasound beams (0.9 MHz frequency) focused at 6 cm in circular trajectory. (Cheung AY, Neyzari A: Cancer Res (suppl)44:4736s, 198412)

:rod its ,. .wua!2p total,_xeflectioi~ at tissue-air interfaces, ultrasound-induced hyperthermia is not suited to therapeutic heating of lesions in the brain and chest wall because of the presence of tile skull and ribs, respectively; it is also not suited to heating of lesions in the thorax because of the presence of air in the lungs.

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

Local Heating with Radiofrequency Electric Fields Localized tissue heating with radiofrequency electric fields may be carried out with both external and interstitial applicators. External applicators that may be employed for this purpose include pairs of conducting plates and both pancake and solenoidal coils. For interstitial heating with radiofrequency electric fields, electrical!y connected arrays of metallic needles (e.g., stainless steel implant guides), defining electrode pairs in vivo, may be used. The tempera-

(a)

(b)

(c)

332

Principles and Practice of Radiation Oncology

ture elevations obtained in clinical hyperthermia with radiofrequency electric fields ma, y be produced through conductive, dielectric or inductive heating of the tissue of interest (Fig. 15-25). Conductive or resistive heating refers to heating with radiofrequency ion currents that are driven between pairs of external or interstitial electrodes. The resulting power deposition is effected through collisions of moving ions with tissue molecules. With dielectric heating, power is deposited in tissue through the interaction of the electric fields produced between plate electrode pairs with the rotational motion of molecules within the tissue. In contrast to conductive heating, which is best achieved with good electrical contact between plates and tissue, effective dielectric heating may be produced with the plate electrodes physically removed from the respective tissue surfaces. Therefore, in situations in which electrode plate-tissue coupling is poor, dielectric heating will often predominate over conductive heating. Inductive heating refers to heating of tissue with radiofrequency "eddy currents" induced (in the tissue) by the radiofrequency magnetic fields produced in the tissue by the coil applicator employed. Whatever the type of radiofrequency heating used, the electric and magnetic fields referred to here are not associated with waves propagating through tissue. Therefore, the concepts of penetration depth, beam spreading, and reflection coefficients (central to the analysis of power deposition by microwaves and ultrasound) are irrelevant to an analysis of power deposition by radiofrequency electric fields. The absorbed power density distribution in homogeneous tissue of a specific type, produced in a given application of conductive or dielectric heating, will depend very little on the frequency employed. In such an application, both axial and lateral distributions of absorbed power density will be governed primarily by the ratio of the characteristic dimension of the electrodes to their separation. If this ratio is much greater than one, then the absorbed power density distribution will be approximately uniform over the entire volume between the plates, except very near the edges of the region. As the electrode size-to-separation ratio decreases, the distribution becomes increasingly nonuniform, with the higher absorbed power densities located nearer the plates (the highest absorbed power density will usually be found adjacent to the edge of the smaller plate electrode). The characteristics of the absorbed power density distributions suggest that for plate electrodes of a given size (e.g., diameter) heating at midplane depth will become less efficient as plate separation increases. Moreover, at a given tissue depth therapeutic field size wil! also decrease with increasing separation of plates of a given diameter. Power deposition in inhomogeneous tissue by radiofrequency electric fields will be influenced critically by the resistive and dielectric properties of the component tissue types and also by the orientation of electric fields relative to tissue interfaces within the medium. For example, for conductive heating in a tissue region containing fat and muscle, in which all the current driven between the plate electrodes passes through both the fat and muscle slabs (in series), the ratio of absorbed power density in fat to that in muscle can easily equal or exceed the ratio of resistivities in the two media. Since the fat to muscle resistivity ratio (e.g., for a frequency of 1 MHz) is nearly 10, it is evident that therapeutic heating in the muscle slab will almost certainly be accomplished by excessive heating in the overlying fatty tis-

sue. Radiofrequency electric fields approximately parallel to tissue (or media) interfaces can be produced in vivo through conductive heating between properly placed interstitial electrodes or through inductive heating with coils placed near the tissue surface. Local hyperthermia with external radiofrequency applicators is generally produced most effectively through conductive or dielectric heating, employing pairs of plate electrodes. The frequencies typically used in such applications range from 0.1 to 27 MHz. Typical area coverage is 10 to 200 cm2 (single pair of plates). Therapeutic depths in muscle of up to 8 cm have been reported. The total power required for therapeutic heating in a given application ranges from 20 to 300 watts. Radiofrequency-induced hyperthermia may also be produced through inductive heating, employing pancake coils placed parallel to the tissue surface. Frequencies employed typically range from 5 to 27 MHz. Area coverage is typically from 10 to 400 cm2, and therapeutic depths of up to 4 cm may be obtained. ~n contrast to conductive or dielectric "plate" heating, ind~,_.cive heating can raise temperatures in muscle behind fat or bone to therapeutic levels without producing unacceptably high temperatures in the overlying fat or bone layers. This is because radiofrequency electric fields (driving the eddy currents) induced in vivo will often be nearly parallel to fat-muscle or bone-muscle interfaces of clinical interest.

Interstitial Heating with Radiofrequency Electric Currents


Interstitial heating with radiofrequency electric fields is essentially resistive heating, produced by currents driven between electrically connected arrays of needles (or between an intracavitary electrode and a needle array) (Fig. 15-26A and B). Thus connected, the respective needle arrays constitute flat or curved electrodes in vivo. The slabs of tissue between respective pairs of adjacent arrays can be heated simultaneously, either by connecting alternate arrays to form a circuit with two "multiplane" electrodes (i.e., arrays 1, 3, 5, etc., as one electrode; arrays 2, 4, 6, etc., as another) or by heating only one slab at any instant but sweeping rapidly back and forth (via electronic switching) through successive pairs of "single plane" electrodes. Either of these techniques will permit the entire implanted volume to be heated in a single application. The frequencies used in such applications are typically in the range 0.1 to 1".0 MHz. The power required typically ranges from 10 to 200 watts ...... ,, Regional (Deep) Heating

The basic physical characteristics of deep heating have recently been reviewed by Cheung and Neyzari.l"- Description of facilities and techniques for regional heating also have been published.~129 Several systems for deep heating have been designed at a few institutions or are commercially available. Corry and Barlogie16 previously outlined the characteristics of an ideal regional hyperthermia system, which includes evaluable depth of penetration with half penetration distances of t,p to 12 cm, field size from 20 cm to 30 cm, field locahzation to the tumor to minimize normal tissue toxicity and op~.imize therapeutic range, simple and safe patient machine interface that is preferably noninvasive, not requiring con-

Chapter 15 Hyperthermia ~ 333


EXTERNAL AND INTRACAVITARY
RecfumPosterior Wall

(
Electrocie

INTERSTITIALAND INTRACAVtTARY Vaginal WalLateral Extension

Electrode

Thermometer

Component Electro~ie

FIGUILE 15-26. Radiofrequency current heating. Examples of interstitial and intracavitary techniques.

tact with the body surface and permitting operation with an awake and alert patient and allowance for simple and accurate thermometry and dosimetry. These authors point out that there is no system that can meet all of these criteria to provide the optimal characteristics for regional hyperthermia. The following systems are available for deep (regional) heating: 1. Capacitive radiofrequency consists of the placement of at least two electrodes at a distance from the skin, connected to an appropriate generator that creates electromagnetic fields between the two electrodes, causing rotation in isotropic molecules within the volume of interest,s7 Capacitive heating has been used by Japanese scientists and is apparently capable of heating localized volumes at the depth of human body without superficial overheating.16~ The Thermotron-8 (Yamamoto Viniter Co. Ltd., Japan) is in clinical use in a few centers71a66; however, more investigation is needed both from a physics and clinical point of view to test its value in clinical hypertherrnia. 2. Resistive radiofrequency requires the contact to the skin of the patient of two electrodes attached to a radiofrequency generator that will produce electromagnetic currents within the treatment volume. Chilled water has been used to cool the electrodes. Although the system may permit localization and moderate size of the heated volume, according to Corry and Bar!ogie~6 it is not optimal for deep heating. 3. Inductive radiofrequency, represented by the Magnetrode,~5 consists of a large circular coil, up to 30 inches in diameter, which operates at 13.56 MHz. This geomemc configuration makes no provision for physical localization of the magnetic fields to the area of the tumor. Experiments on homogeneous or heterogeneous animal tissue phantoms showed that power at 400 to 500 watts

resulted in preferential surface heating with ineffective central heating.~25 Experiments by Storm and coworkers~6 in the live dog resulted in surface tissue temperature remaining within physiologically tolerable levels and the central organs being heated to temperatures in the range of 42C; the authors pointed out that static phantoms and dead animals are inadequate models to predict magnetic loop induction heating patterns since they do not account for redistribution of heat by an intact circulatory system Gibbs49 has extensively evaluated the clinical applications of concentric coil (Magnetrode) operated at 13.56 MHz and the annular phased array. He has made spatial temperature measurements during clinical treatments with Magnetrode, and his observations are consistent with theoretical predictions and phantom measurements: [emperatures fall with increasing radial depth and ineffective heating in deep-seated tumor sites is observed. The magnetic induction coaxial electrode system !ocalizes magnetic fields in relation to the tumor, resulting in a greater depth of penetration than with magnetic induction techniques. According to Corry~6 and Olesonns the only significant drawback is the necessity for skii~ cooling. The field localization is better than that provided by Magnetrode but not as good as that possibly obtained with ultrasound. The annular phased array consists of a series of concentrically arranged MW applicators operated in phase at 50 to !00 MHz (BSD Corp., Salt Lake City, Utah).~4sa~9 Several studies have reported its ability to deliver heat homogeneously to deep-seated structures in the thorax, abdomen, or pelvis. Gibbs and associates4s have described many of the characteristics of this device as we11 as results in patients treated to abdomen and pelvis. A clinical comparison study of the Magnetrode and the annular phased array system was recently published by Gibbs.4~ The ultrasound multi-transducer unit is a prototype employing multiple focused, computer-coordinated ultrasound transducers with capability for obtaining different thermal configurations by selective motion of the transducer. It was developed by Varian Associates (Palo Alto, California) and is under preliminary clinical evaluation at the Mallinckrodt Institute of Radiology.~29 A steered, focused ultrasound system has been designed by Leles5 who reported preliminary results.

Techniques of Regional Heating

The techniques and preparation of patients to receive regional hyperthermia have been described.49a29 During the course of treatment, blood pressure, pulse, systemic temperature, and general condition of the patient should be monitored continuously. ECG monitoring during the course of hyperthermia by taking a sample trace of lead II every 10 to 15 minutes is strongly recommended (radiofrequency power supply must be off because it interfers with an ECG device). During the course of hyperthermia, not only the tumor temperature but the systemic temperature must be monitored continuously via the esophageal thermometer. Systemic temperature (core temperature) of above 40C may put the patient in danger of malignant hyperthermia. Care should be taken that core hyperthermia does not exceed 40.5C.

