HYPERTHERMIA, SYSTEMIC

R. WANDA ROWE-HORWEGE

University of Texas MedicalSchoolHouston, Texas

INTRODUCTION

Systemic hyperthermia is deliberate heating of the wholebody to achieve an elevated core temperature for thera-peutic purposes. Other terms used are whole-bodyhyperthermia, systemic or whole body thermal therapy,and hyperpyrexia. The goal of systemic hyperthermia is toreproduce the beneficial effects of fever. Typically, corebody temperatures of 41–42 8C are induced for 1–2 h, oralternatively 39–40 8C for 4–8 h. Systemic hyperthermia,by virtue of application to the whole body, aims to alleviatesystemic disease conditions, in contrast to local or regionalhyperthermia that treats only a specific tissue, limb, orbody region.

HISTORICAL BACKGROUND

The use of heat to treat disease goes back to ancient times.Application of fire to cure a breast tumor is recorded in anancient Egyptian papyrus, and the therapeutic value ofelevated body temperature in the form of fever was appre-ciated by ancient Greek physicians. Hippocrates wrote,‘‘What medicines do not heal, the lance will; what thelance does not heal, fire will,’’ while Parmenides stated,

‘‘Give me a chance to create a fever and I will cure anydisease.’’ In the first century AD, Rufus (also written asRefus or Ruphos) of Ephesus advocated fever therapy fora variety of diseases. Hot baths were considered thera-peutic in ancient Egypt, Greece, Rome, China, and Indiaas they still are in many aboriginal cultures today, alongwith burying diseased individuals in hot sand or mud.Hot baths and saunas are an integral part of healthtraditions throughout the Orient, in Indian Ayurvedicmedicine, as well as in Eastern European and Scandina-vian countries. Following several earlier anecdotalreports, several nineteenth century German physiciansobserved regression or cure of sarcoma in patients whosuffered prolonged, high fevers due to infectious diseases.This led to efforts to induce infectious fevers in cancerpatients, for example, by applying soiled bandages or theblood of malaria patients to wounds. The late nineteenthcentury New York physician, William Coley, achievedcancer cures by administration of erysipelas and otherbacterial endotoxins, now known as Coley’s toxins, andattempted to create standardized preparations of thesepyrogens (1). At around the same time, treatment ofsyphilis by placing the patient in a stove-heated room,or a heat box, became commonplace. Successful hyperther-mic treatment of other sexually transmitted diseases, suchas gonorrhea, and neurological conditions, such as choreaminor, dementia paralytica, and multiple sclerosis alongwith arthritis, and asthma were widely reported. Interest-ingly, it was noted by Italian physicians that upon comple-tion of the draining of the Pontine Swamps near Rome byMussolini in the 1930s, not only was malaria eradicated,but the prevalence of cancer in the area was the same as inthe rest of Italy, whereas earlier the whole malaria-infected region was noted for its absence of cancer. Itwas concluded that the frequent fever attacks commonin malaria stimulated the immune system to prevent thedevelopment of cancers.

The science of hyperthermia became grounded in thefirst few decades of the twentieth century when some of thebiological effects of elevated body temperature were eluci-dated and attempts were made to understand and controlthe therapeutic application of heat. Numerous deviceswere developed to produce elevated temperatures of thebody, by a variety of physical means. After a shift in focus tolocal and regional hyperthermia, there is now a resurgenceof interest in systemic hyperthermia for treatment of cancer,as well as other systemic diseases. Whole-body hyperther-mia treatment is now carried out at several universitycenters in the United States, and Europe (Table 1), wherecontrolled clinical trials are being carried out. Numerousprivate clinics, principally in North America, Germany,Austria, Eastern Europe, Japan, and China also performsystemic hyperthermia, mostly as part of holistic, alterna-tive, treatment regimens.

PHYSICS OF SYSTEMIC HYPERTHERMIA

As shown schematically in Fig. 1, in order to achieve bodytemperature elevation, there must be greater depositionof heat energy in the body than heat energy lost from

42 HYPERTHERMIA, SYSTEMIC

Encyclopedia of Medical Devices and Instrumentation, Second Edition, edited by John G. WebsterCopyright # 2006 John Wiley & Sons, Inc.

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conduction, convection, radiation and evaporation, that is,

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where Q0 ¼ DQ/Dt represents the change in heat energy,Q (measured in Joules or calories), over a time periodDt. Net heat energy deposition in a volume element DVof tissue of density rtis results in an increase in tem-perature DT dependent on the specific heat of the tissue,ctis,

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Heat deposition is the sum of the absorbed power den-sity, Pabs, from external sources and heat generated bymetabolism, Qmet,

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DV¼ Pabsðx; y; z; tÞ þ

DQ0met

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If the air temperature is higher than the body surfacetemperature, heat is absorbed from air surrounding thebody by the skin, as well as during respiration. Powerdeposition in tissue from external electromagnetic fieldsdepends on the coupling of the radiation field (micro-wave, RF, ultrasound, visible or IR light) with tissue.The body’s metabolic rate depends on the amount ofmuscular activity, the temperature, pressure andhumidity of the environment, and the size of the body.Metabolic rate increases nonlinearly with core bodytemperature, in part due to the exponential increaseof the rate of chemical reactions with temperature(Arrhenius equation). An empirical relationship between

basal metabolic rate and core temperature has beendetermined as

Basal MR ¼ 85 � 1:07ðTcoreÞ

0:5ð4Þ

whichcanbeexploited tomaintainelevatedbodytemperatures(2). At room temperature a human body produces � 84 W,which increases to �162 W at a core temperature of 41.8 8C.

Heat losses from the body are often termed sensible(convective, conductive, radiative) and insensible (evapora-tive, latent). The primary mode of heat loss from the body isby radiation, as described by the Stefan–Boltzmann law,

Q0rad

DV¼ eskinsAskinðTskin � TsÞ4 ð5Þ

where Q0rad/DV is the power radiated, eskin is the emissivity

of the skin (radiating material), s is Stefan’s con-stant ¼ 5.6703 � 10�8 Wm�2/K, Askin is the skin surfacearea, Tskin is the temperature of the skin (radiator), and Ts

is the temperature of the surroundings (e.g., air, water,wax). Human skin is a near perfect radiator in the IR, withan emissivity of 0.97. At room temperature, >50% of theheat generated by metabolism is lost by radiation; a clothedadult loses some 50 W at room temperature. This increasesto �66% at a core temperature of 41.8 8C, as is targeted in anumber of systemic hyperthermia protocols, when the skintemperature rises to 39–40 8C (3).

Direct transfer of body heat to the molecules around thebody (typically air) occurs by conduction, or molecularagitation within a material without any motion of thematerial as a whole, which is described by Fourier’s law,

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DT

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where DQcond is the heat energy transferred per unitvolume in time Dt, k is the thermal conductivity (WmK�1)of the material surrounding the body (air, water), and DT isthe temperature difference across thickness Dx of thematerial. Air is a poor thermal conductor, therefore heatloss by conduction is relatively low. On the other hand,water has a thermal conductivity 20 times that of air at0 8C, increasing further with temperature, therefore dur-ing hyperthermia it is important that any water in contactwith the skin is not at a lower temperature. The relativethermal conductivity of body tissues is important in deter-mining thermal conduction within the body from externalsources of heat. For example, fat is a relative thermalinsulator with a thermal conductivity one third of that ofmost other tissues, therefore fat bodies are slower to heat.

Convective heat transfer involves material movementand occurs principally via blood moving heat to, or from,the skin and other tissues, and air currents (respiratoryand environmental) moving warm air to or from the body.Equation 7 is written for the blood,

DQ0conv

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ð7Þ

where wb is the specific capillary blood flow rate, Ub is thespecific blood flow through other vessels. In the context of

44 HYPERTHERMIA, SYSTEMIC

Figure 1. Schematic of heat balance mechanisms in the humanbody. Body temperature is determined by the balance of metabolicheat production plus heating from external sources, and heatlosses by radiation, evaporation, convection, and conduction.

systemic hyperthermia, where a patient is in a closedchamber, environmental air currents can be minimized.Heat loss by respiration, however, can amount to almost10% of metabolic heat generation.

Another route of heat loss from the body is evaporationof perspiration from the skin. Because of the very largeheat of vaporization of water, cooling of the blood in skincapillaries occurs due to evaporation of sweat. Evaporationfrom exhaled moisture also results in cooling of the sur-rounding air.

DQ0evap

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Lv

Dtð8Þ

where mw is the mass of the water and Lv is the latent heatof vaporization (2.4 � 106 Jkg�1 at 34 8C). In hot condi-tions with maximal rates of evaporation, heat loss throughevaporation of sweat can be as much as 1100 W. Heat lossin the lungs is �10 W.

