clinical use of thermal enhancement and therapeutic gain ... · clinical use of thermal enhancement...

[CANCER RESEARCH (SUPPL.) 44, 4836s-4841s, October 1984]

Clinical Use of Thermal Enhancement and Therapeutic Gain forHyperthermia Combined with Radiation or Drugs1

Edward L. Gillette

Department of Radiology and Radiation Biology, Comparative Oncology Unit, Colorado State University, Fort Collins, Colorado 80523

Abstract

Values for thermal enhancement and therapeutic gain areuseful for deciding future directions of hyperthermia combinedwith other cancer therapy modalities. Evidence of thermal enhancement of effects on normal tissues is important as it indicates the need for dose modification. Specific values cannot beused generally to determine the degree of dose modification forclinical applications. A range of values accounting for manyvariables, including method of dose delivery for heat and theother modalities and knowledge of the normal tissues at risk,would be required for such specific application. There is frequently hyperthermic enhancement of radiation damage toacutely responding tissues. That may be avoided if tumors canbe selectively heated, but extensive temperature monitoring isnecessary to avoid hot spots. Irradiation and heating of spontaneous canine tumors resulted in an increased probability fortumor control with no apparent increase in late complications.Human clinical studies have shown that, with care, tumor response can be enhanced without significantly increasing normaltissue damage and that a therapeutic gain can be achieved.Caution must be exercised because, with few exceptions, follow-

up was not long, and the tissues at risk were limited. Mosthuman studies have been of relatively superficial tumors of smallvolume. Little information is available on whole-body or regional

hyperthermia for assessment of thermal enhancement or therapeutic gain. Also, there is little information about chemotherapycombined with heat, although studies of heat with perfusionchemotherapy for malignant melanomas of the extremity haveshown significantly increased survival rates.

Introduction

The objective of new modalities for cancer treatment is toimprove control of the disease while maintaining a good qualityof life. The need for assessment of quality of survival as well asmeasuring survival rates has been stressed by radiation oncologists (35, 44). Enhancement of tumor control must be considered in conjunction with the maximum acceptable probability ofcomplications to determine a therapeutic gain.

Hyperthermia is one of several methods considered in recentyears to improve tumor control. Surgery and radiation therapyprovide limited control for deep-seated tumors in several anatom

ical sites. There are also more accessible tumors which recurlocally following irradiation or surgery for which improved controlrates could be achieved (41). Clinical interest in hyperthermiaincreased, based on experiments indicating an enhancement oftumor control in rodents when heat was combined with radiationor chemotherapy (8, 16, 27, 34, 42). Human clinical studies also

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

March 19 to 21, 1984, Tucson, AZ. This work was supported in part by USPHSGrant CA29582, Department of Health and Human Services.

have shown that the addition of heat to radiation tends toenhance tumor control for short intervals following treatment (3,7, 23, 25, 26, 28, 30, 45). Thermal enhancement of tumorregression was observed, and there were few complications, sothere appeared to be a therapeutic gain. The observations havenot been sufficiently long to evaluate either long-term control orlate complications.

TER2 and TGF

Robinson ef al. (34) were among the first to use TER forcomparing response of mouse tumors and skin to heat plusradiation to the response to radiation alone. They showed that agreater TER could be achieved for mouse tumor than for mouseskin. They defined TER as the ratio of radiation sensitivity at37.5Â° to the sensitivity at an elevated temperature. They ob

tained the TER as follows:

TER = Radiation dose for a specified effect

Radiation dose with heat for a specific effect

When they heated mouse mammary tumors and normal skin inwater bath temperatures of 43Â°for 1 hr and irradiated in the

middle of the heat interval, they obtained a therapeutic gain of2.1. They divided the TER for tumor by the TER of skin to obtainwhat they termed the therapeutic ratio. Subsequently, the termTGF has been used for the value obtained as follows:

TGFTER for tumor

TER for normal tissue

TGF has been calculated for some mouse tumors, but the valuesare much more difficult to obtain from human clinical trials (14,18).