334

Principles and Practice of Radiation Oncology

a known function of temperature. Therefore, for both types of optical probes, analysis of the light returned from the sensor permits the temperature of the sensor to be accuTemperature measurement in phantoms is an important rately determined and establishes these probes as useful aspect of thermal treatment planning and will be discussed in the next section. At present, direct and continuous mom- thermometers. Both the GaAs and rare earth bi-phosphor tonng of temperatures in clinical applications of hyperther- probes are encased in Teflon tubing and can be inserted mia constitutes the only truly reliable method of thermal into 16- to 20-gauge catheters. While temperatures in electromagnetic fields can be treatment verification. Clinical temperature probes should readily measured with minimally and non-conducting be able to measure temperature to both an accuracy and precision of 0.1 C. Therefore, reference thermometers and probes, accurate measurement of temperature with invasive probes placed in ultrasound fields can also pose serious other devices employed for calibration of such probes problems. Through the direct absorption of ultrasound by should be able to establish temperature to within 0.02C by plastic or Teflon probe sheaths or catheters, temperature National Bureau of Standards (NBS) calibrated mercurv-inartifacts of several degrees can easily be p~oduced. As glass thermometers, NBS traceable highly stable thermistor shown by the temperature decay curves (after power ~s shut probes, and by the use of a variety of hydrated salt solutions to establish several physico-chemical thermometric fixed off) in Figure 15-27.8, the magnitude of ultrasound-induced points in the range of 30 to 50C. In clinical hyperthermia temperature artifacts presen[ in measurements with a Teflon-coated: gallium arsenide "optical" probe increases with subsurface thermometry is currently carried out exclusively increasing diameter (decreasing gauge) of the Teflon or with invasive probes,ss plastic catheters employed to house the thermometry probe. Inaccuracies caused by such artifacts can be reduced by employing, for example, thermocoupie probes in hypoThermometers dermic needles, as is demonstrated by the lowest temperature decay curve (0.2C artifact) in Figure 15-27B. In genInvasive thermometers fall into three basic categories: electrically conducting, minimally conducting, and nonconducting (optical) probes. Standard thermistor and thermocouple sensors with metallic leads are conducting FIGURE 15-27. (A) Temperature decay curve with gallium-arprobes; with a thermistor, the sensor is a semiconductor senide probe, after power is shut off. (B) Reduction of artifact whose resistance decreases with increasing temperature; using thermocouple probes in hypodermic needles. with a thermocouple, the temperature sensor is the junction GALLIUM ARSENIDE PROBE between two dissimilar metals. DEPTH: 5cm PORK MUSCLE ULTRASOUND FIELD, 2.SMHZ; ~0 WATTS Redistribution of charge across the junction leads to the establishment of a potential difference whose value depends on the junction temperature. For a given pair of 14 GA. (2.1 ram) metals, the mathematical form of this temperature depen6.2oc*= dence is known. Thus, through measurement of resistance (thermistor) or voltage (thermocouple) and proper conversion of measured values to temperature, these devices can be employed as accurate thermometers. In thermistor and thermocouple probes, the sensors may be exposed or, more typically, encased in 20- to 29-gauge plastic tubes or hypodermic needle sheaths. An example of a minimally conducting probe is the OFF 30 high resistivity thermistor with carbon impregnated plastic leads, developed by Bowman and now marketed by Vitek t l I I I I 20 50 40 50 60 0 10 and BSD Medical Corporations. The sensor, a thermistor TIME (sec) whose resistance at a given temperature is much higher than that of a "standard" thermistor, is encased in a Teflon THERMOCOUPLE: 29GA. HYPO. NEEDLE tube that can be inserted into a 16-gauge catheter. DEPTH: 3cm PORK MUSCLE Non-conducting, "optical" probes employ sensors ULTRASOUND FIELD: 2.5MHZ~ 30 WATTS composed of gallium arsenide and a mixture of two rare earth phosphors, respectively. The "leads" of both optical probes are optical fibers. Gallium arsenide is a semiconductor for which the "band gap" (the energy separation of electrons in the conduction and valence bands) is a known function of temperature. The fraction of an incident beam of light (of a given wavelength) reflected or scattered by the GaAs sensor will depend on the width of the band gap compared with the energy of photons in the beam. The gallium arsenide probe was developed by Christensen and is now marketed by Clini-Therm Corporation. In the rare earth bi-phosphor probe, developed by Wickersheim and marketed by Luxtron Corporation, a pulse of incident light I 1 I I t I excites both phosphor materials, causing them to subse20 30 40 50 60 0 I0 quently fluoresce. The ratio of the intensities of a pair of TIME fluorescence emission lines one from each phosphor is
TI-IERMOMETRY

era]., temperature measurement in ultrasound fields is least problematic when conducting probes (thermistors or thermocouples) are employed and are placed either "bare" or in hypodermic needles directly into the tissue medium. Since the absence of catheters makes mapping along the probe track relatively diiticult to effect, muiti-sensor probes are recommended for acquisition of the multiple-point temperature data desired. Use of catheters fabricated from materials that only weakly absorb ultrasound would substantially reduce temperature artifacts in ultrasound fields. As in the case of conducting probes in electromagnetic fields, measurement errors can also be significantly reduced by sampling temperatures with the power turned off. Use of standard thermistors and thermocouples to monitor temperatures in electromagnetic (microwave and radiofrequency) fields can often lead to substantial uncertainties in temperature determinations caused by noise induction in probe electronics or direct heating of the conducting probe sensors. The nature of field-induced distortions of temperature information and of satisfactory corrective techniques for determining actual tissue temperature are illustrated in Figure 15-28. The rapid decay of temperature with time immediately following power shutoff, seen in the plot of the left of the figure, is a clear indication of the presence of field-induced probe heating or noise. The actual tissue temperature just before power shutdown is determined through identification of the onset of true tissue cooling on the cooling curve (the slower decay, typically 1 to 3C per minute) and the projection of the tangent to the curve at this point to the instant of power removal. From the cooling curve of the temperature-time plot at the right of the figure, it is evident that no such field-induced artifacts are present. Therefore, the temperarare indicated by the corresponding conducting probe may be taken directly as actual tissue temperature. Employmem of the high resistivity (Bowman) thermistors and in particu37.0 40.0 43.0 40.0 43.0

Chapter 15 Hyperthermia 335 lar of the optical temperature probes effectively eliminates the field-induced artifacts mentioned above and permits accurate measurement of temperature, without correction, at all times (i.e., power on and off) during the heating period. Non-invasive thermometry is currently the subiect of considerable research in a number of laboratories and is not likely to be commercially available in the near future. Techniques being evaluated include infrared thermography, microwave thermography (radiometry), and ultrasound reconstruction (to provide mappings of temperaturedependent ultrasound velocity or absorption). Although infrared thermography is a commercially available tool for non-invasive temperature measurement, it can provide information only on surface temperatures.

Thermal Treatment Planning In principle, planning of the desired hyperthermia treatment may be carried out as in radiation therapy through measurements in phantoms and calculations with models of tissue heating. To date, however, thermal modeling has been of little value in predicting temperature distributions produced in a specific treatment of a given patient, partly because of problems with the mathematics of the process but primarily because of the uncertainty in the values of critical patient-specific parameters (e.g., blood flow) and with poorly defined, inappropriate boundary conditions. The fabrication of phantoms that are satisfactorily patient equivalent is far more difficult in hyperthermia than in radiation therapy. For "patient equivalence" in hyperthermia, phantoms must be equivalent to the tissue of interest in both power deposition and heat transfer in viva While the former requirement may be satisfied without excessive difficulty in most cases, the latter equivalence is usually proMGURE 15-28. Representative temperature-time plots, expressed as strip chart recorder output curves, for two different conducting probes (e.g., thermistors) in a microwave radiofrequency field. With the power on, the indicated temperatures at the locations of the respective probe sensors in the given medium are identical at 43C. Analysis of the decay of temperature with time for both probes, after the power is shut off. identifies the actual temperatures at the two points in the medium to be 40 C (left hand curve) and 43C (right hand curve), respectively.

/
power on 1 mln. ~,\ time Increasing

Dower off
~2C/min

~2C/mm.

t=ssue temp. = 40.0C

tissue temp.

336

Principles and Practice of Radiation Oncology

hibitively difficult to establish because of the problem of satisfactorily simulating convective heat transfer due to blood flow. Nevertheless, if properly used, phantoms that are electromagnetically (or acoustically) equivalent to the clinical tissue of interest and also similar to the tissue with regard to static heat transfer (i.e., heat transfer due to thermal conduction) can facilitate the acquisition of valuable information of direct relevance to a specific, proposed treatment. For electromagnetic energies (microwaves and radiofrequency fields) phantom material of value include dielectric liquids: sponges soaked in saline; mixtures of "superstuff," polyethylene powder, salt, and water; salineformaldehyde gels; beef; and of course live animal tissue. In liquid phantoms mappings of electric (or acoustic) fields may be readily made because of the ease with which the appropriate probes may be scanned across the phantom volume. The field distributions obtained with a given applicator can establish the characteristic performance of the applicator in tissue with the same dielectric properties (and topography) as the liquid phantom material. Absorbed power density distributions may also be obtained from measurements of the initial slopes of temperature-time curves at chosen points in solid or gel phantoms. Measurement of absorbed power density distributions (watts/cm~) in such phantoms with site-specific or patient-specific geometries can yield valuable information about the types, sizes, number, and placement of applicators well suited to a specific, proposed application of clinical hyperthermia. Information obtained from measurements of absorbed power density and distributions of leakage intensity can also be used to improve the coupling of the applicators to the patient surface, thereby reducing (e.g., for microwaves) both leakage and field spreading across air gaps, for example. Finally, absorbed power density distributions obtained from measurements in "patient-appropriate" phantoms can be used as input data to calculations of temperature distributions employing thermal models. Temperature distributions obtained from measurements with a given applicator in liquid phantoms will suggest that the heating produced by the applicator is far more uniform than it is likely to be in tissue with similar dielectric properties. It should also be appreciated that the distribution of "static" state temperatures obtained from measurements in solid and gel phantoms cannot be taken as an accurate indication of the three-dimensional temperature distributions produced, with the same set-up and operation of applicators, in the corresponding living tissues, because

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

QUALITY ASSURANCE IN CLINICAL HYPERTI-IERMIA

The delivery of uniform treatment must be the principal goal of a program of quality assurance and assessment in hyperthermia, tf satisfactory compliance with the temperature-time specification in a particular clinical hyperthermia protocol is to result in the administration of approximately equivalent thermotherapy to all patients, the temperature specification itself will have to be sufficiently quantitative and comprehensive as to unambiguously define the thermal state of the heated tissue, in general, both absorbed power density (W/cm~) and local heat transfer (cal/seccm~) will vary considerably over tissue volumes of clinical interest, making it extremely difficult to produce uniform temperature distributions within the heated tissues. It is obvious that non-uniform three-dimensional temperature distributions cannot be described by specification of temperature at a single point. Correspondingly, production and maintenance of equal temperatures at one point in each of several tumors cannot be cited as proof that the thermal states of the respective tumors are equivalent or even comparable. To demonstrate that satisfactory compliance with hyperthermia protocol treatment specifications has in fact been attained, the important characteristics of the treatments must be adequately described. A diagram of the setup of each treatment should be made, indicating clearly the anatomical location of the treatment site, the location and extent of tumor (tumor dimensions should be given), and the location of applicators and thermometers (or thermometry catheters) within and around the tumor volume. Documentation of the set-up for treatment of a tumor on the chest wall of a particular patient in our clinic is shown in Figure 15-29.n2 Additional requirements and procedures for effective quality assurance and assessment-in clinical hyperthermia are discussed by Nussbaum.n2 Practically speaking, it is recommended that before initiation of each treatment of every patient at least three temperature probes (in plastic catheters) be implanted in the tumor and one in the adjacent normal tissues close to the tumor. Additional probes placed on tumor and normal tissue surfaces will also provide additional valuable infor-

FIGURE 15-29. Documentation of the setup of a patient with a minor on the left chest wall. Tumor dimensions are 6 8 x 3 cm The tumor border is indicated by a solid curve. The estimated useful thermal field (10 10 cm2) of the microwave applicator is bounded by a dotted curve. Five catheters are implanted in the tumor, one containing a four-sensor thermometry probe (sensors 9-12). Separation of successive catheters containing probes 8, 7, 9 to 12, and 5 is 2 cm. The depth of the catheters beneath the tumor surface is indicated in the lateral view. Sensors 2, 3, and 4 are on the skin. (Nussbaum GH: Cancer Res 44(suppl):4811s, 1984ha)

SUPERIOR

AP VIEW

~.