Combining the heat generation and heat loss termsleads to a general heat transfer equation, an extensionof the classic Pennes bioheat transfer equation.

DQ0met

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into which the expressions given in Eqs. 2–8 may be sub-stituted. Precise solution of this equation for temperaturedistribution is complex and requires a number of simplifyingassumptions which have generated significant controversyin bioheat transfer circles. Modeling of temperature distri-butions within a body subjected to hyperthermia is alsocomplex because of the heterogeneity of thermal character-istics between and within tissue, the directionality of powerapplication, and the dynamic nature of thermoregulation byhuman body. Nonetheless, the factors governing systemicheating of the body can be appreciated.

INDUCTION OF SYSTEMIC HYPERTHERMIA

Apart from the induction of biological fever by pathogens ortoxins, all methods of hyperthermia involve transfer ofheat into the body from an external energy source. Therequired net power to raise the temperature of a 70 kghuman from 37 to 41.8 8C (2) is 400 W (5.7 mW). While theheat absorption from these sources is highly nonuniform,distribution of thermal energy by the vascular systemquickly results in a uniform distribution of temperature.Indeed, systemic hyperthermia is the only way to achieveuniform heating of tissues. Because physiological thermo-regulation mechanisms such as vasodilation and perspira-tion counteract attempts to increase core body temperature,careful attention must be paid to optimizing the physicalconditions for heating such that there is efficient depositionof heat energy in the body and, even more importantly,minimization of heat losses. Wrapping the body in reflectiveblankets, foil, or plastic film to reduce radiative and eva-porative losses, or keeping the surrounding air moist to

minimize losses by perspiration are key techniques forachieving a sustained increase in body temperature.

Noninvasive methods of heating include immersing thebody in hot water or wax, wrapping the body in a blanket orsuit through which heated water is pumped, placing thepatient on a heated water mattress, surrounding the bodywith hot air, irradiating with IR energy, and applying RFor microwave electromagnetic energy. These techniquesmay be applied singly or in combination. For example, thePomp–Siemens cabinet used until recently throughoutEurope, as well as in the United States, a modificationof a device originally developed by Siemens in the 1930s,has the patient lying on a heated water mattress underwhich an inductive loop generates an RF field, all inside achamber through which hot air is circulated. The RussianYakhta-5 system applies a high frequency (13.56 MHz)electromagnetic field through a water-filled mattress topermit whole body heating up to 43.5 8C and simultaneousdeep local hyperthermia through additional applicators pro-viding 40.6 MHz electromagnetic radiation. The majority ofwhole-body hyperthermia systems currently in clinical useemploy IR radiation to achieve systemic heating. Invasiveapproaches to systemic hyperthermia are extracorporealheating of blood, removed from the body via an arteriovenousshunt, prior to returning it to the circulation, as well asperitoneal irrigationwithheatedfluid (4).A useful schematicsummary of whole-body hyperthermia induction techniquesalong with references is provided by van der Zee (5).

All of these approaches involve a period of steadytemperature increase, followed by a plateau or equilibriumphase where the target temperature is maintained for any-where from 30 min to several hours, and finally a cool-downphase. Depending on the method of hyperthermia induction,the patient may be anesthetized, consciously sedated, admi-nistered analgesia, or not given any kind of medication atall. An epidural block is sometimes given to induce orincrease vasodilation. During radiant heat induction, thetemperature of the skin and superficial tissues (includingtumors) is higher than the core (rectal) temperaturewhereas during the plateau (maintenance) phase, theskin–superficial tissue temperature drops below the coretemperature. As already described, heat losses due to phy-siological mechanisms limit the rate of heating that can beachieved. When insulation of the patient with plastic foilwas added to hot air heating, the heating time to 41.8 8C wasdecreased from 230 to 150 min (65%), and further to 110 min(48%) by addition of a warm water perfused mattress (5).The homogeneity of the temperature distribution was alsosignificantly increased by the addition of insulation and thewater mattress. Noninvasive systemic hyperthermia meth-odologies typically produce heating rates of 1–10 8Ch�1

with 2–3 8Ch�1 being most common. More rapid heatingcan be achieved by the invasive techniques, at the expense ofgreater risk of infection and morbidity.

COMMERCIALLY AVAILABLE WHOLE-BODYHYPERTHERMIA SYSTEMS

A number of commercially available devices have resultedfrom the development of these initially experimental

HYPERTHERMIA, SYSTEMIC 45

systems. The Siemens–Pomp system has already been men-tioned, but is no longer commercially available. Similarly,neither the radiant heat chamber developed by Robins (3),and marketed as the Aquatherm system, nor the similarEnthermics Medical Systems RHS-7500 radiant heatdevice, both producing far IR radiation (IR C) in a moistair chamber, are currently being sold, though they arestill in use in several centers. A close relative is theIratherm2000 radiant heat chamber originally developedby von Ardenne and co-workers (6). In this device, water-filtered infrared radiators at 2400 8C emit their energy fromabove and below the patient bed, producing near-IR (IR A)radiation that penetrates deeper into tissue than far IRradiation, causing direct heating of the subcutaneous capil-lary bed. Thermal isolation is ensured by reflective foilsplaced around the patient. However, note that significantevaporative heat loss through perspiration can be a problemwith this system. Also with a significant market share is theHeckel HT 2000 radiant heat device in which patients lie ona bed enclosed within a soft-sided rectangular tent whoseinner walls are coated with reflective aluminum foil thatensures that the short wavelength infrared A and B radia-tion emitted by four radiators within the chamber uniformlybathes the body surface. Once the target temperature isreached, the chamber walls are collapsed to wrap around thebody, thereby preventing radiative and evaporative heatloss, and permitting maintenance of the elevated tempera-ture, as shown in Fig. 2.

Another radiant heat device, used mainly in Germany,is the HOT-OncoTherm WBH-2000 whole-body hyperther-mia unit which is a chamber that encloses all but thepatient’s head. Special light-emitting diode (LED) radia-tors deliver computer-generated, alloy-filtered IR A wave-lengths that penetrate the skin to deliver heat to thecapillary bed. The manufacturer claims that these wave-lengths also preferentially stimulate the immune system.Recently, Energy Technology, Inc. of China has releasedthe ET-SPACE whole-body hyperthermia system, which

produces IR A radiation in a small patient chamber intowhich warm liquid is infused to help increase the airhumidity and thereby reduce perspiration losses. A num-ber of low cost, far infrared, or dry, saunas are being soldto private clinics, health clubs, and even individuals fortreatment of arthritis, fibromyalgia, detoxification, andweight loss. Examples are the Smarty HyperthermicChamber, the TheraSauna, the Physiotherm, and theBiotherm Sauna Dome. Table 2 summarizes features ofthese commercially available whole-body hyperthermiadevices.

BIOLOGICAL EFFECTS OF SYSTEMIC HYPERTHERMIA

An understanding of the biological effects of systemichyperthermia is critical to both its successful inductionand to its therapeutic efficacy. Systemic responses to bodyheating, if not counteracted, undermine efforts to raisebody temperature, while cellular effects underlie boththe rationale for the use of hyperthermia to treat specificdiseases, and the toxicities resulting from treatment.Although improved technology has allowed easier andmore effective induction of systemic hyperthermia, mostof the recent clinical advances are due to better under-standing and exploitation of specific biological phenomena.

Physiological Effects of Elevated Body Temperature

The sympathetic nervous system attempts to keep all partsof the body at a constant temperature, tightly controlled bya central temperature ‘set point’ in the preoptic–anteriorhypothalamus and a variety of feedback mechanisms. Thethermostat has a circadian rhythm and is occasionallyreset, for example, during fever induced by infectiousagents and endotoxins, but not in endogenously inducedhyperthermia. Occasionally, it breaks down completely asin malignant hyperthermia or some neurological disordersaffecting the hypothalamus. Ordinarily, when core bodytemperature rises, the blood vessels initially dilate, heartrate rises, and blood flow increases in an effort to transportheat to the body surface where it is lost by radiation,conduction, and convection. Heart rate increases on averageby 11.7 beatsmin�1 8C�1 and typically remains elevated forseveral hours after normal body temperature is regained.Systolic blood pressure increases to drive the blood flow, butdiastolic pressure decreases due to the decreased resistanceof dilated vessels, thus there is an increase in cardiacoutput. Heart rate and blood pressure must therefore bemonitored during systemic hyperthermia, and whole-bodyhyperthermia is contraindicated in most patients withcardiac conditions. Interestingly, hyperthermia increasescardiac tolerance to ischemia/reperfusion injury probablydue to activation of manganese superoxide dismutase(Mn-SOD) and involvement of cytokines.