Thrall ef al. (43) also reported response of combined heat andirradiation on mouse tumor systems. In those studies, thermalenhancement was shown for both skin and tumor. A therapeuticgain was achieved only for irradiation under hyperbaric conditionsimmediately before heating. In those studies, heating was in awater bath at 44.5Â° for 15 min. Irradiation was given either

immediately before or after heating. Irradiation after heatingcaused much greater damage to skin. In a study of a veryradiation-sensitive osteogenic sarcoma of mice, tumor control

was achieved without skin damage, regardless of the sequenceof heating and irradiation (15). The total dose was only 600 radsgiven in 3 fractions. At the time of those earlier papers, it wasnot clear that the variables of temperature, time, and sequencingwould significantly affect thermal enhancement and therapeuticgain.

2The abbreviations used are: TER, thermal enhancement ratio; TGF, therapeutic

gain factor; TEF, therapeutic enhancement factor; TRR, thermal relative risk; TCDÂ»,dose at which there was 50% probability for tumor control; RTOG, RadiationTherapy Oncology Group.

4836s CANCER RESEARCH VOL. 44

on June 28, 2020. © 1984 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

http://cancerres.aacrjournals.org/

Thermal Enhancement and Therapeutic Gain

The paper of Robinson ef al. (34) was one of the few indicatinga therapeutic gain, and even in that work, the radiation doserequired to produce the specified level of skin damage wasslightly less than for tumor control. Therapeutic gain was a usefulterm, because values greater than 1 indicated greater relativeeffect on tumor than on skin. Skin response had been establishedas a standard method for comparison and was convenient (4). Itwas not known then, as now, what tissues might be dose limiting,as that would depend on the sites chosen for hyperthermictherapy. Skin is a reasonable comparative tissue for oral mucos-

itis and intestinal damage but does not predict for late effects(47,49). Late-effects studies must be done on the specific tissue

of concern as the level of acceptable toxicity, sensitivity, andtime of appearance of lesions vary among tissues.

The term "therapeutic ratio" is sometimes used for comparing

different treatment methods. It has limited meaning in cancertherapy, because maximum tolerated doses are routinely used.For some other diseases, the dose of the therapeutic agentneeded to control the disease is much less than that accompanied by significant toxicity. A therapeutic ratio or index generally is obtained by dividing the dose accompanied by anacceptable level of toxicity by that which will control the disease.The therapeutic ratio is one for radiation therapy and is not likelyto change. For most radiation therapy, the maximum dose isgiven which is accompanied by an acceptable probability forcomplications, and there will be a varying probability for tumorcontrol. If a new method of therapy were developed which ismore effective, the doses would probably be given to the samelevel of acceptable toxicity. The important change would be anincreased percentage of tumor control.

Therapeutic Gain with Heat and Radiation of Human Tumors

Most of the human clinical trials have shown thermal enhance

ment of tumor response. Normal tissue damage was moredifficult to evaluate in humans as the trials were designed toavoid significant damage to normal tissues. The following reportswere chosen for discussion, because the studies were designedprospectively to compare heat and radiation with radiation alone,so that thermal enhancement and, in some cases, therapeuticgain could be determined.

Chang ef al. (6) listed some of the limitations encountered inRTOG Phase 1 trials. Thermal enhancement values for tumorfrequently could not be obtained because of insufficient survivaltime or the failure of at least one lesion to regrow. Thermalenhancement for tumor was evaluated from regrowth data.Thermal enhancement for skin response could not be determinedadequately if the lesions were in different anatomical sites. In acontinuation of that study, a therapeutic enhancement of 2 wasobtained for tumor, based on early complete tumor responses(37). Those studies were done with standard fractionation radiation therapy and hyperthermia given 30 min following radiation.The interval between heat treatments was at least 72 hr. At the6-month follow-up, the therapeutic enhancement ratio for 35

patients stabilized at approximately 1.3 (Table 1). That valuewas maintained in 20 patients for 12 to 18 months after therapy.For the 18 of 20 patients who had 2 lesions, one lesion wastreated with heat and radiation, and the other lesion served as aradiation-only control. The authors stated that no long-termtoxicity due to hyperthermia was observed. For the RTOG 77-