LATERAL VIEW

Chapter 15 Hyperthermia

337

marion. For consistency, the following (but by no means unique) distribution of subsurface probes is useful:
1. One probe on central axis of the minor, at the greatest possible depth 2. Two probes, one on each side of the central axis of the tumor, at the greatest possible depth, within 1 cm of lateral margins of tumor

As alluded to above, plastic catheters that can be left in situ for several days should be employed whenever possible to permit reinsertion of the probes during several treatment sessions and to facilitate a linear mapping of temperature for each probe without making additional wounds in the implanted tissue. Initially, in the early phases of heating, location of the temperature maxima within the respective catheters should be determined. With the temperature sensors at these points, temperatures should be recorded every 1 to 2 minutes until the desired temperature equilibrium is reached. Temperature mappings along the respective catheter tracks should then be made. It is also advisable that during the steady-state portion of the heating interval tern-

peratures be recorded every 2 minutes (certainly no less frequently than every 5 minutes). For each application of hyperthermia, the diagram of the treatment set-up discussed earlier (e.g., Fig. 15-30) should include cross-sectional views of the tumor when appropriate and also the positions of the thermometry catheters within this cross section. The time required to reach the desired steady-state temperature, the interval of time the tissue is kept in this steady thermal state, and the time for decay of the elevated temperatures about halfway back to their pre-heating values (after the power is shut off) should also be recorded. Other information of value should be gathered and recorded, such as the physical agent employed to heat the tissue (e.g., microwaves, 915 MHz; ultrasound, 2 MHz); the nature, size, shape, number, and placement of the applicators; and the method of coupling the applicator to the tissue. The total net power delivered to the applicators and also to the tissue load should be estimated and recorded. If skin cooling is used, it should be clearly noted. Finally, problems encountered and adjustments made during the course of treatment should be noted, as they may serve as the basis for subsequent changes or improvements in apparatus or procedure.

HYPERTHERMIA TREATMENT RECORD Treat,.ont


PAT IEIIT I;AHE: SITE }IEATED: ~ O~I@~A IIEATIIIG I-IODAL I TY : DURATIOtl OF TREATI.IEt~T:

FIGURE 15-30. Example of a hand-written hyperthermia treatment record.

Rat~ of T~p~raturo Docay Following

DIAGRA)I OF TREATI.IEIT SET-UP: ~"

The~ometr~ RI: penetr.~m , depth~j,~ BI: penetr.~m , deptl~jm R2: penetr.~m , depth~m BE: penetr.~r,., depti~__~m ban9o probe: location rectal probe:location

P~T.

By: Trea~ent Administered

A~
~i gna tu~re

338 Principles and Practice of Radiation Oncology CLINICAL APPLICATIONS OF HYPERTHERMIA

Depending on the volume treated, hyperthermia can be classified as: local, regional (deep), or systemic (whole body). A complete hyperthermia clinical service will require the availability of several heating modalities and clinical thermometw systems. As indicated in Figure 15-3!, a typical hyperthermia clinical setup is composed of the following basic elements: 1. Variable power supply with stabilizing electronic circuitry 2. Applicators, transducers, or antennas for the delivery of heat in the tissues 3. Coupling devices, when necessary (surface applicators), to improve heat deposition in the tissues and decrease leakage 4. Thermometry system (thermistor, thermocouples, optical thermometers) and appropriate devices to record the temperature 5. Feedback mechanisms, either manual or controlled by electronic circuits, and microprocessors to vary power supply to maintain tissue temperature at a constant level Several commercially available models are available for a variety of clinical applications (Fig. 15-32). The depth at which the measuring probes are inserted into the tissues must be carefully documented (if necessary with conventional radiographs or computed tomography). Before initiation of treatment, a minimum of two and ideally three dimensions of the tumor should be measured. A diagram of the lesion and the treatment set-up should be made, indicating the location and topography of the tumor as well as the location of the probes employed for thermometry. As indicated above, temperatures should be recorded continuously in at least two or three locations at the depth of the tumor (central axis and periphery) and at the surface. Electromagnetic field-probe coupling cannot always be eliminated and may interfere with satisfactory readings. An attempt should be made to place the hypodermic thermistor probes perpendicular to the microwave applicator antenna. Direct measurements with the power off should be taken every 15 minutes (as a minimum). If pretreatment studies in patient-specifi~ phantoms inFIGURE 15-31. Typical hyperthermia clinical setup. Depending on the volume treated, heating may be considered (1) local, (2) regional (deep), or (3) whole-body.

dicate that electromagnetic leakage intensities in critical "non-target" areas of the patient (e.g., the eye) are likely to exceed 10 mW/cm2, then these areas should be shielded. Coupling of externally applied microwave applicators to the patient surface is made with plastic bags containing deionized water, circulating through a temperature-regulated water bath.
SELECTION OF MODALITIES FOR SPECllaIC ANATOMICAL SITES

Depending on the composition of the tissues, volume, and depth to be treated, one or several methods of heat delivery may have specific applications or limitations in a given topographic area (radiofrequency, microwave, ultrasound).
Head and Neck

Normal tissue topography and tumor location make microwaves, ultrasound, and radiofrequency ,urrents (external or interstitial) all potentially appropriate for this region. The indications for a particular modality in a given case depend on the depth and size of the lesion, c Brain The use of ultrasound to heat brain tissue, even if multiple beams are used, is questionable because of the pronounced absorption of ultrasound in bone (the skull) unless "a window" (bone flap) is created in the skull. The preferred approaches are either microwave heating with single or multiple external beams or radiofrequency currents (external or interstitial). The availability of longer microwave antennas could popularize the use of this method. The presence of the skull and the inability to probe the brain repeatedly with invasive thermometers make adequate thermometry in this region difficult at present.
Lung, Mediastinum, and Esophagus

Ultrasound cannot be employed effectively to heat tissue in these sites because of enhanced absorption in bone (ribs, sternum) and virtually tota! reflection at muscle-air inter-

ROUTING BOXES

,~TELETHERMOMETERS FEEDBACK DEVICES

THERMISTOR PROBES

A~UCAroR
TISSUE LOAD
COUPLING

~
TUNER
STUB

WATTMETER ~
ISOLATOR

BAG

POWER SUPPLY 915 MHz, 100 WATTS

Chapter 15 Hyperthermia

339

FIGURE 15-32. Commercial hyperthermia systems for a variety of clinical applications. (A) CliniTherm unit for local external and interstitial microwave (915 MHz) heating. (Courtesy of Clini-Therm Corp.) (B) Thermotron capacitive radiofrequency unit for regional hyperthermia. (Courtesy of Yamamoto Vinyter Co, Ltd.) (C) Annular phased array multiple electrode unit for regional heating. (Courtesy of BSD Corp.)

,., fa,-~ ,,; (lung, trachea). Microwaves may be applied exterc:aI!x, in single or multiple beams (independent or phaselocl~ed) or with interstitial techniques. Antennas may also be placed inside intraesophageal tubes or. in the case of the lung, mounted on flexible bronchoscopes or small intrabronchial tubes. Tissue in the tung, esophagus, and mediastinum may also be heated employing radioffequency currents, driven between appropriately placed pairs of intracavitarv and external electrodes. Interstitial thermometry in the lung or mediastinum is permissible for relatively superficial intmthoracic lesions, particularly when the solid tumors are adiacent to the chest wall.
intact Breast and Chest Wall

Tumors of the intact breast are essentially high water content lesions in a fatty tissue environment. For both microwaves and ultrasound, power absorption in muscle is much

more pronounced (5 to 15 times greater) than in fat. In addition, penetration depths in fat for microwaves and ultrasound are sufficiently large (e.g., 26 cm for microwaves at 433 MHz and 31.3 cm for ultrasound at 1 MHz) to permit delivery of significant power to even deep-seated lesions with only modest normal tissue heating. Finally, the magnitude of the reflection coefficients at fat-muscle interfaces for microwaves (0.5) and ultrasound (0.1) is sufficiently modest to minimize the likelihood of problems of hot and cold spots (thermally speaking) at such interfaces, especially with ultrasound. From the considerations noted above, it is clear that both microwaves and ultrasound are extremely well suited to heat lesions m intact breast. Given the pronounced absorption of ultrasound in the ribs and sternum, its application to chest wall heating may be less desirable than that of microwaves. Lesions in the breast may also be heated with radiofrequency currents or microwaves, employing interstitial electrodes alone or combined with external applicators However, when such currents are

340

Principles and Practice of Radiation Oncology


oooo~ o o

forced to pass through both fat and muscle (in series), power absorption in fat is much more pronounced (about tenfold greater) than in muscle. Abdomen or Pelvis

~ o _L_ o

o o o
o o o

Typicolly:

The presence of air within and in the vicinity of abdominal viscera, such as the stomach, bowel, bladder, or rectum, may in many cases contraindicate the use of ultrasound to heat some abdominal tumors. However, single or multiple beams of ultrasound may be employed effectively to heat large solid lesions in this region. For deeper heating, multiple microwave beams, preferably phase-locked, may be the preferred modality. Extremities
As in the head and neck region, the diameter of the extremities and the location of malignant lesions in these areas permit microwaves, ultrasound, and radiofrequency currents to be employed effectively in specific applications of hyperthermia. However, the presence of bone should generally restrict the use of ultrasound to heating tissue thicknesses in excess of 3 cm. Moreover, multiple beams of ultrasound should be employed with caution.

Thermometers "Mu/tiplane" electrode oair

/~Thermomefers

electrode oairs

FIGURE 15-33. Interstitial hyperthermia with radiofreq~1.~cy electric currents.

fined bythe implant to be heated in a single application and is preferred over the one slab at a time approach, which can make total time spent heating a large volume ..... .ceptably long. Electric fields between pairs of subarrays will become increasingly non-uniform over the distance between the electrode pairs as the electrode width is reduced, leading to increasingly non-uniform heating across the slab. In general, heating of a given slab will be most satisfactory when Techniques for Interstitial Hyperthermia the ratio of the electrode width to the electrode separation is kept as large as possible. The ideal range of radiofreInterstitial hyperthermia can be done with either coaxial quency for interstitial hyperthermia is 0.1 to 1.0 MHz. microwave antennas or by radiofrequency electric currem It has been proposed that hollow stainless steel guides or with externally heated (induction) ferromagnetic seeds. (needles) be used for implantation, which can be used both Interstitial microwave hyperthermia may be produced for radiofrequency heating and interstitial radiation therthrough the use of coaxial microwave antennas inserted in apy, similar to "old-fashioned" preloaded radium needles. Teflon catheters (tubes) implanted in the tissue volume of This procedure will require iigid metallic needles to be in interest. Generally, the frequency required is 300 to 915 place (in the tumor) for about 6 to 8 days. The discomfort to MHz. The heating pattern of a coaxial antenna operating at the patient and misarrangement of needles due to patient microwave frequencies is etlipsoidal, with the long axis of motion during these several days, resulting in unsatisfactory the ellipsoid coincidental with the inner conductor of the thermoradiotherapy, will be of great concern. antenna. Both longitudinal and transverse extent of the There is a newly developed material (polyethylene therapeutically significant power absorption and therefore carbon impregnated material) that conducts radiofreheating from a given antenna will depend on the length of quency currents. These catheters can be used with both the exposed inner conductor and on the frequency of operradiofrequency and microwave antennas. ation. For a given microwave antenna currently commerFerromagnetic implants may be used tn conjunction cially available, the therapeutically useful volume of heatwith the magnetic induction technique to absorb energy ing is approximately 3.0 to 4.0 cm (longitudinally) and 1.0 preferentially from an applied radiofrequency magneqc to !.5 cm (transverse section). The greatest absorbed power field. The tissue in the vicinity, of the implant is heated by density and therefore the greatest amount of heating will thermal conduction from the heated seed rather than by occur m the immediate vicinity of the antenna and specifidirect absorption of energy from the magnetic field. At frecally at the junction of the antenna. Engineering attempts quencies near 13.5 MHz the tissue will absorb significant are under way to solve this problem. power directly, whereas at lower frequencies (near i MHz) the ferromagnetic seeds will heat preferentially. The fact Radiofrequency interstitial byperthermia may be produced through resistive heating induced by radiofrequency that seed temperatures are always significantly hotter than currents driven between pairs of electrically connected the surrounding medium causes little concern because the arrays of stainless steel implant guides. Thus connected, the tissue next to the seeds would have been traumatized by the respective needle arrays constitute flat or curved electrodes very act of insertion. Similar trauma occurs for a correlain vivo. The slabs of tissue between respective pairs of such tional radiation implant as well. The attractive feature of this arrays can be heated simultaneously, either by connecting technique is the seeds thermal regulating properties. Spealternate arrays to form a circuit with two "multiplane" cial alloys have been developed (e.g., Ni + 4.% Si) that pass electrodes or by heating only one slab at any instant by from a ferromagnetic state at low temperature throug]-, a switching rapidly back and forth (via electronic switching) Curie transition near therapeutic temperatures to a nonthrough successive pairs of single-plane electrodes (Fig. magnetic state. Such seeds would not require thermomatic 15-33). Either technique will permit the entire volume de- maturing but would function as a thermostat themselves to