Respiration rate also increases and breathing becomesshallower. Perspiration results in evaporation of sweatfrom the skin and consequent cooling, while the respirationrate increases in order to increase cooling by evaporation ofmoisture from expired air. Weight loss occurs despite fluidintake. There is a decrease in urinary output and the urinehas a high specific gravity, concentrating urates and

46 HYPERTHERMIA, SYSTEMIC

Figure 2. Heckel HT-2000 radiant heat whole body hyperthermiasystem. Unit at the University of Texas Medical School at Houston.Patient is in the heat maintenance phase of treatment, wrapped inthe thermal blankets which form the sides of the chamber duringactive heating.

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phosphates. In endogenously induced hyperthermia, butnot in fever, glomerular filtration, as evidenced by thecreatinine clearance, decreases with increasing tempera-ture. As already mentioned, metabolic rate increases non-linearly with temperature, which leads to an increase inblood sugar, decreased serum potassium levels, andincreased lactic acid production. All the above normalphysiological effects may be enhanced or counteracted byanesthesia or sedation, as well as by disease states such ascancer because of drugs used in treatment or intrinsicpathophysiological consequences of the disease.

At �42.5 8C, the normal thermocompensatory mechan-isms break down and the body displays the symptoms ofadvanced heat stroke, namely, lack of sweating, rapidheart beat, Cheyne–Stokes breathing, central nervoussystem disfunction, and loss of consciousness. Ultimately,breathing ceases despite the continuation of a heart beat.

Cellular Thermal Damage

When temperature is increased by a few degrees Celcious,there is increased efficiency of enzyme reactions (Arrhe-nius equation), leading to increased metabolic rates, but attemperatures > 40 8C molecular conformation changesoccur that lead to destabilization of macromolecules andmultimolecular structures, for example, to the side chainsof amino acids in proteins, which in turn inhibit enzymeaction. Small heat shock proteins (HSP) interact with theunfolding proteins to stabilize them and prevent theiraggregation and precipitation. Eventually, however, at�42 8C, complete denaturation of proteins begins thattotally disrupts many molecular processes, including deox-yribonucleic acid (DNA) repair. Thus systemic hyperther-mia can have significant effects when paired with drugsthat cause DNA damage (e.g., for chemotherapy of cancer).

Membranes are known to be extremely sensitive toheat stress because of their complex molecular composi-tion of lipids and proteins. At a certain temperature, lipidschange from the tightly packed gel phase to the lesstightly packed liquid crystalline phase, and permeabilityof the cell membrane (membrane fluidity) increases. Astemperature increases further, the conformation of proteinsalso becomes affected, eventually resulting in disorderlyrearrangement of the lipid bilayer structure and receptorinactivation or loss. Temperature changes of �5 8C arenecessary to cause measurable changes in normal cellmembrane permeability. Heat-induced cell membrane per-meability can be exploited to increase drug delivery, forexample, transdermally, or into tumor cells. Increased vas-cular permeability due to thermal increase of endothelialgap size also aids drug delivery into tumors. At highertemperatures, heat damage to membranes can cause celldeath, but it will also interfere with therapeutic approachesthat depend on membrane integrity (e.g., receptor targeteddrug delivery, antibodies, etc.). Irreversible disruption ofcytoplasmic microtubule organization and eventual disag-gregation, as well as disruption of actin stress fibers andvimentin filaments, occur at high temperatures (43–45 8C)above those used in whole-body hyperthermia, but thesecytoskeletal effects are of concern with loco-regional hyper-thermia.

A variety of effects in the cell nucleus also occur at hightemperatures (>41 8C) including damage to the nuclearmembrane, increases in nuclear protein content, changesin the structure of nucleoli, inhibition of DNA synthesisand chromosomal damage in S-phase. These changes innuclear structure compromise nuclear function and maycause cell death, though they are unlikely to be significantat the temperatures achieved in systemic hyperthermia.Disaggregation of the spindle apparatus of mitotic cellsmay be responsible for the high thermal sensitivity of cellsin mitosis, as well as in S phase. Hyperthermic inactivationof polymerase b, an enzyme primarily involved in DNArepair, is sensitized by anesthetics and may have a role toplay in the enhancement of the effects of ionizing radiationby systemic hyperthermia, as well as in augmenting thecytotoxic effect of drugs that cause DNA damage.

Metabolic Effects

Moderate increases in temperature lead to increased cel-lular reaction rates, which may be seen as increased oxy-gen consumption and glucose turnover. In consequence,cells may become deprived of nutrients, the intracellularATP concentration falls, accumulation of acid metabolitesincreases pH, and thermal sensitivity increases. Suchconditions are found in tumors and may contribute to theirsensitivity to heat. Further acidifying tumor cells duringhyperthermic treatment seems a promising approach as isdiscussed further below. At high temperatures, the citricacid cycle may be damaged leading to other acidic meta-bolites. Increased plasma acetate has been measured fol-lowing clinical whole-body hyperthermia treatments,which reduces both release of fatty acids from adiposetissue into plasma and subsequent lipid oxidation.

Endocrine Function

Increases in plasma levels of an array of hormones havebeen noted after whole-body hyperthermia. IncreasedACTH levels appear to be accompanied by increased levelsof circulating endorphins. This may explain the sense ofwell-being felt by many patients after systemic hyperther-mia treatment, and the palliative effect of hyperthermiatreatments for cancer. Increased secretion of somatotropichormone after systemic hyperthermia has also been mea-sured (7).

Thermal Tolerance

Thermal tolerance is a temporary state of thermal resis-tance, common to virtually all mammalian cells, whichdevelops after a prolonged exposure to moderate tempera-tures (40–42 8C), or a brief heat shock followed by incuba-tion at 37 8C, and also certain chemicals. The decay ofthermotolerance occurs exponentially and depends on thetreatment time, the temperature, and the proliferativestatus of the cells. Several days are usually required forbaseline levels of heat sensitivity to be regained, which hasimportant implications for fractionated therapy. When pHis lowered, less thermal tolerance develops, and its decay isslower. Thus the long periods at moderate temperatureachieved by clinical systemic hyperthermia systems should

48 HYPERTHERMIA, SYSTEMIC

induce thermal resistance in normal cells, while the acidicparts of tumors should be relatively unaffected. This hasnot, however, been studied clinically. The mechanismsinvolved in the induction of thermotolerance are not wellunderstood, but there is mounting evidence that heat shockproteins are involved.

Step-Down Sensitization

Another distinct phenomenon is step-down sensitization inwhich an exposure of cells to temperatures >43 8C resultsin increased sensitivity to subsequent temperatures of42 8C or lower. This can be important clinically for localand regional hyperthermia if there are marked variationsin temperature during the course of treatment, the mag-nitude of the effect depending on the magnitude of thetemperature change. It has been suggested that this phe-nomenon could be exploited clinically by administering ashort, high temperature treatment prior to a prolongedtreatment at a lower temperature, thereby reducing painand discomfort. Since temperatures >43 8C cannot be tol-erated systemically, a local heat boost would be required totakeadvantageof this effect for whole bodyhyperthermia. Sofar, there is no evidence that tumor cells are differentlysensitized by step-down heating than normal cells.

Effect of Hyperthermia on Tumors

It was initially thought that tumor cells have intrinsicallyhigher heat sensitivity than normal cells, but this is notuniversally true. Although some neoplastic cells are moresensitive to heat than their normal counterparts, thisappears to be the case at temperatures higher than thoseused in systemic hyperthermia. Tumors in vivo, on theother hand, often do have a higher thermal sensitivity thannormal tissues because of abnormal vasculature (reducedblood flow), anaerobic metabolism (acidosis), and nutrientdepletion. Due to their tortuous and poorly constructedvasculature, tumors have poor perfusion, thus heat dis-sipation by convection is reduced. At high temperatures(43 8C and up) this means that tumors become a heatreservoir with a consequent rise in temperature, whichif maintained for too long damages the microcirculationand further impairs convective heat loss. Also increasedfibrinogen deposition at damaged sites in the vascular wallleads to clusion of tumor microvessels. Significant heatingof the tumor cells results, which may be directly cytotoxic.Additionally, the impaired blood flow brings about acidosis,increased hypoxia and energy depletion all of whichincrease the heat sensitivity of tumor cells (8). At lowertemperatures, typical of those achieved in whole-bodyhyperthermia, blood flow increases (9) though the mechan-ism is not well understood. For these reasons, along withthe historical evidence for antitumor effects of fever and themetastatic nature of malignant disease, cancer has becomethe main focus of systemic hyperthermia.