10 protocol reported by Scott ef al. (36), a thermal enhancementvalue of 2.2 was given for tumors. They stated that this greaterthermal enhancement was obtained because the radiation therapy was not definitive and was applied as palliation for patientsknown to have limited survival because of mÃ©tastases. Thesecond protocol, RTOG 78-06, was devised in which patients

were given definitive radiotherapy to which hyperthermia wasadded. There was less thermal enhancement in the second

Table 1

Thermal enhancement and therapeutic gain with radiation and hyperthermia of human tumors

Ref. Tumor type and site Heat treatment

No. of Thermalheat Radiation enhancement Thera-treat- Sequence of Aa fraction Total dose peutic

ments and XRT size (Gy) (Gy) Tumor Skin gain

ScotterÃ /. (36,37)Kim

et al.(20)Arcangeli

et al. (1)Superficial

epithelialtumorsincludingmelanomasRecurrent

melanomas;s.c.andlymphnodesNeck

node mÃ©tastasesofcarcinomasVarious

superficialrecurrenttumorsVarious

superficialrecurrenttumorsVarious

superficialrecurrenttumors42.5-43.5Â°/45

min42.0-43.5Â°/30

minforallprotocols42.5Â°/45

min42.5Â°/45

min42.5Â°/45

min45.0Â°/30

min1213107678862

A/wk 30minafterXRT2

A/wk immediately beforeXRT2A/wk immediately beforeXRT1A/wk immediately beforeXRT1A/wk immediately beforeXRT3

A/wk immediatelyafterXRT2

A/wk immediatelyafterXRT2

A/wk 4hrafterXRT2

A/wk immediatelyafterXRT1.8-2.03.345.56.61.5-2.055650-6042.94038.539.660

(Acceleratedschedule)4040301.3

12.3

11.4

11.5

11.4

11.74

1.12.05

1.781.79

1.282.63

1.251.32.31.41.51.41.581.151.42.1

* A, heat; XRT, radiation.

OCTOBER 1984 4837s



E. L Gillette

study, which was not due to less satisfactory results fromhyperthermia but the result of more effective radiation therapy inthe patients treated only with irradiation. There was no observedincrease in toxicity from the addition of hyperthermia. That wasan important observation, because heat had been added to a fullcourse of radiation therapy.

One of the earlier reports was of the use of temperatures of41 to 43.5Â°for 30- to 90-min sessions combined with radiation

therapy (19). A variety of tumors was included. When comparingcomplete response of tumors which were treated with heat andirradiation to those which received radiation alone, a thermalenhancement of 3 was obtained. Enhanced skin reactions wereonly in areas where there was previous scarring, skin grafting,or when fractionated doses in excess of 5 Gy per session wereused.

In a later paper by that same group, more than 100 lesions in38 patients were treated with radiation alone and hyperthermiacombined with radiation (20). Most of the lesions were treatedonce or twice a week. The tumor control rate for an unspecifiedperiod of time was 75% for radiation combined with heat and46% for radiation alone. A thermal enhancement of 1.6 could beobtained from those data. Minimal normal tissue response wasobserved. The values for thermal enhancement for human tumors are usually derived from comparisons of percentages oftumor response and are not ratios of doses as defined earlier forTER.