Chapter 15 Hyperthermia establish the absolute temperature within the implanted region. The Curie point for the alloy mentioned above is within 40 to 50C. Whether transition can be made sharper and what constructions are required for making seeds dioactive and biocompatible is the r~sk of future research. Interstitial hyperthermia has also been used for deepseated tumors (in lung) in phase I studies~ Atthough initial results are promising, the technique needs more refinement before it is considered for wider clinical use. Future developments include: Whole-Body Hyperthermia

341

1. Better microwave antennas (i.e., to heat larger volumes) 2. More routine utilization of multi-sensor thermometers to determine the temperature profile over the volume of implant 3. In vitro (phantom) and in vivo thermal dosimetry studies 4. Advancements in ferromagnetic seed implants
Teclmiques for Interstitial Thermoradiotherapy Implants

Basic rules of interstitial radiation therapy indicate that the entire gross tumor volume with at least 1 cm margin be encompassed within implanted volume. The same principle also holds for interstitial hyperthermia. The microwave antennas should be implanted 1 to 1.5 cm apart. The radiofrequency electrodes must be implanted at similar, uniform distances; however, here it is extremely important to line up the electrodes in parallel rows to achieve uniform electromagnetic fields and temperature distributions. Lack of attention to this basic principle will result in severe undertreatment of certain portions of a given tumor or hot spots that may increase morbidity of the treatment. The implantation procedure for microwave antennas or radiofrequency local current electrodes to be combined with interstitial irradiation is carried out using the Quimby or Patterson Parker systems. Afterloading techniques are most suited, for this type of therapy. The space between each Teflon tube will be 1.0 to 1.2 cm. The inner diameter of the Teflon tubes should be adequate for placement of 192Ir radioactive sources (ribbons) and microwave coaxial antenna. The entire palpable gross tumor with an adequate margin should b.. encompassed. Depending on whether the specific volt: .ne has been previously irradiated, the total tumor dose will be in the range of 4000 to 7000 cGy, over a period of 4 to 8 days (1000 cGy +/- 10% per day). The Teflon catheters prevent the conduction of radiofrequency current and therefore are not useful for hyperthermia with this modality (unless E-M conducting materials are used to manufacture catheters). Attention to minimum tumor temperature (T min) within the target volume is extremely critical. Minimum tumor temperature has to be within therapeutic temperarares of 42.5 to 43C. In the University of Arizona experience116 the average T min was 40.7C, which resulted in 38% complete response; in the series reported from the Institute of Gustav-Roussy,2 using similar technique, T min was 44C, which resulted in 83% complete response. Analysis of the University of Arizona experience indicates that there was a significant correlation of complete response with T min (p--0.003). Attention als0 must be paid to T max for its possible relation to complications.

Whole-body hyperthermia has been used for the treatment of disseminated disease, alone or combined with chemotherapeutic agents. It may have value not only in the treatment of overt metastatic disease, but perhaps later as an adjuvant, combined with chemotherapy for the treatment of micrometastasis. Whole-body hyperthermia has been administered using (1) hot water or wax baths, (2) a "space suit" with circulating hot water, or (3) extracorporeal temperature elevation employing a heat exchanger through which the blood is circulated (after shunting it with an arteriovenous femoral bypass). Temperatures in the range of 45.5C to 41.5C have been delivered to patients with distant metastases for several hours, sometimes in combination with cytotoxic drugs. In many instances general anesthesia is required and carefu! monitoring of body temperature and multiple physiological functions is mandatory (cardiovascular, respiratory, neurologic, fluids, electrolyres, etc~). Preliminary reports by Barlogie and associates,~ Parks,n and Kubota8 suggest that there may be definite therapeutic efficacy in the combination of these agents for treatment of advanced or disseminated human neoplasia.
CURRENT CLINICAL EXPERIENCE

An increasing number of reports on the clinical application of hyperthermia have been published recently.2,6Ta7v8~l2,l~avl It is not known whether, as reported by Hornback and co-workers7a and Scott and colleagues,~46 higher doses of irradiation will provide more tumor control than will moderate doses (3000 to 4000 cGy). In evaluating the results of local hyperthermia it must be remembered that there are a variety of factors that influence the effectiveness of this modality, such as: (1) tumor characteristics, including size (volume), status (primary, recurrent, metastatic), and anatomical location; (2) dose of irradiation (including fractionation); and (3) thermal dose (minimal temperature and time of exposure). In analyzing the many reports on the subject, it is pertinent to identify the characteristics of an adequate clinical trial in hyperthermia (Table 15-6). Many of the reports published fail to adhere to these criteria, making the evaluation of results more di~cult. LOCAL EXTERNAL HYPERTHERMIA AND IRRADIATION Patients receiving irradiation and hyperthermia have been treated with daily doses ranging from 200 to 300 cGy or with two to three fractions per week of 300 to 600 cGy. Total doses of irradiation have varied from 1800 to 6000 cGy. Most of the patients have been treated with electron beam, although some have been irradiated with 6Co or conventional x-rays. Although in a few institutions heat has been given before irradiation, in most instances, because of logistic convenience, heat is given 15 to 30 minutes after irradiation. In general, temperatures in the range of 42 to 44C have been employed for 30 to 60 minutes, 2, 3, or even 5 times a week. External microwaves (usually 915 MHz) have been employed more frequently, albeit by few institutions. An-

342

Principles and Practice of Radiation Oncology

Table 15-6 Criteria for Reliable Clinical Trials in Hyperthermia Clinical Criteria Patient selection (probability of survival) Tumor selection (histology, size, location) Evaluation of results (quantitative end points) Survival Tumor regression and control Normal tissue effects

Technical Criteria Irradiation (volume, doses, energy) Heat (modality, temperature-time, fractionation, thermal dose) ThermometW methods
Quality Assurance t~ocedures Patient/tumor eligibility Evaluation procedures Irradiation (calibration, dosimetry) Heat (delivery equipment evaluation, thermometr3, calibration, clinical thermometry) Sratistical considerations Safety (patient, operators)

derson and Stanford have published their experience with ultrasound. In most instances skin cooling has been employed when there is no evidence of superficial tumor involvement. A few reports, summarized in Table 15-7, compared results in matched comparable lesions or by randomized allocation to treatment with irradiation alone or irradiation and hyperthermia. The complete response rate with irradiation alone ranges from 7% to 42%, with an average of 30%. With irradiation and hyperthermia the complete response has ranged from 47% to 87%, with an average of 70%. The only report that describes tumor control lasting from 3 months to several years is that by Perez and associates,13 who observed 80% to 100% tumor control in pa-

tients initially exhibiting a complete response for various tumor histologies. Perez and associateslz* described greater tumor control in 46 recurrences from carcinoma of the breast treated with various doses of irradiation and hyperthermia (43C, 60 minutes delivered twice weekly after irradiation) in comparison with the results observed in a group of 118 historical controls treated with comparable doses of irradiation alone (Fig. 15-34). Except for thermal burns, noted in 6% of the patients, the normal tissue effects were similar in both groups. Some of the most significant studies comparing irradiation alone with irradiation and hyperthermia are by Arcangeli and associates~~ and in a preliminary form by the Radia~ tion Therapy Oncology Group.ls~~35 Arcangeli and associates~ have described their experience in four separate randomized trials using various doses and fractionation schedules of irradiation, ranging from 4000 to 6000 cGy, with two or five daily fractions per week and hype~,~hermia at 42.5C for 45 minutes or 45C for 30 minutes appiiec! before or after irradiation. These authors have shown a tumor control of 75% with irradiation and hyperthermia compared with about 40% with irradiation alone. The resuits with simultaneous or sequential administration of radiation therapy followed by heat were comparable, although simultaneous administration was slightly more effective than sequential (Fig. 15-35). They also noted an increase in tumor control with a larger number of heat fractions and with higher thermal doses. These authors showed that the best therapeutic gain was achieved when the skin was cooled and that the tolerance of normal tissues was better when smaller daity dose fractions were used (200 to 250 cGy) than when larger fractions (400 to 500 cGy) with similar total doses were delivered. For the past 3 years the Radiation Therapy Oncology Group (RTOG Protocol 81-04) has conducted a randomized study for superficial, measurable recurrent, or metastatic tumors less than 4 cm in depth. Patients are randomized to receive irradiation alone (400 cGy twice weekly for a

(A) Photograph of a patient with a 4 cm 5 cm recurrent malignant schwannoma in the right zygomatic area (arrow), previously treated witE 6000 cGy total dose delivered with two wedge fields and 6 MV photons. Recurrent lesion was treated with 4400 cGy, foilowed by hyperthermia (microwave, 42.5C for 90 minutes). (B) Patient one year later, showing complete regression and disappearance of the tumor. Chronic otitis was present before treatr,.:_nt and limited necrosis of the middle ear is present. (Perez CA, etal: IntJ Radiat Oncol Biol Ph.ys 7:765, 1981)

Chapter 15 Hyperthermia

343

A
_(A) Patient with recurrent epidermoid carcinoma of the floor of the mouth in the right upper neck following surgical resection and postoperative radiation therapy (6000 cGy total dose). Additional resection and reconstruction were done for recurrence. Subsequent recurrence (shown in photograph) was treated with irradiation (4000 cGy, 10 fractions delivered twice weekly) combined with interstitial and external hyperthermia. (B) Photograph taken 6 months after completion of therapy shows complete regression of tumor. A small ulceration and subcutaneous fibrosis are noted. (Perez CA, Emami BN, Scott RS. In Chretien P, et al (eds): Head and Neck Cancer, p 372. Philadelphia, B.C. Secher Inc, t985)

Table 15- 7 Complete Responses of Superficial Lesions to Irradiation and Irradiation Plus Hyperthermia
Institution Evaluable Patients (Treatment Trials) Same Patient Comparisons Irradiation Alone Irradiation + Hyperthermia Treatment End Point

Duke Universiw:vx Memorial Hospital7~


M. D. Anderson~s IMRS (Rome) Study~ I" II III Roswell Park1.6 Stanford University~: Malmo~" ~r Tianjinl" 9s

7 86
182~ 26 16 15 31 15 73/33 124

7 59
13 26 16 15 3! 15

14% 33%
0% 42% 37.5% 33% 39% 7%

86% 80%
62% 73% 67%, 77%* 87% 87% 47% 54% 68%

Complete response within 1 month of therapy Complete response during followup or improved disease-free interval with combined therapy Complete response for 2 months Complete response at therapy completion or soon after Complete response at 6 months Superior response: CR versus partial response or more than 6 weeks difference in time to regrowth Complete response, 3 to 6 months Complete response

53/17 62

30% 29%

* H,vperthermia immediately after radiotherapy (77%) or delayed 4 hours (67%). .~" Comparable lesions not necessarily in same patient. (Modified from Meyer JL: Cancer Res 44 (Suppl)47:4745s, 1984)

total of 3200 cGy) or a similar dose of irradiation followed the patients treated with irradiation and hyperthermia by hyperthermia (42.5C for 60 minutes twice weekly). Pre- (Table 15-9). liminary results show improved complete response for the The Radiation Therapy Oncology Group is also conpatients treated in arm B, presumably the combination ther- ducting a phase I/II prospective clinical trial to evaluate the apy. In recurrent primary tumors the complete response efficacy and tolerance of normal tissues to a combination of rate is 22% versus 48.8% in arms A and B, respectively definitive doses of radiation therapy (6000 to 6500 cGy (Table 15-8). The side effects of this therapy are compara- delivered in five weekly fractions of 200 cGy) and hyperble, except for a 24% incidence of thermal burn in thermia (42.5C, 60 minutes, twice weekly after irradia-

Principles and Practice of Radiation Oncology

/
0 21137 0 419 0

Table 15-8 Radiation Therapy Oncology Group Protocol 81-04 Preliminary Results (716 Evaluable Sites)
Treatment Option A o 5/~
LESIONS I-3cm DIAMETER 0--0 RT ALONE H RT plus HYPERTHERMIA I I