Systemic hyperthermia results in increased delivery ofdrugs to tumor sites because of increased systemic bloodflow. It can also increase blood vessel permeability byincreasing the effective pore size between the loosely boundendothelial cells forming tumor microvessels, permittinglarger molecules, such as nanoparticles and gene therapyvectors, to pass into the interstitium (10). Figure 3 showsincreased uptake of 210 nm liposomes in rat breast tumorsafter 1 h of 41.5 8C whole-body hyperthermia. Heat mayalso be toxic to endothelial cells, resulting in a transientnormalization of vascular architecture and improvementin blood flow (11). Another barrier to drug delivery is thehigh interstitial pressure of many tumors. Since whole-body hyperthermia, even at fever-range temperatures,causes cell death (apoptosis and necrosis) within tumorsit reduces the oncotic pressure allowing greater penetrationof large molecules. Table 3 summarizes the interactions ofsystemic hyperthermia which facilitate nanoparticle deliv-ery to tumors.

HYPERTHERMIA, SYSTEMIC 49

0.0

1.0

2.0

100 nm 210 nm

41.5

˚C/3

7˚C

up

take

rat

io

Liposome size

Figure 3. Increase in tumor uptake of large liposomes after 1 hof 41.5 8C whole-body hyperthermia. Systemic heat treatmentincreased the effective pore size from �210 to 240 nm. Becauseof the large pore size in MTLn3 tumors, 100 nm (average diameter)liposomes were able to pass into the tumor equally well at normaland elevated temperatures. The increased effective pore size dueto hyperthermia allowed larger 200 nm liposomes, which werepartially blocked at normal temperatures, to pass more effectivelyinto the tumor.

Table 3. Whole-Body Hyperthermia Facilitates Nanoparticle Therapy

Heat Interaction Therapeutic Effect

" Blood flow " Nanoparticle delivery to tumor" In endothelial gap size " Nanoparticles in interstitium" Endothelial cell apoptosis/necrosis ! transient normalization of vasculature " Nanoparticles in interstitium" Tumor cell apoptosis/necrosis # oncotic pressure " Nanoparticles in interstitiumTemperature-dependent " in permeability of liposome bilayer " And synchronization of drug releaseCellular and molecular effects in tumor " Drug in tumor cell " drug efficacyDirect interactions with drug " Drug efficacy

Whole-Body Hyperthermia and the Immune System

An increase in ambient temperature can serve as a naturaltrigger to the immune system and it appears that the thermalmicroenvironment plays a critical role in regulating events inthe immune response. The early work of Coley on cancertherapy with infectious pyrogens implicated fever-inducedimmune stimulation as the mediator of tumor responses (1).While there have been numerous in vitro studies of the effectof temperature on components of the immune system, indi-cating that the thermal milieu regulates T lymphocytes,natural killer (NK) cells, and dendritic cells (DC), in vivoexaminations of the immune effects of systemic hyperther-mia are relatively few. Initial animal model studies con-cluded that whole-body hyperthermia resulted inimmunosuppression, but high temperatures were used,tumors were mostly immunogenic, and immune responsewas merely inferred from the incidence of metastatic spreadrather than from measurement of specific markers ofimmune system activation. The majority of in vivo studiesin animals provide evidence of a nonspecific host reactionin response to hyperthermia in which both T and Blymphocytes, as well as macrophages, are involved (12).Although NK cells are intrinsically more sensitive in vitroto heat than B and T cells, their activation by systemichyperthermia has been observed. Microwave inducedwhole-body hyperthermia of unrestrained, unanesthe-tized mice at 39.5–40 8C for 30 min, three or six timesweekly, resulted in increased NK cell activity and reducedpulmonary metastasis in tumor-bearing mice, but none innormal mice (13). Evidence for hyperthermia-inducedhuman tumor lysis by IL-2 stimulated NK cells activatedby HSP72 expression also exists (14). Increased numbersof lymphocyte-like cells, macrophages, and granulocytesare observed in the tumor vasculature and in the tumorstroma of xenografts and syngeneic tumors in mice imme-diately following a mild hyperthermia exposure for 6–8 h.In the SCID mouse/human tumor system tumor cellapoptosis seen following treatment was due largely tothe activity of NK cells. The investigators hypothesizeheat dilatation of blood vessels and increased vessel per-meability may also give immune effector cells greateraccess to the interior of tumors (15). In balb/C mice,fever-range whole-body hyperthermia increased lympho-cyte trafficking, resulting in early responsiveness to anti-gen challenge (16). Thus systemic hyperthermia may bean effective, nontoxic adjuvant to immunotherapy.

A recent clinical study examined the effect of whole-body hyperthermia combined with chemotherapy on theexpression up to 48 h later of a broad range of activationmarkers on peripheral blood lymphocytes, as well as serumcytokines and intracellular cytokine levels in T cells, andthe capacity of these cells to proliferate. Immediately aftertreatment with 60 min of 41.8 8C WBH as an adjunct tochemotherapy, a drastic but transient, increase in periph-eral NK cells and CD56þ cytotoxic T lymphocytes wasobserved in the patients’ peripheral blood. The numberof T cells then briefly dropped below baseline levels, aphenomeonon that has also been observed by others (17).A marked, but short-lived, increase in the patients’ serumlevels of interleukin-6 (IL-6) was also noted. Significantly

increased serum levels of tumor necrosis factor-alpha(TNF-alpha) were found at 0, 3, 5 and 24 h posttreatment.Further immunological consequences of the treatmentconsisted of an increase in the percentage of peripheralcytotoxic T lymphocytes expressing CD56, reaching a max-imum at 48 h post-WBH. Furthermore, the percentage ofCD4+ T cells expressing the T cell activation marker CD69increased nearly twofold over time, reaching its maximumat 48 h. Since similar changes were not observed inpatients receiving chemotherapy alone, this study pro-vided strong evidence for prolonged activation of humanT cells induced by whole-body hyperthermia combined withchemotherapy (18).

Activation of monocytes has been observed following hotwater bath immersion such that response to endotoxinstimulation is enhanced with concomitant release ofTNF-a. Macrophage activation and subsequent lysosomalexocytosis were observed in the case of a patient treated forliver metastases by hyperthermia. Lysosomal exocytosisinduced by heat may be an important basic reaction of thebody against bacteria, viruses, and tumor growth and wasproposed as a new mechanism of thermally induced tumorcell death mediated by an immune reaction (19).

Several investigators have suggested that the immunechanges seen during in vivo whole-body hyperthermia aremediated by elevations in the plasma concentrations ofeither catecholamines, growth hormone, or beta-endorphins.In volunteers immersed in a heated water bath, neitherrecruitment of NK cells to the blood, nor the percentagesor concentrations of any other subpopulations of blood mono-nuclear cells were altered by hormone blockade. However,somatostatin partly abolished the hyperthermia inducedincrease in neutrophil number. Based on these data andprevious results showing that growth hormone infusionincreases the concentration of neutrophils in the blood, itwas suggested that growth hormone is at least partlyresponsible for hyperthermia induced neutrophil increase.A similar study suggested that hyperthermic inductionof T lymphocytes and NK cells is due to increased secre-tion of somatotropic hormone (7).

The peripheral blood level of prostaglandin E2 (PGE2),which may act as an angiogenic switch, transforming alocalized tumor into an invasive one by stimulating newblood vessel growth, and which also has an immunosup-pressive effect, is elevated in patients with tumors com-pared to healthy control subjects. In a clinical study ofcancer patients receiving 1–2 h of 41.8–42.5 8C whole-bodyhyperthermia, or extracorporeal hyperthermia, bloodlevels of PGE2 decreased markedly after treatment andcorrelated with tumor response (20).

In addition to their role as protectors of unfoldingproteins, extracellular heat shock proteins (HSP) can actsimultaneously as a source of antigen due to their ability tochaperone peptides and as a maturation signal for dendri-tic cells, thereby inducing dendritic cells to cross-presentantigens to CD8þ T cells (21). Heat shock proteins can alsoact independently from associated peptides, stimulatingthe innate immune system by eliciting potent proinflam-matory responses in innate immune cells. The heat shockresponse also inhibits cyclooxygenase-2 gene expression atthe transcriptional level by preventing the activation of

50 HYPERTHERMIA, SYSTEMIC

nuclear factor-kappaB (NFkB) (22). Thermal upregulationof HSPs (HSP70 and HSP110) is strongest in lymphoidtissues and may relate to the enhanced immune responsesthat are observed during febrile temperatures. It has beenproposed that local necrosis induced by hyperthermictreatment induces the release of HSPs, followed by uptake,processing and presentation of associated peptides by den-dritic cells. By acting as chaperones and as a signal fordendritic cell maturation, HSP70 might efficiently primecirculating T cells. Therefore, upregulating HSP70 andcausing local necrosis in tumor tissue by hyperthermiaoffers great potential as a new approach to directly activatethe immune system, as well as to enhance other immu-notherapies (23,24).