Arcangeli et al. (1) reported the results of treatment of 57patients, each having at least 2 lesions. A total of 123 lesionswas treated with either radiation alone or radiation combinedwith hyperthermia. Three main studies were carried out. The firstwas done on 26 patients with a total of 52 neck node mÃ©tastasesfrom head and neck carcinomas. Irradiation was combined withhyperthermia of 42.5Â°for 45 min. Although the radiation fraction

sizes were small, they were given on an accelerated schedule.Three doses per day were given of 2, 1.5, and 1.5 Gy with a 4-

hr interval between fractions. These were given 5 days a weekfor a total dose of 60 Gy. For that group of patients, heat wasapplied immediately after the second daily fraction of irradiationevery other day for a total of 7 sessions. In another study, 5 Gyper fraction were given twice a week at intervals of 72 to 96 hrfor a total dose of 40 Gy. A variety of recurrent tumors wastreated, including melanomas, carcinomas, and undifferentiatedlung tumors. Hyperthermia of 42.5Â° for 45 min was given im

mediately or 4 hr after irradiation. For a third study, 5 fractionsof 6 Gy were given twice a week at intervals of 72 to 96 hr upto a total of 30 Gy and combined with temperatures of 45Â°for

30 min applied immediately after each radiation fraction. A varietyof tumors as in the second group was treated. A TEF wasobtained. They stated that a TEF was usually defined as theratio of thermal enhancement of tumors to the thermal enhancement of skin. As they used only one radiation dose level, theyused thermal enhancement as defined by the ratio of the percentage of response, which was either tumor clearance or moistdesquamation, after combined modality to the percentage ofresponse after a single treatment modality. Using those values,a TEF of 1.58 was obtained with conventional fraction sizes ofradiation and what they termed moderate heat (Table 1). TEFvalues of 1.4 and 1.5 were observed after the second trial inwhich high fraction sizes of irradiation were combined with thedelayed or immediate moderate hyperthermia. The highest TEF

value of 2.1 was obtained with large fraction sizes followedimmediately with hyperthermia of 45Â°for 30 min. In that case,

they were able to preferentially heat the tumor and used activeskin cooling. They stated that tumor control increased with bothradiation fraction size and temperature. They suggested that, ifradiation therapy had never been given before, an optimal treatment would result by adding 5 to 7 immediate or delayedsessions of hyperthermia of 43Â° for 45 min once or twice a

week. That would be added to a full conventional fractionationor hyperfractionation radiotherapy course. They felt that noincrease of radiation damage to normal tissue would result,particularly if tumor could be selectively heated. In heavily irradiated tissues or when rapid treatment of several lesions wasrequired for palliation, an optimal treatment would result by using5 to 7 fractions of 5 or 6 Gy in combination with 5 to 7hyperthermic sessions given twice a week.

Arcangeli et al. (1) pointed out the important differences inthermal enhancement between experimental animal data andthose obtained in humans. Most of the human studies were notdone as radiation dose-response assays as are done in experi

mental animals. Therefore, the thermal enhancement is taken asthe ratio of response to a given radiation dose. That value doesnot represent a true dose-modifying factor and may be consid

erably greater than a TER, which is based on a uniform biologicalresponse. In experimental animals, a dose-response assay is

usually done, and TERs as defined by Robinson are determinedfrom the doses to cause a given level of effect.

Dewhirst ef al. (9) were faced with this problem in analyzingdata from a trial in spontaneous tumors in dogs and cats. Theyused a value which they termed the TRR. They chose that termbecause the study was designed to compare a constant irradiation protocol with that same protocol combined with heat. TheTER was obtained by dividing the percentage of response oftumors to heat and irradiation by that for radiation alone. Theytreated 130 pet animals with squamous cell carcinomas, melanomas, fibrosarcomas, mammary adenocarcinomas, and mastcell sarcomas. They attempted to heat tumors to 44Â°Â±2Â°for

30 min. The radiation dose was 460 rads per fraction twice aweek for 8 fractions. The heat was given once a week immediately following radiation. The TRR for all tumors treated was 2.3.These data have subsequently been analyzed to show theimportant influence of histology, volume, site, and heat treatmentmethod (10, 11). The aspect of greatest importance was theminimum tumor temperature. This seemed to govern the biological response to combined heat and radiation.