0-2000

A
100

40012001- 30013000 4000 5000 DOSES OF RT (CGy)

>5000

Number evaluable sites Overall complete response Complete response in recurrent primary Complete response in metastatic tumors

46 15.2% 4 of 18 (22%) 3 of 18 (10.7%)

54 29.6% 11 of 23 (48.8%) 5 of 31 (16.1%)

(Perez CA, Emami B: Endocurietherapy/Hyperthermia Oncoiogy 1:265, 1985)

LESIONS >3 cm DIAMETER ,~ RT plUl HYPERTHERMIA

Table 15-9 Radiation Therapy Oncotogy Group Protocol 81o04 Preliminary Results-- Toxicity (116 Sites)
~.. 40 Complications RT Alone RT + Heat

~ ~o
~-2000 I I 2001- :50~314001>5000 3OO0 40O0 50O0 DOSES OF RT (CGy)

Erythema Dry desquamation Moist desquamation Skin ulceration/necrosis Thermal blister/burn

38% 11% 11% 20% 0%

31% 9% 4% 8% 24%

(Perez CA, Emami B: Endocurietherapy/Hypenhermia Oncology 1:265, 1985)

FIGURE 15-34. (A) Probability of tumor control for lesions ! cm to 3 cm in diameter, chest wall recurrences of carcinoma of the breast. (B) Probability of tumor conrzol for lesions larger than 3 cm in diameter, chest wall recurrences of carcinoma of the breast. (Perez CA, Kuska RP, Emami B, et ah Int J Hyperthermal 2:179, 1986

FIGURE 15-35. The results of a clinical trial reported by Arcangeli and colleagues in which superficial measurable tumors were treated with radiation therapy alone or with simultaneous or sequential administration of radiation therapy and hyperthermia. Tumor recurrences are shown as a function of time. (Arcangeli C, Civadalli A, Lovisolo G, et ah Proceedings of Fourth International Symposium on Hyperthermic Oncology, vol 1, p 329. London, Taylor & Francis, 19843)
RT+HT SIMULT. o RT + HT SEOUENT, RT
13/16

10o

6/12

3/13 6

MONTHS

tion). Preliminary analyses of 65 patients show response rates higher than with irradiation alone (compared with historical controls) and satisfactory tolerance of the normal tissues.1~5 In a similar study at Roswel! Park Memorial Institute, Scott and associatesa47 have reported on 22 patients with cervical lymph node metastases exhibiting tumor control of 75% with definitive irradiation and hyperthermia. The complete response rate in the patients fully treated was :about 80%. The 75% tumor control nl the cervical lymph nodes is superior to a 54% tumor control in a group of patients with similar tumors treated with definitive irradiation alone at participating Radiation Therapy Oncology Group institutions. Less than 10% of the patients have developed thermal burns, necrosis, or ulceration. The treatment with local hyperthermia and irradiation has been well tolerated, with side effects similar to those observed with irradiation alone, except for some local pain and sensory reactions noted in 20% to 25% of the patient,. and superficial burns or ulceration, which have been reported in about 20% of the patients (Table 15-10). The incidence of local burns is related to the temperature used, the coupling of the applicators on irregtilar surface of :he body, and the use of skin cooling. In general, melanomas, lymphomas, and sarcomas have been shown to respond better to irradiation and hyperthermia than epithelial tumors. However, Oleson and associateslt7 in an analysis of 165 superficial lesions found no correlation between different histologic types of tumor and response to irradiation and hyperthermia. A few reports, such as the one by Perez and co-

Chapter 15 Hyperthermia

345

Table 15-10 Reported Toxicities of Localized Hypertbermia


Institution (Reference) Treatment Courses Toxicity Incidence ( ~)

Duke University~"2 M. D. Anderson~" RoswelI Park~: Stanford University~~

53 30 100 52

Washington University~-~

101

Superficial burn Deep burn Local pain Radicular pain Blistering Neurosensow reactions Local pain Superficial burn Ulceration Systemic (vomiting, syncope) Second and third degree burns

13 8 20 10 13 5 23 19 10 2 6

(MeyerJL: Cancer Res 44(Suppl)47:4745s, 1984)

(A) Thirty-two-year-old patient with recurrent melanoma of the right neck, previously treated with a resection and right radical neck dissection. The lower neck mass measures 5 cm ,~ cm: the upper neck lesion, 2 cm X 1 cm The patient was treated with 4000 cGy in 10 fractions twice weekly followed by hypertherr-ia (915 MHz microwaves. 42.5C for 90 minutes). (B) Photograph taken 3 months later shows complete regression of the lesions. No significant skin or subcutaneous tissue seq.uelae appeared. (Perez CA: J Microwave Power 16:205, 1981)

workers,~3 have described a correlation between the size of the lesion and the temperatures observed in the tumor. Les~ons smaller than 2 cm in diameter have been heated to temperatures of 42.5C or higher in 85% of the instances, in contrast to 71% of those measunng 2.1 to 4.0 cm in diameter and 509/o of those with greater depth of involvement. Similar observations have been reported by Oleson and associates~7 and Kim and colleagues.TM The poorer results in larger tumors are most likely attributable to physical factors (inadequate power deposition) rather than to a negation of the biologic advantages of hyperthermia. Perez and associatesTM reported on the proportion of lesions treated to average temperatures achieved at the greatest tumor depth in superficial lesions heated with external microwaves (915 MHz) after irradiation. They noted that 80% of the tumors less than 2 cm in depth could be heated to 42.5C, in contrast to 65% of those measuring 2~ cm to 4 cm in thickness and only 30% of the lesions 4 cm to 5 cm in thickness.

An attempt was made to correlate the average temperatures at the depth of the lesions achieved with tumor regression in 130 lesions. Complete responses were noted in 65% of the patients with tumors less than 2 cm in depth, 71% of those between 2.1 cm and 4.0 cm, and only 37% of those with 4 cm to 5 cm depth of involvement.~9 Oleson and colleaguesn7 also found a good correlation between minimal temperatures and the prediction of complete tumor response. Further, maximum tumor temperature was substantially correlated with the incidence of thermal effects in normal tissues.

Interstitial Hyperthermia The experience with interstitial microwave or radiofrequency has been more limited than that with external applicators.

346

Principles and Practice of Radiation Oncology

(A) Patient with extensive recurrent carcinoma of the breast in the chest wail. previous]3 treated with 6000 cGy and chemotherapy. Recurrent lesions were treated with 4000 cGv in !0 fractions, twice weekly, using 12 MeV electrons. Irradiation was followed by 1-.yperthermia (microwave 42.5C_ for 90 minutes). (B) Patient -~ months after therapy. There is 90% regression of the tumor. Small ulcerations remain m the subclavicular region. (Perez CA, et aI: intJ Radiat Oncol BioI Phvs 7:765. 1981)

B
(A) Chest wall metastases of undifferentiated carcinoma of lung after fhilure of irradiation and chemotherapy. (B) Pbotograpln taken after treatment with -tO00 cGv irradiation and hvperthermia. (Emami B. Perez CA: Applied Radiol, Nov/I)ec. 1984 ~

The complete response rate is approximately the same as that observed with external irradiation and hyperthermia in various anatomical locations (Table 15-11 ). Emami and co-workers-~ reported 69% complete responses ~n 26 tumors that achieved adequate hyperthermia {42C for at least 30 minutes) in contrast to only one of five receiving inadequate heating. The side effects of therapy have been comparable to those observed with irradiation alone. The Radiation Therapy Oncology Group recently activated a randomized study comparing brachytherapy irradia-

tion alone (5000 to 6000 cGy) or combined with interstitial heat (two sessions. 43C, 60 minutes) in the treatment of superficial measurable tumors.
Deep Hyperthermia

Frazier an~ associates~ used radiofrequency in a few unresectable thoracic tt]mors unresponsive to conventional therapy ranging from -~ 1 C to -+5C for 1 hour, five times per

Chapter 15 Hyperthermia
Table 15-11 Results of Interstitial Thermoradiotherapy Number of Patients Complete Response Partial Response No Response O% 11% 18%

347

Author

Cosset et al)9 Emami et al.6 Manning et al ,0~ Surwit et al)~ Vora et al.I77
" ll patients, 14 implants. ~" 29 patients, 31 lestons. ~ 15 patients. I6 lesions.

11= 29t 17 (71%) 12 (42%) 15{;

83% 69% 29% 50% 68%

17% 19% 0% 8% 6%

Patient with 4 x 4 cm fixed perineal recurrence from colon primary previously treated with surgery and full-course irradiation and recurrence treated with combination of irradiation and hyperthermia. Note catheters placed within the tumor for thermometry. (A) Anteroposterior view. (B) Lateral view.

week. Radiologic or pathologic examination showed destrucnon of malignant tissues in all treated patients. Meoz and colleaguesls reported on nine patients with intrathoracic tumors treated with the coaxial radiofrequency unit designed by Corry.16 Intrathoracic temperatures of 42C were obtained in 30% of the sessions and over-40 C in 75% of the treatments. In two patients there was inadequate heating. The authors reported two partial tumor regressions and five stable responses. There was no significant local or systemic toxicity. Oleson and associates,n5 using a pair of coaxial radiofrequency loops placed on the anterior and posterior side of the body, delivered hyperthermia (42C) to human tumors by magnetic induction. The authors did not elaborate on the tumor response. Storm and co-workers159 carried out 69 heat treatments in 36 tumors in 30 patients (17 with visceral tumors) using the Magnetrode. They concluded that radiofrequency hyperthermia-appears to be safe and potentially useful in selected cancer patients, but no detail of tumor response was provided. In another publication, Storm and associates158 reported on the treatment of 44 tumors (21 superficial and 23 viscera!) in 38 patients with advanced cancer. They reportedly reached temperatures of above 42C, 45C, and 50, in 70%, 52%, and 32% of the patients, respectively. No normal tissue injury at these temperatures was reported. Gibbs and co-workers4s and Sapozinkl~s reported on 43 patients (most of them previously irradiated) treated with the annular phased array (BSD Corporation) for a variety of pelvic or abdominal tumors. Twenty-three patients were evaluable. Temperatures of 43C were achieved in 43% of the patients and 41C in 90%. Obiective response was described in 67% of the pelvic tumors and 9% of the abdominal lesions. Subjective palliation responses were noted in 54% of the patients with abdominal tumors and in 83% of those with pelvic lesions. Among the regtonal side effects, the most frequent were persistent pain, small superficial burns, and occasional tumor necrosis caused by rapid regression of the lesion: Minimal systemic physiologic changes were observed. Other reported toxicities of regional hyperthermia have been described, including an extensive necrosis of the musculature of the low back sacral-coccygeal area, which occurred in an anesthetized patient and required extensive surgical d{bridement, resulting in cauda equina peripheral