CLINICAL TOXICITIES OF WHOLE-BODY HYPERTHERMIATREATMENT

At fever-range temperatures, adverse effects of systemichyperthermia treatment are minimal however, at highertemperatures they can be significant, even fatal. On theother hand, the teratogenic effects (birth defects, stillbirths, spontaneous abortions) and 8Cular damage (catar-act induction) resulting from electromagnetic fields used inlocal hyperthermia are not seen in systemic hyperthermia.The transient cardiorespiratory effects of elevated tem-perature can, however, lead to severe toxicity. Elevatedheart rate, especially at high temperatures may result inarrythmias or ischemic heart failure, consequentlypatients have to be very carefully screened with regardto their cardiac status. Beta blockade has generally beenfound to be deleterious although infusion of esmolol hasbeen safely carried out (25). Pulmonary hypertension andedema due to capillary leak may also be seen, but like thecardiac effects, these return to baseline a few hours aftertreatment. Increased serum hepatic enzymes have beennoted, but these may be cancer related. All these toxicitiesare less prevalent or less severe with radiant heat systems,particularly at lower temperatures, and when light con-scious sedation is used rather than general anesthesia. Forexample, decreased platelet count, decreased plasma fibri-nogen, and other factors leading to increased blood clottinghave been noted, particularly in extra-corporeal hyper-thermia, but also with other methods of heating carriedout under inhalation-administered anesthesia drugs.On the other hand, with whole-body hyperthermia underconscious sedation there is no evidence of plateletdrops (26) and animal studies even show platelet stimula-tion providing protection against radiation inducedthrombocytopenia.

Since systemic hyperthermia is almost never used as asingle treatment modality, it is important to recognize thatwhole-body hyperthermia combined with radiation andchemotherapy can enhance some of the toxicities asso-ciated with these modalities. For example, the cardiotoxi-city of doxorubicin and both the renal toxicity andhematological toxicity of platinum agents may increaseunder hyperthermia (27), while the muscle and peripheralnervous system effects of radiation and some drugs can alsobe enhanced (28). Bone marrow suppression is the limiting

toxicity of many chemotherapy drugs but there is little datato suggest that whole body hyperthermia exacerbates thiseffect. On the contrary, the synergy of hyperthermia withseveral chemotherapy agents may mean that lower dosescan be used, resulting in less toxicity. For example, sys-temic hyperthermia combined with carboplatin achievestherapeutic results without elevation of myelosuppressionand responses have occurred at lower than normal doses(29). Pressure sores can easily develop at elevatedtemperatures thus care must be taken not only in patientplacement and support, but also with application of mon-itoring devices. If heat dissipation is locally impaired, forexample, at pressure points, hot spots occur that can lead toburns. This is rarely a problem with fever-range whole-body hyperthermia, but in anesthetized patients under-going high heat regimens burns are not uncommon.

Following systemic hyperthermia treatments, malaiseand lethargy are almost universally experienced althoughthese may be counteracted by pain relief and a sense ofwell-being due to released endorphins. However, the fasterthe target temperature is reached, the less the exhaustion(6), thus attention to minimizing heat dissipation duringthe heat-up phase and using efficient heating devices, suchas those that generate heat by several mechanisms (e.g.,radiant heat and EM fields), add a regional heat boost, orproduce near-IR radiation that is preferentially absorbed,is advantageous to patient well being. Fever after treat-ment in the absence of infectious disease is not uncommonand may be associated with an inflammatory response totumor regression. Nausea and vomiting during the firstcouple of days after treatment are also common. Outbreaksof herpes simplex (cold sores) in susceptible individualshave also been noted, but are easily resolved with acyclovir.

THERMAL DOSE

The definition of dose for systemic hyperthermia is proble-matic. An applied dose would be the amount of heat energygenerated or delivered to the body but even if it can bemeasured, this quantity does not predict biological effects.By analogy with ionizing radiation, the absorbed dosewould be amount of thermal energy absorbed per unitmass of tissue (Jkg�1), however, this is not a quantitythat can be readily measured, or controlled, neither wouldit necessarily predict biological effects. As indicated in theprevious sections, the effects of systemic hyperthermiadepend on (1) the temperature, and (2) the duration ofheating, but not on the energy required to produce thetemperature rise. This leads to the concept of time at agiven temperature as a practical measure of dose. Inreality, however, temperature is seldom constant through-out a treatment, even in the plateau phase of systemichyperthermia, so time at temperature is at best a crudemeasure. Nonetheless, it is the one that is used most oftenclinically for whole-body hyperthermia because of its sim-plicity. Ideally, the dose parameter should allow for com-parison of treatments at different temperatures. Based onthe Arrhenius relationship and measured cell growth inhi-bition curves, the heating time at a given temperaturerelative to the heating time at a standard temperature or

HYPERTHERMIA, SYSTEMIC 51

thermal dose equivalent (TDE), was defined empirically as,

T1 ¼ t2 RðT1�T2Þ ð10Þ

A discontinuity occurs in the temperature-time curvesbetween 42 and 43 8C for both cells in culture and heatedtissues, thus the value of R changes for temperatures abovethe transition: R � 2< 42.5 8C and R � 5> 42.5 8C in vitrowhile for in vivo heating studies, R ¼ 2.1 below the transi-tion temperature and 6.4 above 42.5 8C. In practice, a finitetime is required for the body or tissue of interest to reach thetarget temperature, temperature fluctuates even after thetarget temperature is reached, and there is a cooling periodafter heating ceases. If the temperature is measured fre-quently throughout treatment, the temperature–timecurves can be integrated to provide the accumulated ther-mal dose that produces an equivalent effect to that resultingfrom holding the cells–tissue at a constant reference tem-perature for a given a period of time:

t43 ¼Zt f

ti

R43�TðtÞdt ð11Þ

where ti and tf are the initial and final times of the heatingprocedure (30). This thermal isoeffect dose (TID) is usuallyexpressed in minutes is sometimes known as the tdm43 orthe cumulative equivalent minutes (CEM 43 8C). While abiological factor has now been built in to the dose measure,and the integrated TID allows for temperature variationsduring heat-up and cool-down phases, it does not take intoaccount thermal tolerance and step-down sensitization. Noris it particularly relevant to clinical whole-body hyperther-mia where multiple physical and biological effects combinein a complex manner although for a given patient, time–temperature profiles are generally reproducible from onetreatment to another. A further modification attempts totake into account temperature inhomogeneity through themeasurement of temperature at multiple sites and definingT90, namely, that temperature exceeded by 90% of themeasurements (or correspondingly 20%: T20; or 50%:T50). The TID is then expressed as cumulative equivalentminutes that T90 is equal to 43 8C (CEM 43 8C T90) (31).

The efficiency of adjuvant hyperthermia in enhancingthe biological effectiveness of other treatments is oftenreported in terms of the thermal enhancement factor(TEF) or thermal enhancement ratio (TER). This quantityis defined in terms of the isoeffect dose as,

TER ¼

dose of treatment to achieve

a given endpoint

dose of treatment with heat

to achieve the same endpoint

ð12Þ

In clinical and laboratory studies, the TER is oftencomputed on the basis of isodose rather than isoeffect,for example, in the case of hyperthermia plus druginduced arrest of tumor growth, TER ¼ TGDHT/TGTRT,where TGDHT is the tumor growth delay due tohyperthermia plus chemotherapy, and TGTRT is thetumor growth delay resulting from chemotherapy at roomtemperature. Similarly, the enhancing effect of hyperther-

mia on radiation treatment may be expressed throughTER ¼ D0HT/D0RT or TER ¼ LD50HT/LD50RT, where D0is the time required to reduce survival to 1/e of its initialvalue, and LD50 is the lethal dose to 50% of cells.