Dose-response studies provide data which can be used toobtain a dose-modifying factor which for heat is called the TER.

A collaborative study at Colorado State University and the University of Arizona was designed to determine TER and TGF forspontaneous tumors in dogs. Preliminary results have beenobtained for squamous cell carcinomas of the oral cavity of dogs.Dogs were randomized to receive radiation only or radiation plusheat. They were also randomized to one of 4 radiation doseswithin each group. The total radiation doses were divided in 10fractions given 3/week for 3 weeks. Heating was done twice aweek with a 72- or 96-hr interval between. A minimum tumortemperature of 42Â°for 30 min was produced by radiofrequency,

microwave, or ultrasound equipment. Data were obtained fromdogs followed for at least 1 year. The curves for radiation onlywere redrawn from a previous dose-response assay of oral





_o(E

0.95

090z ce0 < O.8OC_> UJ

o: ^ 0.701 i- 0.60H ^ 0.50or 5; 0.40Â£g 0.30

Â£w 0.20

coo<ro.

0.10

005

100

Tumor Control

XRT OnlyA XRT +Heat

_ Necrosis* "XRT Only

i l j20 25 30 35 40 45 50 60

RADIATION DOSE (Gy)70 80 90

Chart 1. The tumors treated were oral carcinomas in dogs. The radiation dosewas given in 10 fractions in 3 weeks. The percentage of tumor control for eachdose level used was determined 1 year after treatment. When heat was added tothe radiation dose, the TCDM was reduced from 38.8 Gy to 34 Gy. Bars, 95%confidence intervals. At 35 Gy, there was 50% tumor control for irradiation aloneand 75% control for heat plus radiation. No late necroses developed in dogs givenheat and radiation (XRT).

carcinomas done with radiation only but with the same fraction-

ation scheme (13). This study shows the important differencebetween TERs for experimental animals as compared to thethermal enhancement obtained from the percentage of response(Chart 1). There was 75% tumor control for heat plus 35 Gy ascompared to 50% control for 35 Gy alone. The thermal enhancement was 1.5. If the TCDso for these tumors was used to obtaina TER, a value of 1.1 was obtained, because the TCDso forradiation alone was 38.8 Gy, while it was 34 Gy for radiationplus heat. The slope for the tumor response curve for radiationalone is not parallel to that for necrosis. Tumors of the samestage and histological type are sufficiently heterogeneous toreduce the slope of a dose-response curve (12, 31 , 40). Normal

tissues will have a very steep response curve because of theirmore homogeneous nature. The tumor response curve for radiation plus heat is parallel to that for necrosis and shifted to theleft of the tumor response curve for radiation alone. This isimportant because higher percentages of tumor control could beobtained with lower doses. To date, no late necroses have beenseen in dogs treated with the combination of hyperthermia andirradiation. This has been true of the study with spontaneoustumors in animals at the University of Arizona and is reportedconsistently in the literature of studies of the use of radiationcombined with hyperthermia for human tumors. In this case, ifthere is no increase in late necrosis with the combination of heatand irradiation, the therapeutic gain would be 1.1 by using theratios of TERs but would be 1.5 using values for thermal enhancement or the ratio of tumor response at a specific dose.

Clinical use of TGF will depend on tumor type and locationamong other things. Normal tissue tolerance varies considerably.As pointed out by Withers and Peters (48), it is influenced by thetissue being irradiated, the treatment volume, fractionation pattern, the definition of a complication, the attitude of the therapist,and other clinical variables. Depending on these variables, several levels of complications might be acceptable. Some complications are totally unacceptable, e.g. , spinal cord necrosis. Perhaps a low incidence of medium severity complications, such asmandibular necrosis, might be warranted if there is a high rateof uncomplicated tumor control. A high probability of nondebili-

25 30 36 4O 45 50RADIATION DOSE (Gy)

55 60

Chart 2. Linear plot of the probability of tumor control and necrosis showingrelative levels of tumor control and risk of necrosis at 35,40, and 50 Gy. S-shaped

curves were drawn from data in Chart 1. Dogs with oral carcinomas were treatedwith radiation alone.

tating complications, such as apical lung fibrosis, might be acceptable if demanded for higher tumor control. Therefore, theclinical definition of tolerance is a dose regimen producing themaximum acceptable probability of complications necessary in agiven treatment situation.