348

Principles and Practice of Radiation Oncology Table 15-12 Patients Who May Benefit from Hypertbermia Hj~perthermia in Combination w~th Irradiatio~ Patients with previously irradiated recurrent tumors Patients with advanced tumors not controlled with definitive irradiation alone Patients with tumor not responding to conventional irradiation
Hyperthermia in Combiru~on with Chemotherapy Patients with possible micrometastases Patients with distant metastases

neurotoxicity. An incident of heat stroke during thermal therapy was observed, causing a semicomatose state with unresponsiveness to auditory and pain stimuli for a few seconds. The patient recovered within minutes of the onset of the incident with no neurologic deficiL At Washington University an elderly patient treated for a pelvic recurrence of a rectosigmoid carcinoma developed a severe peripheral neuropathy (motor and sensory deficff of L4 to $2 lumbo-sacral roots) within 8 hours following a single hyperthermia session (42.5C, 30 minutes). Partial improvement was noted 6 months later. Douglas and associates3 reported three cases of sudden myelopathy secondary to therapeutic whole-body hyperthermia delivered after spinal cord irradiation. Postmortem examination in one case revealed findings similar to those seen in myelopathy resulting from long-term radiation injury. This report suggests that in some patients hyperthermia may damage previously irradiated spinal cord. Although this side effect occurred during the whole-body hyperthermia, the potential for complication in regional hyperthermia as well should be kept in mind. FUTURE DIRECTIONS IN RESEARCH Efforts by scientists and manufacturers should continue to improve equipment available for heat delivery and thermometry in clinical practice. It is extremely important to carry out clinical investigations to determine the optimal temperature and time as wel! as the schedule for administration of irradiation and heat. Even though the simultaneous administration of both modalities yields the greatest radiosensitizing effect, heat delivery within a short period of time following irradiation is generally required for practical reasons, and results reported with both schedules are comparable. An interval of as long as 4 hours between irradiation and heat may sometimes be advantageous; Arcangeli and associates4 showed that either simultaneous or sequential heat administration yielded similar tumor control, although a 4-hour delay between irradiation and hyperthermia resulted in less effect in the normal tissues. Overgaard and Overgaard124 also demonstrated in 65 superficial melanoma nodules that if hyperthermia was delivered 4 hours after irradiation, a greater therapeutic gain was observed than when both mocialities were administered simultaneously. Because of the possible development of thermotolerance. even with radiosensitizationnl it is important to identify the number of hyperthermia fractions and time between the fractionated treatments that should be delivered to obtain optimal clinical results. Even though therapeutic equivatencies of time-temperature have been used to express thermal doses (T equivalent 43C) based on the Arrhenius plot and observations in animal and human skin,69a4 clinical studies are needed to evaluate these parameters. In the near future the Radiation Therapy Oncology Group will initiate a study in which the administration of hyperthermia at 42.5C for 60 minutes will be compared with 45C for 15 minutes, delivered after fractionated radiation therapy (4000 cGy in mn fractions of 400 cGy each, given twice weekly). Preliminary observations such as those reported by Scott and colleagues~4s suggest that large head and neck lymph nodes respond better to, and normal tissues tolerate well, definitive doses of radiation therapy (6500 cGy) delivered with conventional fractionation in combination with hyperthermia. It may be possible to increase the anti-tumor

effect of high doses of irradiation without increasing toxicity in patients with advanced primary carcinoma of the head and neck, breast, and some soft tissue sarcomas. While a great deal of clinical investigation remains to be done, it can be stated that several groups of patients may benefit from current hyperthermia clinical apl~lications (Table 15-12). Clinical trials should be continued to evaluate adequately the potential role of hyperthermia in the primary management of patients with malignant tumors.

1. Anderson RL, Minton KW, Li GC, Hahn GM: Temperature-induced homeviscous adaptation of Chinese hamster ovary ceils. Biochem Biophys 641:334, !981 2. Arcangeli G, Barni E, Cividalli A, et al: Effectiveness of microwave hyperthermia combined with ionizing radiation: Clinical results on neck node metastases. Int J Radiat Oncol Biol Phys 6:143, 1980 3. Arcangeli G, Civadalli A, Lovisolo G, et al: The clinical use of experimental parameters to evaluate the response to combined heat and radiation. In Overgaard J (ed): Proceedings of 4th International Symposium on Hyperthermic Oncology, Vol I. London. Taylor & Francis, 1984, p 329 4. Arcangeli G, Cividalli A, Nervi C, et al: Tumor control and therapeutic gain with different schedules of combined radiotherapy and local external hyperthermia in human cancer. Int J Radiat Oncol Biol Phys 9:1125, 1983 5. Bieher HI, Hetzel FW, Sandhu TS, eta!: Effects of hyperthermia on normal and tumor microenvironment. Radiology 137:523, 1980 6. Bicher HI, Sandhu TS, Hetzel F~1: Hyperthermia and radiation in combination: A clinical fractionation regime. Int J Radiat Oncol Biol Phys 6:867, 1980 7. Bleehen NM, Honess DJ, Morgan~E: The combined effects of hyperthermia and hypoxic cell sensitizers. In Streffer C, van Beuningen D, Dietzel F, et al (eds): Cancer Therapy by Hyperthermia and Radiation. Baltimore. Urban & Schwarzenberg, 1978, p 62 8. Busch W: Uber den Einl]uss Welchen heftigere Erysipelen zuweilen auf Organsierte Neubildungen Amiben. Verb des Naturh: Preuss Rheinl 23:28, 1866 9. Braun J, Hahn GM: Enhanced cell killing by bleomycin and 43 hyperthermia and the inhibition of recove.y from potentially lethal damage. Cancer Res 35:2921, 1975 t0. Calderwood SK, Dickson JA: Effect of hyperglycemia on blood flow, pH and response to hyperthermia (42) of the Yoshid sarcoma in the rat. Cancer Res 40:4728, 1980 11. Cavaliere R, Ciocatto EC, Giovanella BC, et al: Selective heat sensitivity of cancer ceils. Cancer 20:1351, !967 12. Cheung AY, Neyzari A: Deep local hyperthermia for cancer therapy: External electromagnetic and ultrasound techniques. Cancer Res (suppl) 44:4736s, 1984 13. Clark EP, Dewey WC, Lett JT: Recovery of CHO cells from hyperthermia potentiation to x-rays: Repair of DNA and chromatin. Radiat Res 85:302, 198t 14. Coley WB: The treatment of malignant tumors by repeated

Chapter 15 Hyperthermia 349 inoculations of erysipelas--with a report of 10 original cases. 37. Emami B, Nussbaum GH, Hahn N, et al: Histopathological Am J Med Sci 105:487, 1893 study on the effects of hyperthermia on microvasculature. Int 15. Connor WG, Gerner EW, Miller RC, et al: Prospects for hyJ Radiat Oncol Biol Phys 7:343, 1981 perthermia in human cancer therapy. Part iI: implications of 38. Emami B, Nussbaum GH, Ten Haken RK, et al: Physiological biological and physical clara for applications of hyperthermia effects of hyperthermia: Response of capillary blood flow and to man. Radiology 123:497, 1977 structure to local tumor heating. Radiology 137:805, !980 16. Corry PM, Barlogie B: Clinical application of high frequency 39. Emami B, Song CW: Physiological mechanisms in hyperthermethods for local tumor hyperthermia. In Nussbaum GH mia: A review. IntJ Radiat Oncol Biol Phys 10:289, 1984 (ed): AAPM Monograph No 8.: Physical Aspects of Hyper40. Endrich B, Zweifach BW, Reinhold HS, et aI: Quantitative thermia. New York, American Institute of Physics, 1982, p 307 studies of microcirculatory function in malignant tissue: In17. Chrry PM, Barlogie B, Tilchen EJ, et al: Ultrasound-induced fluence of temperature on microvascular hemodynamics hyperthermia for the treatment of human superficial tumors. during the early growth of the BA-1112 rat sarcoma. Int J IntJ Radiat Oncol Biol Phys 8:1225, 1982 Radiat Oncol Biol Phys 5:2021, 1979 18. Corry PM, Spanos wJ, Tilchen EJ, et al: Combined ultrasound 41. Fajardo LF, Egbert B, Marmor J, et al: Effects of hyperthermia and radiation therapy treatment of human superficial tumors. in a malignant tumor. Cancer 45:613, 1980 Radiology 145:165, 1982 42. Field SB: Cancer Therapy by Hyperthermia, Drugs and Radia!9. Cosset JM, Bmle JM, Dutreix J, et al: Low frequency contact tion._The Third International Symposium, Fort Collins, CO, and interstitial hyperthermia association with brachyrherapy. June 22-26, 1980, p 83 (abstract) IntJ Radiat Oncol Biol Phys 10:307, 1984 43. Field SB, Bleehen NM: Hyperthermia in the treatment of 20. Cosset JM, Dutriex J, Hale C, et al: Interstitial thermoradiocancer. Cancer Treatment Rev 6:63, 1979 therapy: A technical and clinical study of 29 implantations 44. Field SB, Morris CC: The relationship between heating time performed at the Institute Gustave-Rousssy. Int J Hypertherand temperature: Its relevance to clinical hyperthermia. Ramia 1:3, 1985 diotherapy and Oncology 1:179, 1983 21. Cress AE, Gemer EW: Cholesterol inversely reflect the ther45. Frazier OH, Corry PM: Treatment of advanced thoracic mamal sensitivity of mammalian cells in culture. Nature 283:677, lignancies with regional hyperthermia. 2nd Annual Meeting 1980 of the North American Hyperthermia Group, Salt Lake City, 22. Dewey WC, Highfield DP, Freeman ML, et al: Cell biology of UT, 1982 hyperthermia and radiation. In Okada S: 6th International 46. Freeman ML, Holahan EV, Highfietd DP, et al: The effect of Congress Radiat Research, Tokyo, !979, p 832 pH on hyperthermia and x-ray induced cell killing. Int J Ra23. Dewey WC, Hopwood LE, Sapareto SAI er al: Cellular rediat Oncol Biol Phys 7:211, 198t sponses to combinations of hyperthermia and radiation. Radi47. Fry wJ, Dunn F: Ultrasound: Analysis and experimental ology 125:463, 1977 methods in biological research. In Oster G, Moore D, Pollis24. Dewey WC, Sapareto SA, Betten DA: Hyperthermia radiosenter A (eds): Physical Techniques in Biological Research, vol sitization of synchronous Chinese hamster ceils: Relationship 4. New York, Academic Press Inc, 1962 between lethality and chromosomal aberrations. Radiat Res 48. Gibbs FA Jr: Non-invasive electromagnetic heating tech76:48, 1978 niques and the operational characteristics of the annular 25. Dewey WC, Westra A, Miller HH, et al: Heat-induced lethality phased array. Front Radiat Ther Oncol 18:56, 1984 and chromosomal damage in synchronized Chinese hamster 49. Gibbs FA Jr: Regional hyperthermia: A clinical appraisal of ceils treated with 5-bromodeoxyuridine. Int J Radiat Oncol noninvasive deep-heating methods. Cancer Res (suppl) Biol Phys 20:505, 1971 44:4765s, 1984 26. Dewhirst MW, Sim DA, Sapareto SA, et al: Importance of 50. Gibbs FAJr, Peacock LM, Settles KS, et al: Preliminary experiminimum tumor temperature in determining early and longence with induction of deep regional abdominal hypertherterm response of spontaneous canine and feline tumors to mia using the BSD annular phased array applicator system. heat and radiation. Cancer Res 44:45, 1984 Radiat Res 91:423, 1982 27. Dickson JA, Shah DM: The effects of hyperthermia (43C) on 51. Giovanella BC, Morgan AC, Stehlin JS, et al: Selective lethal the biochemistry and growth of a malignant celt line. Eur J effect of supranormal temperatures on mouse sarcoma cells. Cancer 8:561, 1972 Cancer Res 33:2568, 1973 28. Dike PG, Machler RC: Thermometry. In Licht S (ed): Thera52, Giovanella BC, Stehlin JS, Morgan AC: Selective lethal effect peutic Heat and Cold, 2nd ed. New Haven, Elizabeth Licht, of supranormal temperatures on human neoplastic cells. Publisher, 1965, p 36 Cancer Res 36:3944, 1976 29. Donaldson SS. Protective effect of hyperthermia against the 53. Goldfeder A, Brown DM, Berger A: Enhancement of radiorecytotoxicity of actinomycin-D on Chinese hamster ceils. sponse of a mouse mammary carcinoma to combined treatCancer Treat Rep 62:1439, 1978 ments with hyperthermia and radiosensitizer misonidazole. 50. Douglas MA, Parks LC, Bebin J: Sudden myelopathy secondCancer Res 39:2966, 1979 ary to therapeutic total-body hyperthermia after spinal cord 54. Goldin EM, Leeper DB: The effect-of reduced pH on the irradiation. New Engl J Med 304:585, 1981 induction of thermototerance. Radiology !41:505, 1981 31. Dube KD, Seal G, Loeb LA: Differential heat sensitivity of 55. Goss SA, Johnston RL, Dunn F: Comprehensive compilation mammalian DNA potymerases. Biochem Biophys Res Comof empirical ultrasonic properties of mammalian tissues. J mun 76:483, 1977 Acoust Soc Am 64: August 1978 32. Eddy HA: Microangiographic techniques in the study of nor56. Gullino PM: Extracellular compartments of solid tumors. In mal and tumor tissue vascular systems. Microvasc Res 11:391, Becket FF (ed): Cancer, vol 3. New York, Plenum, !975, p 1976 317 35. Eddy HA: Alterations in tumor microvasculamre during hy57. Gullino PM, Grantham GH, Smith SH, et al: Modifications of perthermia. Radiology 157:515, 1980 the acid-base status of the internal millieu of tumors. J Natl 34. Eddy HA, Sutherland RM, Chmielemski G: Effects of hyCancer Inst 34:857, 1965 perthermia alone and in combination with radiation and 58. Gyton AC: Textbook of Medical Physiology, 6th ed. Philadeldrags on the tumor vascular system (meeting abstract). Int J phia, WB Saunders Co, 1981, p 448 Radiat Oncol Biol Phys 6:1385, 1980 59. Hahn GM: Hype~thermia and Cancer. New York, Plenum 35. Elliou RS, Harrison WH, Storm FK: Hyperthermia: ElectroPress, 1982 . magnetic heating of deep-seated tumors. IEEE Trans Biomed Eng 29:61, 1982 60. Hahn GM: Potential for therapy of drugs and hyperthermia. Cancer Res 39:2264, 1979 36. Emami B, Marks JE, Perez CA, et al: Interstitial thermoradiotherapy in the treatment of recurrem/residual tumors. Am 61, Hahn GM, Li GC, Shiu E: Interaction of amphotericin B and J Clin Oncol 7:699, 1984 43 hyperthermia. Cancer Res 37:761, 1977