TEMPERATURE MEASUREMENT

Since systemic hyperthermia achieves a uniform tempera-ture distribution, except for possible partial sanctuary sites,thermometry for systemic hyperthermia is much less chal-lenging than for regional or intracavitary hyperthermia, butit is still important to prevent adverse effects, especiallyburns. Also, convection can induce steep thermal gradients,especially around major blood vessels, so that careful place-ment of temperature probes is required. Most practitionersof whole-body hyperthermia measure temperature in sev-eral locations, typically the rectum, the esophagus, and atseveral skin sites. During heat-up, the esophageal tempera-ture is usually 1–2 8C higher than the rectal temperature,but during plateau phase it drops to 0.5–1.5 8C below therectal temperature. Continuous and accurate temperaturemeasurement is particularly important when temperatures>418C are to be achieved, as critical, life-threateningchanges can occur in minutes or even seconds and overchanges in temperature of as little as 0.1–0.2 8C because ofthe nonlinear response to temperature. For moderate tem-perature systemic hyperthermia, temperature measure-ment to within 0.1 8C is usually adequate, but a precisionof 0.01 8C is desirable when heating to >41 8C and alsoallows determination of the specific absorption rate from theslope of the temperature versus time curve. The tempera-ture measuring device must be insensitive to all otherinfluences, such as ambient temperature, moisture, nearbyelectromagnetic fields, and so on and satisfying this criter-ion can be difficult. Frequent calibration of thermometers inthe working range of temperatures is important since somethermometers appear fine at 30 8C, but drift substantially at40 8C and above. Stringent quality control of any thermo-metry system is required to monitor accuracy, precision,stability, and response time.

Table 4 summarizes the different types of thermometerprobes available for internal and external body tempera-ture measurements, and their relative merits and disad-vantages for systemic hyperthermia. Thermistors are mostoften used for standard temperature monitoring sites whilethermocouples are used for tumor or other intra-tissuemeasurements. Recently, noninvasive methods of tem-perature measurement have been developed that arebeginning to see application in hyperthermia. Thermogra-phy provides a two-dimensional (2D) map of surface tem-perature by measurement of infrared emission from thebody, though deep-seated hot structures may be visualizedbecause of heat carried by blood flow from the interior heatsource to the skin. It is useful to detect skin hotspots andtherefore in burn prevention. Since temperature-inducedchanges in the mechanical properties of tissue lead toaltered ultrasound propagation velocity, mapping of ultra-sound velocity can also provide a visual map of tempera-ture. Tomographic reconstruction of 2D or 3D temperatureis theoretically possible, but it is difficult in practicebecause of the heterogeneity of tissue characteristics. A

52 HYPERTHERMIA, SYSTEMIC

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number of magnetic resonance (MR) techniques have beenused for thermal mapping and BSD Medical and SIEMENSMedical Systems have collaborated to develop a hybridhyperthermia/MRI system, although it is not a whole-bodyhyperthermia machine. Currently, the most widelyaccepted MR technique is the proton resonance frequency(PRF) method that exploits the temperature dependence ofthe chemical shift of water. Unlike the value of the waterspin-lattice relaxation time or the molecular diffusioncoefficient, both of which have been used for MRI tempera-ture measurements, the thermal coefficient relating tem-perature to the water chemical shift has been shown to beessentially independent of tissue type and physiologicalchanges induced by temperature (32). Recently an inter-leaved gradient echo–echo planar imaging (iGE-EPI)method for rapid, multiplanar temperature imaging wasintroduced that provided increased temperature contrast-to-noise and lipid suppression without compromising spa-tio-temporal resolution (33).

CLINICAL EXPERIENCE

Cancer

Systemic hyperthermia has been used mostly for treatmentof cancer because of its potential to treat metastatic dis-ease. Initial treatments aimed to produce direct killing oftumor cells based on the premise, now understood not to beuniversally true, that cancer cells are more susceptible toelevated temperatures than normal cells, and the higherthe temperature the greater the tumor cell kill. Maximallytolerated temperatures of 41.5–42 8C were therefore main-tained for 1–2 h as the sole treatment. Response rates were,however, disappointing. Tumor regressions were observedin less than half the cases, no tumor cures were achieved,and remissions were of short duration. It became apparentthat the heterogeneity of cell populations within tumors,along with micro-environmental factors, such as blood/nutrient supply, pH, and oxygen tension prevent the ther-motoxic results achieved in the laboratory. Consequently,the focus of research on systemic hyperthermia shifted tousing hyperthermia as an adjunct to other cancer thera-pies, principally chemotherapy and radiotherapy. It isimportant to note that because of the experimental statusof systemic hyperthermia treatment for cancer, almost allclinical trials, summarized in Table 5, have been performedon patients with advanced disease for whom whole-bodyhyperthermia, either as a sole therapy, or as an adjunct, isa treatment of last resort. In these cases, any responsewhatsoever is often remarkable. Nonetheless, a number ofhyperthermia centers in Europe have discontinued sys-temic hyperthermia because the high temperature proto-cols required intensive patient care and led to unacceptabletoxicities, especially in light of the efficacy and reducedtoxicities of newer generation chemotherapies. Large, ran-domized, multicenter, Phase III trials are, however, neededto firmly establish the benefits of systemic hyperthermia inconjunction with chemotherapy and radiation. Also, vali-dation and optimization of fever-range temperature proto-cols are much needed.

Systemic Hyperthermia and Chemotherapy. The bene-ficial interaction of hyperthermia with several classes ofchemotherapy agents, acting via several mechanisms assummarized in Table 6, has spurred a variety of thermo-chemotherapy regimens and several clinical trials of sys-temic hyperthermia and chemotherapy are ongoing. Whilethe results have been mixed, elevated response rates wererecorded in the treatment of sarcoma when systemichyperthermia was combined with doxorubicin and cyclo-phosphamide (54) or BCNU (34). Systemic hyperthermia isthe only way to heat the lung uniformly, and impressiveresponse rates and increased durations of response havebeen achieved in both small cell and nonsmall cell lungcancer treated with the combination of whole bodyhyperthermia at 41 8C for 1 h with adriamycin, cyclopho-sphamide, and vincristine (ACO protocol) (34). Neuroendo-crine tumors also appear to have increased sensitivity tosystemic hyperthermia and multidrug chemotherapy (51).

Optimal combination of whole-body hyperthermia withchemotherapy requires an understanding of the mechan-isms of interaction of heat with individual drugs or drugs incombination. Preclinical data is consistent with the conceptthat the timing of chemotherapy during whole-bodyhyperthermia should affect therapeutic index. For exam-ple, Fig. 4 shows the effect on tumor cures in mammarycarcinoma bearing rats of 6 h of 40 8C whole-bodyhyperthermia administered with, or 24 or 48 h after gem-citabine. A synergistic response was obtained whenhyperthermia was begun with gemcitabine administrationor 48 h later. The effect of gemcitabine was completelynegated, however, when hyperthermia was administered24 h after the start of heating, perhaps due to cell cycleeffects. With cisplatin, the greatest therapeutic index isachieved if the drug is given 24 h before the start of whole-body hyperthermia, thereby preventing thermal augmen-tation of cisplatin induced nephrotoxicity (55). In a clinicalinvestigation of multiple cycles of radiant heat whole-bodyhyperthermia combined with carboplatin, Ifosfamide, eto-poside, and granulocyte colony stimulating factor, it wasfound that toxicity was minimized when carboplatin was

56 HYPERTHERMIA, SYSTEMIC

0.0

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Figure 4. Schedule dependence of fever range whole-bodyhyperthermia enhanced gemcitabine tumor cures. A supraaddi-tive cure rate occurred when whole-body hyperthermia (WBH)was given at the same time as gemcitabine administration or 48 hlater. When hyperthermia followed gemcitabine by 24 h the numberof cures droppedtoalmostzero, wellbelow thenumber achieved withgemcitabine alone.

given during the plateau phase of WBH, 10 min after targettemperature was reached (56).

A major rationale for whole-body hyperthermia in can-cer treatment is the ability to treat metastases, but this isactually a controversial issue. There have been no clinicalstudies specifically designed to study the effect of systemichyperthermia on either the efficacy against metastaticdisease or prevention of development of metastases.Increased survival in advanced malignancies is often inter-preted to mean a reduction in metastatic disease, but directmeasurement of the incidence and response of metastasesis rare. Based on some animal studies, it has been sug-gested that systemic hyperthermia could actually promotethe metastatic spread of tumor cells, but this has not beenconfirmed. One clinical study found an increase of tumorcells in blood 24 h after 41.8 8C WBH, but there was no

evidence that this caused metastatic spread of disease (57).Several animal experiments do support the efficacy ofwhole-body hyperthermia against metastases. In mousemodels of lung cancer and melanoma, the number of lungmetastases was scored after repeated systemic microwaveheating. It was found that the number of lung metastaseswas significantly reduced, and NK-cell activity was higher,in treated animals. The authors hypothesized that WBHinterferes with the spread of organ metastases, possiblythrough a mechanism involving NK cells (13). Anotherstudy of mouse Lewis lung carcinoma in which the animalswere treated with 60 min of systemic hyperthermia at42 8C, demonstrated a reduction in the number andpercentage of large metastases (>3 mm) on day 20 post-tumor implantation. Addition of radiation led to a reduc-tion to 50% of control of the number of lung metastases as