The levels of complications and associated tumor control areshown for tumors of the oral cavity of dogs (Chart 2). Thecomplication curve is for bone necrosis. If normal tissue complications are to be avoided, the probability for tumor control wouldbe low. In the example given, the tumor control probability wouldbe only 30% for 35 Gy. At 40 Gy, the tumor control probabilitywould be about 65% with normal tissue complications less than5%. To achieve a 90% tumor control probability, a complicationrate of about 65% would have to be accepted.

If hyperthermia causes the tumor control curve to shift to theleft as in Chart 1 with no accompanying shift in the normal tissuecurve, a 90% tumor control probability could be achieved with avery low probability for complications.

Hyperthermia and Drugs

There is far less information on hyperthermia combined withchemotherapy than with radiation. The combination of hyperthermia plus irradiation is complicated by many variables, andthe combination of hyperthermia with drugs is even more complex because of the pharmacokinetics and varying toxicity associated with each drug. A few reports of human tumor responseindicated an advantage to be obtained from this method (33, 38,39).

Stehlen (38) used chemotherapy and heat for treatment of

OCTOBER 1984 4839s



E L. G///eÃÃe

melanomas for several years. He used melphalan perfusion withregional hyperthermia at temperatures up to 40Â°for 2.5 hr. The

5-year survival increased from 22 to 77% when heat was addedto perfusion. In a more recent study of perfusion chemotherapyfor Stage I malignant melanomas of the extremity, hyperthermiacombined with chemotherapy was compared to more conventional surgical methods (33). The survival rates for clinical StageI patients at 5, 10, and 15 years were 91, 86, and 77%. Thedisease-free survivals for those same periods were 85, 80, and

80%. These values were significantly better than the surgicalcontrols. Fifteen % of the patients failed the perfusion treatmentcompared to 33% in the control group. Two major complicationsoccurred. One patient perforated an ulcer of the upper gastrointestinal tract, and another developed a gangrenous foot requiringabove-the-knee amputation. The authors stated that no signifi

cant drug toxicity occurred. As there were no controls for perfusion without heat, a thermal enhancement of therapeutic efficacy could not be determined.

Thermal enhancement for whole-body hyperthermia is even

more difficult to evaluate. Those patients usually have widelydisseminated disease. In a recent report of 27 patients treatedwith whole-body hyperthermia in combination with either chem

otherapy or radiotherapy, there was an improved therapeuticeffect in 6 of the patients (46). It was stated that toxicity, suchas liver damage and respiratory problems, was considerable,and there were 2 fatalities. Most reports indicate that whetherwhole-body hyperthermia is used alone or combined with chemotherapy, it results in only transient responses (2, 5, 22, 29, 32).

Another area of interest in the combination of hyperthermiaand chemotherapy is in treatment of bladder carcinoma (17, 21).Bleomycin with warm 0.9% NaCI solution (saline) at 43 to 45Â°

has been used (21). Recurrence of disease was frequent in manypatients who had complete remissions. Of a total of 33 patients,there were complete responses in 14 patients. It was felt thatthese responses may be longer term because the study alsoincluded a 4-week exposure to 35 to 40 Gy for treatment oftransitional cell carcinomas of the bladder, which was also irrigated with a solution of warmed saline which contained bleo-

mycin (30 mg/ml).Some of the problems which have prevented more widespread

use of hyperthermia with chemotherapy have been discussed(24). A suggestion was that, while the radiation therapist mightmore readily accept use of the necessary equipment, the chem-

otherapist would be more comfortable trying another drug combination than adding the unknown complications of heat. Thereis also far less preclinical information on the interaction of hyperthermia and drugs than with radiation. Much work needs to bedone on the effects of local and whole-body hyperthermia on

pharmacokinetics and toxicity.