350

Principles and Practice of Radiation Oncology

87. LeVeen HH, OBrien P, Wallace KM: Radiofrequency ther62. Harisiadis L, Hal! EJ, Kraljevic U, et al: Hyperthermia-biologimotherapy for cancer. J SC Med Assoc 76:5. 1980 cal studies at cellular level. Radiology 1t7:447, 1975 88. LeVeen HH,Wapnick W, Piccone V, et al: Tumor eradication 63. Harris M: Temperature-resistant variants in clonal populaby radio-frequency therapy. JAMA 235:2198, 1976 tions of pig kidney cells. Exp Cell Res 46:30t, 1967 89. Leybovich L, Nussbaum GH: Multiple antenna applicators for 64. Harris M: Stable heat-resistant variants in populations of Chimicrowave-induced, local hyperthermia. Submitted for nese hamster cells. J Natl Cancer Inst 64:1495, 1980 publication. 65. Henle KJ: Sensitization to hyperthermia below 43C induced 90. Leybovich L, Nussbaum GH, Straube W, et al: Multi-element, in Chinese hamster ovary, cells by step:down heating. J Natl conformable applicators for local microwave hyperthermia. Cancer Inst 64:1479, 1980 Submitted for publication. 66. Hente KJ, Dethlefsen LA: Heat fractionation and thermoto91. Li GC, Cameron RB, Sapareto SA, et al: Reinterpretation of lerance. A review. Cancer Res 38:1843, 1978 arrhenius analysis of cell inactivation by heat. Natl Cancer 67. Henle KJ, Dethlefsen LA: Time-temperature relationships for Inst Monogr 61:111, 1982 heat-induced killing of mammalian cells. Ann NY Acad Sci 92. Li GC, Hahn GM: Ethanol-induced tolerance to heat and 335:234, t980 Adriamycin. Nature 274:699, 1978 68. Henle KJ, Leeper DB: Interaction of hyperthermia and radiation in CHO cells: Recovery kinetics. Radiat Res 66:505, 1976 93. Li GC, Hahn GM: Adaptation of different growth temperatures modifies some mammalian cell survival responses. Exp 69. Henriques FC: Studies of thermal injury. V. The predictability Cell Res 128:475, 1980 and the significance of thermally induced rate processes 94.-Li GC, Kal HB: Effect of hyperthermia on the radiation releading to irreversible epidermal injury. Arch Pathol 43:489, sponse of two mammalian cell lines. EurJ Cancer Clin Oncol 1947 13:65, 1977 70. Hilt SA, DenekampJ: The Third International Symposium on 95. Li GC, Petersen NS, Mitchell HK: Induced thermal tolerance Cancer Therapy by Hyperthermia, Drugs and Radiation. Fort and heat shock synthesis in Chinese hamster ovary ceils. BrJ Collins, CO, June 22-26, !980, p 91 (abstract) Cancer 45:132, 1982 71. Hiraoka M, Jo S, Takahashi M, et al: Clinical application of RF capacitive heating for deep-seated tumors. In Matsuda T, Ki96. Li GC, Shrieve DC, Werb Z: Correlations between symhe:is of heat shock proteins and development of tolerance to heat kuchi M (eds): Hyperthermic Oncology. Proceedings of the and to Adriamycin in Chinese hamster fibroblasts: Heat shock Sixth Annual Meeting of Hyperthermia Group of Japan. and other inducers. In Schlesinger M (ed): Heat Shock. From Tokyo, Japanese Society, of Hyperthermic Oncology, 1984, p Bacteria to Man. Cold Springs.Harbor, NY, Cold Spring Har190 bor Laboratory, 1982 72. Hornback NB, Shype RE, Shidnia H, et al: Preliminary clinical results of combined 433 Megahertz microwave therapy and 97. Li RY, Shazng TZ, Lin SY, et al: Effect of hyperthermia combined with radiation in the treatment of superficial malignant radiation therapy on patients with advanced cancer. Cancer lesion in 90 patients. In Overgaard J (ed): Proceedings of the 40:2854, 1977 4th International Symposium on Hyperthermic Oncology, 73. Hume SP, Rogers MA, Field SB: Heat induced thermal resisvol. 1, Summary Papers. London, Taylor & Francis, 1984, p tance and its relationship to lysosome response. Int J Radiat Oncol Biol Phys 34:503, 1978 395 98. Lindholm CE, Kjellen E, Landberg T, et al: Microwave-in74. Jahde E, Rajewsky MF, Baumgartl H: pH distributions in duced hyperthermia and radiotherapy. Clinical results. In transplanted neural tumors and normal tissues of BDIX-rats Overgaard J (ed): Proceedings of the 4th International Symas measured with pH microelectrodes. Cancer Res 42:1505, posium on Hyperthermic Oncology, vol. 1, Summary Papers. 1982 London, Taylor & Francis, 1984, p 341 75. Joines WT, Jirtle RL, Rafal MD, et al: Microwave power absorption differences between normal and malignant tissue. 99. Luk KH, Jiang HB, Chou CK: SAR patterns of a helical microwave intracavitary applicator. In Overgaard J (ed): HyperIntJ Radiat Onco! Biol Phys 6:681, 1980 thermic Oncology, vol. 1. Taylor and Francis, London, 1984, 76. Kal HB, Hatfield M, Hahn GM: Cell cycle progression of p 591 murine sarcoma cells after irradiation or heat shock. Radiol100. Marmot J: Reactions of hyperthermia and chemotherapy in ogy 117:215, 1975 animals. Cancer Res 39:2269, 1979 77. Kim JH, Hahn EW: Clinical and biological studies of loca101. MarmorJB, Hahn GM: Combined radiation and hyperthermia lized hyperthermia. Cancer Res 39:2258, 1970 in superficial human tumors. Cancer 46:1986, 1980 78. Kim JH, Hahn EW, Ahmad S: Combination hyperthermia and 102. Marmor JB, Hahn GM: Ultrasound heating in previously irraradiation therapy for malignant melanoma~ Cancer 50:478, diated sites. Int J Radiat Oncol Biol Phys 4:1029, 1978 1982 103. Marmor JB, Pounds D, Hahn GM: Clinical studies with ultra79. Kim JH, Hahn EW, Antich PP: Radiofrequency hyperthermia for clinical cancer therapy. Natl Cancer Inst Monogr 61:339, sound induced hyperthermia. Natl Cancer Inst Mongr.61:333, 1982 1982 80. Kim SH, Kim JH, Hahn EW: The enhanced killing of irra104. Marmor JB, Pounds D, Postic TB, et al: Treatment of superficial human neoplasms by local hyperthermia induced by uldiated HeLa cells in synchronous culture by hyperthermia. trasound. Cancer 43:188, 1979 Radiat Res 66:337, 1967 105. Meoz RT, Corry P, Frazier OH, et al: Hyperthermia and radia81. Krogh A: The Anatomy Physiology of Capillaries. New Haven, tion therapy for the treatment of intrathoracic human maligCT, Yale University Press, 1922 82. LandryJ, Bernier D, Chretien P, et al: Synthesis and degradanant tumors: Initial clinical and technical observations (abtion of heat shock proteins during development and decay of stract). Radiat Res 94:541, 1983 thermotolerance. Cancer Res 42:2457, 1982 106. Meyer JL: The clinical efficacy of localized hyperthermia. 83. Law MP, Ahier RG, Field SB: The response of the mouse ear Cancer Res 44(suppl) 47:4745s, 1984 107. Mitchell HK, Moiler G, Petersen NS, et al: Specific protection to heat applied alone or combined with x-rays. Br J Radiol from phenoscopy induction by heat shock. Dev Genet 1:181, 51:132, 1978 84. Leeper DB, Karamuz JE, Henle KJ: Effect of inhibition of 1979 108. Mittal B, Emami B, Sapareto S, et al: Effects of sequencing of macromolecular synthesis on the induction of thermo-tolerthe total course of combined hyperthermia and radiation or. ance. Proc Am Assoc Cancer Res 18:139, 1977 the RIF-! murine tumor. Cancer 54:2889.. 1984 85. Lele PP: Local hyper~hermia by ultrasound. InNussbaum GH: AAPM Monograph No. 8, Physical Aspects of Hyperthermia. 109. Mondovi B, Argo AF, Rotillio G, et al: The biochemical mechNew York, American Institute of Physics, 1982, p 393 anism of selective heat sensitivity of cancer ceils. II. Studies on nucleic acids and protein synthesis. Eur J Cancer Clin 86. Lepock JR, Massicotte-Nolan P, Rule GS, et aI: Lack of a corOncol 5:137, 1969 relation between hyperthermic cell killing, thermotolerance, 110. Mondovi B, Strom R, Rotillio G, et a!:.The biochemical mechand membrane Iipid fluidity. Radiat Res 87:300, 1981.