HYPERTHERMIA, SYSTEMIC 57

Table 6. Chemotherapy Agents Used with Whole-Body Hyperthermia

Class of AgentLikely Mechanismof Heat Interaction

Drugs Used withWBH in Clinical Studies

InvestigatorReferencesa

Alkylating agents Impaired DNA repair Cyclophosphamide (CTX) Parks, 1983 (4)Improved pharmacokinetics Engelhardt, 1988 (34)

Dacarbazine (DTIC) Lange, 1983 (35)Melphalan (L-PAM) Robins, 1997 (36)Ifosfamide (IFO) Engelhardt, 1988 (34)

Issels, 1990 (37)Westermann, 2003 (38)

Nitrosoureas Impaired DNA repair BCNU Parks, 1983 (4)Improved pharmacokinetics Bull, 1992 (39)

Me-CCNU Bull, 1992 (39)Platinum agents Impaired DNA repair Cisplatin (CDDP) Parks, 1983 (4)

Altered plasma protein binding Herman, 1982 (40)Engelhardt, 1990 (41)Robins, 1993 (42)Douwes, 2004 (43)

Carboplatin (CBDCA) Westermann, 2003 (38)Hegewisch-Becker, 2002 (44)Hegewisch-Becker, 2003 (45)Douwes, 2004 (43)Richel, 2004 (46)Strobl, 2004 (47)

Oxaliplatin Elias, 2004 (48)Hegewisch-Becker, 2002 (44)

Anthracyline antibiotics Impaired DNA repair Adriamycin Engelhardt, 1990 (41)Enzyme activation Bull, 2002 (49)

Bleomycin Herman, 1982 (40)Antimetabolites Increased drug transport 5-FU Lange, 1983 (35)

Cell cycle arrest Larkin, 1979 (50)Impaired DNA repair Bull, 2002 (49)

Hegewisch-Becker, 2002 (44)Gemcitabine Bull, 2004 (51)

Antiproliferatives Impaired DNA repair Etoposide (VP-16) Barlogie, 1979 (52)Issels, 1990 (37)Westermann, 2003 (42)

Topoisomerase inhibitors Impaired DNA repair Irinotecan (CPT-11) Hegewisch-Becker, 2003 (45)Elias, 2004 (48)

Taxanes Microtubule disruption Paclitacel Strobl, 2004 (49)Apoptosis Docetaxel Strobl, 2004 (49)

Biological responsemodifiers

Increased anti-viral andantiproliferative activity

Interferon Robins, 1989 (53)

Bull, 2002, 2004 (34,49)

aReferences prior to 1980, or not in English, are not provided in the Bibliography at the end of this article.

well as the percent of large metastases on day 20 (58). In abreast cancer ocult metastasis model in rats, 6 h of 40 8Cwhole-body hyperthermia combined with daily, low dose,metronomic irinotecan resulted in delayed onset, andreduced incidence, of axillary lymph node metastases com-pared to control in rats, as did treatment with 40 8C WBHalone. The combination therapy also reduced axillarymetastasis volume. Interestingly, none of the therapiessignificantly affected inguinal lymph node metastases,but lung metastases were decreased in both the combina-tion therapy and WBH alone groups. Rats treated withfever-range whole-body hyperthermia and metronomicirinotecan also survived significantly longer (36%) thancontrol animals (59).

Systemic Hyperthermia and Radiotherapy. The augmen-tation of ionizing radiation induced tumor kill byhyperthermia is well documented for local hyperthermiaand has led to numerous protocols combining whole-bodyhyperthermia with radiation therapy (60,61). Hyperther-mia is complementary to radiation in several regards:ionizing radiation acts predominantly in the M and G1

phases of the cell cycle while hyperthermia acts largelyin S phase; radiation is most effective in alkaline tissueswhereas hyperthermic cytotoxicity is enhanced underacidic conditions; radiation is not effective in hypoxicregions yet hyperthermia is most toxic to hypoxic cells.Thus when hyperthermia is combined with radiotherapy,both the hypoxic, low pH core of the tumor is treated as wellas the relatively well perfused outer layers of the tumor.Furthermore, because of its vascular effects, hyperthermiaenhances tumor oxygenation thus potentiating radiationcell kill. Hyperthermia also increases the production of oxy-gen radicals by radiation, and reduces the repair of DNAdamage caused by ionizing radiation. Thus hyperthermiaand radiotherapy together often have a synergistic effect,and this combination is now well accepted for treatment of anumber of tumors.

Fever-Range WBH. Like systemic hyperthermia alone,combined modality treatments were initially aimed toachieve maximally tolerated temperatures. Such regi-mens, however, carry significant risk to the patient,require general anesthesia, and necessitate experienced,specialist personnel to provide careful monitoring of vitalsigns and patient care during the treatment. Morerecently, it has been appreciated that lower core bodytemperatures (39–40 8C) maintained for a longer time(4–8 h), much like fever, can indirectly result in tumorregression through effects on tumor vasculature, theimmune response, and waste removal (detoxification).The optimum duration and frequency of mild hyperther-mia treatment has, however, not yet been determined.Protocols range from single treatments of 4–6 h, or similarlong duration treatments given once during each cycle ofchemotherapy, to daily treatments of only 1 h. Severalstudies of mild, fever-range, whole-body hyperthermiawith chemotherapy have demonstrated efficacy against abroad range of cancers (34,17) and clinical trials are cur-rently being conducted at the University of Texas HealthScience Center at Houston, Roswell Park Cancer Institute,

New York, and by the German Interdisciplinary WorkingGroup on Hyperthermia (62).

Systemic Hyperthermia and Metabolic Therapy.Increased rates of metabolic reactions lead to rapid turn-over of metabolites, causing cellular energy depletion,acidosis, and consequent metabolic disregulation. Tumors,which have increased metabolic rates [glucose, adenominetriphosphate (ATP)] compared to normal cells, may beparticularly sensitive to thermally induced energy deple-tion and this has been exploited in the Cancer MultistepTherapy developed by von Ardenne, which is a combinedhyperthermia–chemotherapy–metabolic therapy approachto cancer (63). The core of this approach is systemichyperthermia at 40–42 8C, sometimes with added localhyperthermia to achieve high temperatures within thetumor. A 10% solution of glucose is infused into the patientto achieve a high accumulation of lactic acid within thetumor that cannot be cleared because of sluggish blood flowand confers an increased sensitivity to heat to the tumorcells. Administration of oxygen increases the arterial oxy-gen pressure and stimulates lysozymal cytolysis. Finallylow dose chemotherapy is added.

Palliation. Pain relief is reported by many patientsreceiving systemic hyperthermia treatment, whether withchemotherapy or radiation. Indeed, almost all patientsundergoing thermoradiotherapy report pain relief.Immediate pain relief following treatment is likely to stemfrom an increased level of circulating b-endorphins, whilelonger term pain relief may be due to increased blood flow,direct neurological action, and disease resolution, forexample, tumor regression in cancer patients, or detoxifi-cation. Meaningful improvements in quality of life typi-cally result from such pain relief. Localized infraredtherapy using lamps radiating at 2–25 mm is used forthe treatment and relief of pain in numerous medicalinstitutes in China and Japan.

Diseases Other than Cancer. Therapeutic use of heatlamps emitting IR radiation is commonplace throughoutthe Orient for rheumatic, neurological and musculoskele-tal conditions, as well as skin diseases, wound healing, andburns. The improvements reported appear to be largelydue to increased blood flow bringing nutrients to areas ofischemia or blood vessel damage, and removing wasteproducts. Scientific reports of these treatments are, how-ever, difficult to find. Application of heat via hot baths orultrasound has long been standard in physical therapy forarthritis and musculoskeletal conditions, though ice packsare also used to counter inflammatory responses. Heatdecreases stiffness in tendons and ligaments, relaxes themuscles, decreases muscle spasm, and lessens pain. Unfor-tunately, few clinical trials of efficacy have been performed,and methodological differences or lack of rigor in thestudies hinder comparisons (64). A clinical trial inJapan reported a supposedly successful solution for sevenout of seven cases of rheumatoid arthritis treated withwhole-body IR therapy, and it is reported that the King ofBelgium was cured of his rheumatoid arthritis in threemonths due IR treatments. Systemic hyperthermia with

58 HYPERTHERMIA, SYSTEMIC

whole-body radiant heat units is being carried out inclinical centers as well as many private clinics in Germanyfor the purpose of alleviating rheumatoid arthritis. It hasbeen proposed that the induction of TNF receptors by WBHmay induce a remission in patients with active rheumatoidarthritis. The use of heat packs has long been standard torelieve the pain of fibromyalgia. Again, the therapeuticeffect is believed to be due to increased circulation flushingout toxins and speeding the healing process. Whole-bodyhyperthermia treatment for fibromyalgia and chronic fati-gue syndrome (CFS) is to be found in a number of privateclinics. Hyperthermia increases the number and activity ofwhite blood cells, stimulating the depressed immune sys-tem of the CFS patient.