Summary

Far more work has been done with the combination of hyperthermia and radiation than with drugs. The main complicationsreported have been thermal burns due to excessive heat fromapplicators at some surface point. The reports have criticizedthe inability of available equipment to produce uniform deephyperthermia and emphasized problems with thermometry.Given those limitations, there is reason for optimism for thecombined use of heat and radiation. No increased incidence in

serious late complications has been observed in the somewhatlimited duration human studies or in the longer-term large-animal

studies specifically designed to evaluate for late complications.It appears that thermal enhancement of tumor response can beobtained with a relatively low risk of increased complications.For the most part, relatively superficial tumors and small treatment volumes have been evaluated. The true thermal enhancement and therapeutic gain will be obtained only after many yearsof clinical observations in which tumors of similar stages, locations, and histology will be compared with ongoing evaluationsof more conventional treatments. The thermal enhancementsreported are often modest but could still lead to a significantlyincreased number of tumors for which local control is achieved(Table 1).

A major objective of hyperthermia has been to achieve controlof some deep-seated tumors that currently are difficult to control.

Until effective methods for deep heating and thermometry areobtained, this may be difficult to do. It may be possible to usewhole-body hyperthermia for uniform temperature control and

use that in combination with either radiation or chemotherapy.In the meantime, if hyperthermia is to be used to improve clinicalcontrol rates, it may necessarily be limited to relatively superficialtumors. That could also be an advantage in that there aresignificant numbers of local failures following conventional treatment. In addition, hyperthermia may be used for retreatment oftumors which have failed conventional radiotherapy. The clinicaldata suggest that most methods of treatment can achieve aminimum tumor temperature of 42Â°.With care, it is possible to

prevent heating of surrounding normal tissues. Where that ispossible, there should be a significant enhancement of responseto radiation without an increase in probability of serious complications.

Acknowledgments

The author wishes to thank Sharon L. McChesney for technical assistance andpreparation of data, R. Nadine Hisam for assistance with literature search, andDiane R. Farquhar for preparation of the manuscript.

References

1. Arcangeli, G., Cividalli, A., Nervi, C., and Creton, G. Tumor control andtherapeutic gain with different schedules of combined radiotherapy and localexternal hyperthermia in human cancer. Int. J. RadiÃ¢t.Oncol. Biol. Phys., 9:1125-1134,1983.

2. Barlogie, B., Corry, P. M., Yip, E., Lippman, L., Johnston, D. A., Khalil, K.,Tenczynski, T. F., Reilly, E., Lawson, R., Dosik, G., Rigor, B., Hankenson, R.,and Freireich, E. J. Total body hyperthermia with and without chemotherapyfor advanced human neoplasms. Cancer Res., 39:1481-1489,1979.

3. Brenner, H. J., and Yerushalmi, A. Combined local hyperthermia and X-irradiation in the treatment of metastatic tumours. Br. J. Cancer, 33: 91-95,1975.

4. Brown, J. M., Goffinet, 0. R., Cleaver, J. E., and Kallman, R. F. Preferentialradiosensitization of mouse sarcoma relative to normal skin by chronic intra-arterial infusion of halogenated pyrimidine analogs. J. Nati. Cancer Inst., 47:75-89,1971.

5. Bull, J. M., Lees, D., Schuette, W., Whang-Peng, J., Smith, R., Bynum, G.,Atkinson, R., Gottdiener, J. S., Gralnick, H. R., Shawker, T. H., and DeVita, V.T., Jr. Whole body hyperthermia: a Phase-1 trial of a potential adjuvant tochemotherapy. Ann. Intern. Med., 90: 317-323,1979.