Chapter 15 Hyperthermia 351

anism of selective heat sensitivity of cancer cells. I. Studies 131. Perez CA, Sapareto SA: Thermal dose expression in clinical on cellular respiration. EurJ Cancer Clin Oncol 5:129, 1969 hyperthermia and correlation with tumor response control. 111. Nielson OS. Overgaard J, I~m,ara T: Influence of thermoto. Cancer Res 44 (suppl) 44:4818s, 1984 lerance on the interaction between hyperthermia and radia132. Pettigrew RT, Gait LJM, Ludgate CM. et al: Clinical effects of tion in solid tumor in vivo. BrJ Radiol 56:267 1983 whole-body hyperthermia in advanced malignancy. Br Med J 112. Nussbaum GH: Quality assessment and assurance in clinica] 4:679, 1974 h,vperthermia: Requirements and procedures. Cancer Res 133. Raaphorst GP, Romano SL. Mitchell JB, et al: Intrinsic differ44(suppl):4811s, 1984 ences in heat and/or x-ray sensitivity of seven mammalian 113. Nussbaum GH, Goodman RE. Bruce AA: Improved applicacell lines cultured and treated under identical conditions. tor-patient coupling in microwave-induced hyperthermia. Cancer Res 39:396, 1979 Med Phys 10:897, 1983 134. Radiation Therapy Oncology Group, Progress Report on Pro114. Nussbaum GH. Leybovich L. Emami B. et ai: Techniques for tocol 81-04, p D201. 1984 improved administration of interstitial hyperthermia with !35. Radiation Therapy Oncology Group, Progress Report on Promicrowaves. Submitted for publication. tocol 81-13, p D229, 1984 115. Oleson JR, Manning MR, Heusink-veld RS: H,vperthermia by t36. Reinhold HS, Van Den Berg-Block A: Enhancement of thermagnetic induction. II. Clinical experience with concentric mal damage to the microcirculation of "Sandwich" tumors by electrodes. Int J Radiat Oncol Biol Phys 9:549. 1983 additional treatment. EurJ Cancer Clin Oncol 17:781. 1981 116. Oleson JR, Manning MR, Sim DA. et al: A review of the Uni- 137. Roti Roti JL, Winward RT: The effects of hyperthermia on the versity of Arizona human clinical hyperthermia experience. protein-to-DNA ratio of isolated HeLa cell chromatin. Radiat Front Radiat Ther Oncol 18:136, 1984 Res 74:159, 1978 117. Oleson JR, Sim DA. Manning MR: Analysis of prognostic van138. Rubin P, Casaret~ G: Microcirculation of tumors. Part I: Anatables in hyperthermia treatment of 161 patients. Int J Radiat omy function, and necrosis. Clin Radiol t7:220, 1966 Oncol Biol Phys, 10:2231, 1984 139. Ry~ KH. Kang MS, Levitt SH, et al: Effect of hyperthermia on 118. Overga~rd J: Influence of sequence and interval on the biothe lactic acid content in tumor and muscle. Submitted to logical response to combined hyperthermia and radiation. Radiat Res Cancer therapy by hyperthermia, drugs and radiation. The 140. Sapareto SA. Dewey WC: Thermal dose determination in Third International Symposium. Fort Collins CO, June cancer therapy. Int J Radiat Oncol Biol Phys, 10:787. 1984 22-27, !980, p 105 (abstract) 141. Sapareto SA. Hopwood LE, DeweyWC: Combined effects ofx 119. Overgaard J: Effect of hyperthermia on malignant cells in irradiation and hyperthermia on CHO cells for various temvivo. Cancer 39:2637 1977 peratures and orders of application. Radiat Res 73:221. 1978 t20 Overgaard J: The effect of local hyperthermia alone, and in 142. Sapareto SA, Hopwood LE, Dewey WC: In Streffer C van combination with radiation, on solid tumors. In Streffer C Beuningen D, Dietzel F, et al (eds): Cancer Therapy by Hy(ed): Cancer Therapy by Hyperthermia and Radiation. Properthermia and Radiation. Baltimore-Munich. Urban & ceedings of the 2nd International Symposium, Essen, 1977. Schwarzenberg, 1978, p 199 Munich. Urban & Schwarzenberg, 1978, p 49 t43. Sapareto SA, Hopwood LE, Dewey WC, eta!: Effects of hy121. Overgaard J: Simultaneous and sequential hyperthermia and perthermia on survival and progression of Chinese hamster radiation treatment of an experimenta! tumor and its surovary, cells. Cancer Res 38:393, 1978 rounding normal tissue in vivo. Int J Radiat Oncol Biol Phys 144. Sapareto SA. Raaphorst GP, Dewey WC: Cell killing and the 6:1507. 1980 sequencing of hyperthermia and radiation. Int J Radiat Oncol t22. Overgaard J, Nielson OS: The role of tissue environmental Biol Phys 5:343, 1979 factors on the kinetics and morphology of tumor cells ex145. Sapozink MD, Gibbs FA Jr, Gates KS, et al: Regional hyperposed to hyperthermia. Ann ICY Acad Sci 335:254, 1980 thermia in the treatment of clinically advanced, deep seated 123. Overgaard K. Overgaard J: Investigations on the possibility of malignancy: Results of a pilot study employing an annular a thermic tumor therapy. I. Short wave treatment of a transarray applicator. IntJ Radiat Onco] Biol Phys 10:775, 1984 planted isologous mouse mammary carcinoma. Eur J Cancer 146. Scott RS, Perez CA, Johnson RJR, et al: Enhanced clearance Clin Oncol 8:65, 1972 and downstaging of advanced node positive head and neck 124. Overgaard J, Overgaard M: A clinical trial evaluating the efcancer by the addition of local hyperthermia to deflnmve fect of simultaneous or sequential radiation and hypertherradiotherapy. Submitted for publication. mia in the treatment of ma,;gnant melanoma. In Overgaard J 147. Scott RS, Johnson RJR, Kowal H. et al: Hyperthermia in com(ed): Proceedings of the 4th International Symposium on bination with radiotherapy: A review of five years experience Hyperthermia Oncoiogy, vol ~.. London. Taylor & Francis, in the treatment of superficial tumors. Int J Radiat Oncol Biol 1984, p 383 Phys 9:1327, 1983 125. Paliwal BR. Gibbs FA Jr, Wiley AL Jr: Heating patterns in- 148. Scott RS, Johnson RJR, Story K-V, et al: Local hyperthermia in duced by a 13.56 MHz radiofrequency generator in large combination with definitive radiotherapy: Increased tumor phantoms and pig abdomen and thorax. Int J Radiat OncoI clearance, reduced recurrence rate in extended followup. Int Biol Phys 8:857, 1982 J Radiat Oncol Bio] Phys 10:2119, 1984 126. Parks LC: Cancer therapy by hyperthermia, drugs and radia149. Song CW: Effect of local hyperthermia on blood flow and tion. The Third International Symposium, Fort Co!lins, CO, microenvironment: A review. Cancer Res 44(suppl):4721s, June 22-26, 1980, p !13 (abstract) 1984 127. Perez CA, Emami B: A review of current clinical experience 150. Song CW: Effect of hyperthermia on vascular function of nor. with irradiation and hyperthermia Endocurietherapy/Hymal tissue and experimental tumors. J Natl Cancer Inst perthermia Oncology 1:265, 1985 60:711, 1978 128. Perez CA: Kuske RP, Emami B, et al: Irradiation alone or 151. Song CW., Kang MS, Rhee JG, et al: Vascular damage and coml~ined with hyperthermia in the treatment of recurrent delayed cell death in tumors after hyperthermia. Br J Cancer carcinoma of the breast in the chest wall: A nonrandomized 4t 309, 1980 comparison. Int J Hyperthermia 2:179, 1986 152. Song CW, Kang MS, Rhee JG, et ah Effect of hyperthermia on 129. Perez CA, Emami B, Nussbaum GH: Regional (deep) heatvascular function in normal and neoplastic tissues. Ann NY ing, clinical studies in progress. Front Radiat Ther Oncol Acad Sci 335:35, 1980 18:108, !984 153. Song CW, Kang MS, Rhee JG, et al: Effect of hyperthermia on 130. Perez CA, Emami B, VonGerichten D: Clinical results with vascular function, pH and cell survival. Radiology 137:795, irradiation and local hyperthermia in cancer therapy. In 1980 Overgaard J (ed): Proceedings of 4th International Sympo154. Song CW, Rhee JG, Levitt SH: Effect of hyperthermia on hysium on Hyperthermic Oncology, vol 1, Summary Papers. poxic cell fraction in tumor. Int J Radiat Oncol Biol Phys London, Taylor and Francis, !984, p 398 8:851. 1982

352

Principles and Practice of Radiation Oncology

155. Spiro IJ, Raaphorst GP, Sapareto SA, et al: Int J Radiat Oncol Biol Phys (in press) 156. Stewart FA, Denekamp J: Sensitization of mouse skin to X-irradiation by moderate heating. Radiology" 123:195, 1977 157. Stewart FA. Denekarnp J: The therapeutic advantage of combined heat and x-rays on a mouse fibrosarcoma. Br J Radiol 51:307. 1978 158. Storm FK, Harrison WH, Elliott RS, et al: Hyperthermic therapy for human neoplasms: Thermal death time. Cancer 46:1849, 1979 159. Storm FK, Harrison WH, Elliott RS, et al: Normal tissue and solid tumor effects of hyperthermia in animat models and clinical trials. Cancer Res 39:2245. 1979 160. Storm FK, Harrison WH, Elliott RS, et ai: Thermal distribution of magnetic-loop induction hyperthermia ~n phantoms and animals: Effect of the living state and velocity of heating. Int J Radiat Oncol Biol Phys 8:865, 1982 161. Streffer C. Ffengstebeck S, Tamulevicius P: Glucose metabolism in mouse tumor and liver with and without hyperthermia. Henry Ford Hosp MedJ 29:41, 1981 162. Subjeck JR, Sciandra JJ, Chao CF, et al: Heat shock proteins and biological response to hyperthermia. Br J Cancer 45:127, 1982 163. Suit HD. Gerweck LE: Potential for hyperthermia and radiation therapy. Cancer Res 39:2290, 1979 164. Surwit EA. Manning MR, Aristizabal SA, et al: Interstitial thermoradiotherapy in recurrent gynecologic malignancies. Gynecol Oncol 15:95, 1983 165. Sutton CH: Necrosis and altered blood flow produced by microwave-induced tumor hyperthermia in a murine glioma. Am Assoc Cancer Res (abstract). 1976 166. Suvama S, Yabumoto E Furunishi H, et al: A RF unit for deep-seated tumors. In Matsuda T, Kikuchi M (eds): Hyperthermic Oncology. Proceedings of the Sixh Annual Meeting of Hyperthermia Group of Japan. Tokyo, Japanese Society of Hyperthermic Ontology, 1984, p 116 167. Tannock IF: The relation between cell proliferation and the vascular system in transplanted mouse mammary tumor. Cancer Res 30:2470, 1970 168. Tomasovic SP, Turner GN, Dewey WC: Effect of hyperthermia on nonhistone proteins isolated with DNA. Radiat Res 73:535, 1978 !69. Turner PF: Annular phased array: Initial trial results. Thermal J 3:10, 1981 170. Turner PF, Kumar L: Computer solution for applicator heating patterns. Natl Cancer Inst Monogr 6!:521, 1982

171. U R, Noell KT, Woodward KF, et al: Microwave induced local hyperthermia in combination with radiotherapy of human malignant tumors. Cancer 45:638, 1980 172. U R, Worde BT, Fishburn RI. et al: Hyperthermia in cancer treatment: Current and future prospects. Gan to Kagaku Ryoho 9:343, 1982 173. Vaupel P, Ostheimer K, Muller-Klieser W: Circulatory and metabolic responses of malignant tumors during localized hyperthermia. J Cancer Res Clin Oncol 98:15, 1980 174. Vaupel P: Hypoxia in neoplastic tissue. Microvasc Res 13:399, 1977 175. Von Ardenne M, Lippmann HG, Reitmauer PG, et al: Histological proof for selective stop of microclrculation in tumor tissue at pH 6.1 and 41C. Naturwissenschaften 66:59, 1979 176. Von Ardenne M: Selective multiphase cancer therapy: Conceptual aspects and experimental basis. Adv Pharmacol Chemother 10:539, 1982 177. Vora N, Forell B. Joseph C, et al: Interstitial implant with interstitial hyperthermia. Cancer 50:2518, 1982 178. Wallach DFH: In Streffer C. van Beuningen D, Dietzel F, et al (eds): Cancer Therapy by Hyperthermia and Radiation. Baltimore-Munich, Urban & Schwarzenberg, 1978, p 19 179. Warocquier R, Scherrer K: RNA metabolism in mammalian cells at elevated temperature. EurJ Biochem 10:362, 1969 180. Warren SL: Preliminary study of the effect of artificial fever upon hopeless tumor cases. Am J Roentgenol 33:75, 1935 181. Wafters RL, Roti-Roti JL: Nucleosome structure in chromatin from heated cells. Radiat Res 84:504, 1980 182. Wafters RL, Roti-Roti JL, Winward RT: Production and excision of 5, 6-dihydroxydihydrothymine type products in the DNA of preheated ceils. Int J Radiat Oncol Biol Phys 34:381, 1978 183. Westermark F: Uber die Behandlung des Ulcerirended Cerixacarcinoms. Mittle Konstanter Warme. Zentralbl Gynakol 22:1335, 1898 184. Westra A, Dewey WC: Variation in sensitivity to heat shock during the cell-cycle of Chinese hamster ceils in vitro. Int J Radiat Oncol Biol Phys 19:467, 1971 185. Wong TZ, Strohbehn JW, Jones JA, et al: SAR patterns from an interstitial microwave antenna array hyperthermia system. Submitted for publication. 186. Yatvin MB: The influence of membrane lipid composition and proteins on hyperthermia death of ceils. Int J Radiat Oncol BioI Phys 32:513. 1977

You might also like