Because of its immune stimulating effects, whole-bodyhyperthermia is a strong candidate for treatment of chronicprogressive viral infections, such as HIV and hepatitis C. Aclinical trial at the University Medical Center Utrecht, TheNetherlands has evaluated extracorporeal heating to inducesystemic hyperthermia of 41.8 8C for 120 min under propo-fol anesthesia for treatment of hepatitis C (65). Humanimmunodeficiency virus (HIV)-infected T cells are moresensitive to heat than healthy lymphocytes, and suscept-ibility increases when the cells are presensitized by expo-sure to tumor necrosis factor. Thus, induction of whole-bodyhyperthermia or hyperthermia specifically limited to tissueshaving a high viral load is a potential antiviral therapy foracquired immunodeficiency syndrome (AIDS). An Italianstudy has found treatment of AIDS with beta-carotene andhyperthermia to be synergistic, preventing progression ofearly disease and also increasing the survival time inpatients with severe AIDS. A single treatment of low flowextracorporeal hyperthermia was found effective againstAIDS associated Kaposi’s sarcoma, though there was sig-nificant toxicity. Core temperature was raised to 42 8C andheld for 1 h with extracorporeal perfusion and ex vivoblood heating to 49 8C. Complete or partial regressionswere seen in 20/29 of those treated at 30 days post-treat-ment, with regressions persisting in 14/29 of those treatedat 120 days post-treatment. At 360 days, 4/29 maintainedtumor regressions with 1 patient being in complete remis-sion still at 26 months (66).

THE FUTURE OF SYSTEMIC HYPERTHERMIA

While there is a resurgence of interest in systemichyperthermia, this modality has not yet been adopted asa mainstream therapy, and optimal clinical trials havenot yet been carried out. Well-designed, well-controlled,multicenter clinical trials need to be conducted. In order tounequivocally demonstrate the utility of whole-body hyper-thermia inthetreatmentofcanceraswellasotherdiseases, itwill be important to accrue a sufficiently large number ofpatients who do not have end-stage disease. Thanks to thecommercial availability of systemic hyperthermia systems,the variability between induction techniques at differentinstitutions can be removed. Newer instrumentation, parti-cularlynear-IR radiantheatdevices,alongwithtreatmentatlower temperatures (fever-range thermal therapy) shouldlead to significantly reduced toxicity. Better exploitation of

the narrow window of effective temperatures within whichthe cellular effects of heat can be exploited yet damageremains minimal, and improved understanding of the biolo-gical interactions invivoof systemicheatwithchemotherapyand radiation will be essential to optimize therapy.

The effects of systemic hyperthermia on tumor bloodflow and vascular permeability have the potential toincrease delivery of various small molecules, nanoparticles,and gene therapy vectors to tumors. Ferromagnetic nano-particles can be heated by external magnetic fields and offerthe potential for internal hyperthermia, both locally andsystemically. Thermally sensitive liposomes that releasetheir contents at designated temperatures are also of inter-est. The ability of systemic hyperthermia to aid in systemicdelivery of gene therapy vectors (the holy grail of genetherapy) and enhance transfection of cells with therapeuticgene plasmids is under investigation in several laboratories(67,68), and shows potential along with targeted gene ther-apy via the heat shock response. For example, Fig. 5 shows afourfold hyperthermic increase of therapeutic gene deliveryto tumor when plasmid DNA was injected intravenouslyinto mammary carcinoma bearing rats immediately after 6h of whole-body hyperthermia at 40 8C. Thus systemichyperthermia is likely to see increasing application as anenhancer of drug delivery.

There is a great deal of interest in the immunologicalconsequences of whole-body hyperthermia, and as theybecome better understood, the combination of systemichyperthermia with specific immunotherapies will undoubt-edly be pioneered, not just for cancer but also, by analogywith fever, in a broad range of diseases.

SUMMARY

Systemic hyperthermia is founded on solid physical andbiological principles and shows promise in the treatmentof a number of diseases. Modern whole-body hyperther-mia devices use IR-A radiation sources together witheffective heat loss techniques to achieve a controlled,uniform temperature distribution throughout the bodywith minimal patient toxicity. A shift in paradigm hasoccurred away from achieving direct cell killing with short

HYPERTHERMIA, SYSTEMIC 59

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Figure 5. Fever range whole-body hyperthermia increasestherapeutic gene (grp78-HSVtk) delivery in tumor.

bouts of maximally tolerated temperatures, to inducingindirect curative effects through longer duration treatmentsat lower temperatures, and synergy with other modalities,such as radiotherapy. Better understanding of the interac-tions of elevated temperature with metabolic and geneticpathways will allow thermally driven targeted therapies.Of particular promise is the use of systemic hyperthermiaas an immune system stimulator and adjunct to immu-notherapy. Application of systemic hyperthermia to nano-particle delivery and gene therapy is emerging. Whole-bodyhyperthermia is moving from being dubbed an alternativetherapy to becoming a standard treatment and clinicalhyperthermia centers are to be found all over the world.

Useful Websites

http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat6.section.40680

Techniques andDevices Usedto ProduceHyperthermia

http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cmed.section.7813

Physics andPhysiology ofHeating

http://www.duke.edu/~dr3/hyperthermia_general.html

Clinical HyperthermiaBackground

http://www.eurekah.com/isbn.php?isbn=1-58706-248-8&bookid=143&catid=50

Online book:LocoregionalRadiofrequency-perfusionaland Whole BodyHyperthermia inCancer Treatment:New Clinical Aspects,E.F. Baronzio andA. Gramaglia (eds.),Eurekah BioscienceDatabase

http://www.esho.info/professionals/

European Society forHyperthermicOncology

http://www.hyperthermie.org/index2.html

GermanInterdisciplinaryWorking group onhyperthermia

http://www.uth.tmc.edu/thermaltherapy/

Systemic ThermalTherapy at theUniversity of Texas

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Further Reading

Bakhshandeh A, et al. Year 2000 guidelines for clinical practice ofwhole body hyperthermia combined with cytotoxic drugs fromthe University of Lubeck and the University of Wisconsin. JOncol Pharm Practice 1999;5(3):131–134.

Field SB, Hand JW, editors. An Introduction to the Practical Aspectsof Clinical Hyperthermia. London: Taylor & Francis; 1990.

Gautherie M, editor. Methods of External Hyperthermic Heating.Berlin/Heidelberg: Springer Verlag; 1990.

Gautherie M, editor. Whole Body Hyperthermia: Biological andClinical Aspects. Berlin/Heidelberg: Springer Verlag; 1992.

Hahn GM. Hyperthermia and Cancer. New York: Plenum Press, 1982.Hildebrandt B, et al. Current status of radiant whole-body

hyperthermia at temperatures > 41.5 degrees C and practicalguidelines for the treatment of adults. The German Interdisci-plinary Working Group on Hyperthermia. Int J Hyperthermia2005;21(2):169–183.

Issels RD, Wilmanns W, editors. Recent Results in CancerResearch, Vol. 107: Application of Hyperthermia in theTreatment of Cancer. Berlin/Heidelberg: Springer Verlag;1988.

Nussbaum GH, editor. Physical Aspects of Hyperthermia. AmericanAssociationofPhysicists inMedicineMedicalPhysicsMonographNo. 8. New York: American Institute of Physics; 1982.

Guan J, et al. The clinical study of whole-body hyperthermia(WBH) improving the survival state of patients with advancedcancer. Proc 26th Congress of the International ClinicalHyperthermia Society, Sept. 9–12, 2004, Shenzhen, China;2004; p 66.

Kurpeshev OK, Tsyb AF, Mardynsky YS. Whole-body hyperthermiafor treatment of patients with disseminated tumors- Phase II. In:P.H. Rehak, K.H. Tscheliessnigg, editors. Proceedings 22nd.Annual Meeting of the European Society for HyperthermicOncology, June 8–11, 2005, Graz, Austria, 2005; p 103.

Hou K. Assessment of the effects and clinical safety of the treat-ment of advanced malignant tumor with extracorporeal wholebody hyperthermia. Proceedings of the 26th Congress of the

International Clinical Hyperthermia Society, Sept. 9–12, 2004,Shenzhen, China; 2004 p 71.

See also BIOHEAT TRANSFER; HEAT AND COLD, THERAPEUTIC; HYPERTHER-

MIA, INTERSTITIAL; HYPERTHERMIA, ULTRASONIC; RADIATION DOSIMETRY FOR

ONCOLOGY.

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