6. Chang, C., Johnson, R., Rubin, P., Luk, K., George, F., and Perez, C. AnR.T.O.G. study developed to assess the effect of hyperthermia on the tumourand normal tissue response to radiation. Br. J. Cancer, 41 (Suppl. 4y 52,1980.

7. Corry, P. M., Spanos, W. J., Titehen, E. J., Barlogie, B., Barkley, H. T., andArmour, E. P. Combined ultrasound and radiation therapy treatment of humansuperficial tumors. Radiology, 145:165-169,1982.

8. Crile, G., Jr., Selective destruction of cancers after exposure to heat. Ann.Surg., 156: 404-407,1962.

9. Dewhirst, M. W., Connor, W. G., and Sim, D. A. Preliminary results of a Phase





III trial of spontaneous animal tumors to heat and/or radiation: early normaltissue response and tumor volume Â¡nfuenceon initial response. Int. J. RadiÃ¢t.Oncol. Biol. Phys., 8; 1951-1961, 1982.

10. Dewhirst, M. W., Sim, D. A., Sapareto, S., and Connor, W. G. Importance ofminimum tumor temperature in determining early and long-term responses ofspontaneous canine and feline tumors to heat and radiation. Cancer Res., 44:43-50,1984.

11. Dewhirst, M. W., Sim, D. A., Wilson, S., DeYoung, D., and Parsells, J. L.Correlation between initial and long-term responses of spontaneous pet animaltumors to heat and radiation or radiation alone. Cancer Res., 43: 5735-5741,

1983.12. Fischer, J. J., and Moulder, J. E. The steepness of the dose-response curve

in radiation therapy. Theoretical considerations and experimental results. Radiology, 117: 179-184, 1975.

13. Gillette, E. L. Hyperthermia effects in animals with spontaneous tumors. Nati.Cancer Inst. Monogr., 67. 361 -364,1982.

14. Gillette, E. L., and Ensley, B. A. Effect of heating order on radiation responseof mouse tumor and skin. Int. J. RadiÃ¢t.Oncol. Bid. Phys., 5:209-213,1979.

15. Hahn, E. W., Alfieri, A. A., and Kim, J. H. Increased cures using fractionatedexposures of X irradiation and hyperthermia in the local treatment of theRidgway osteogenic sarcoma in mice. Radiology, 773:199-202,1974.

16. Hahn, G. M., Braun, J., and Har-Kedar, l. Thermochemotherapy: synergismbetween hyperthermia (42-43Â°C) and Adriamycin (or bteomydn) in mammaliancell inactivation. Proc. Nati. Acad. Sci. USA, 72: 937-940,1975.

17. Hall, R. R., Schade, R. O. K., and Swinney, J. Effect of hyperthermia onbladder cancer. Br. Med. J., 2: 593-594,1974.

18. Hill, S. A., and Denekamp, J. Response of six mouse tumours to combinedheat and X raysâ€”implications for therapy. Br. J. Radiol., 52: 209-218,1979.

19. Kim, J. H., and Hahn, E. W. Clinical and biological studies on localizedhyperthermia. Cancer Res., 39: 2258-2261,1979.

20. Kim, J. H., Hahn, E. W., and Ahmed, S. A. Combination hyperthermia andradiation therapy for malignant melanoma. Cancer (Phila.), 50: 478-482,1982.

21. Kubota, Y., Shuin, T., Miura, T., Nishimura, R., Fukushima, S., and Takai, S.Treatment of bladder cancer with a combination of hyperthermia, radiation,and bleomycin. Cancer (Phila.), 53:199-202,1984.

22. Larkin, J. M., Edwards, W. S., Smith, D. E., and Clark, P. J. Systemicthermotherapy: description of a method and physiologic tolerance in clinicalsubjects. Cancer (Phila.), 40: 3155-3159,1977.

23. Luk, K. H., Purser, P. R., Castro, J. R., Meyler, T. S., and Philips, T. L. Clinicalexperiences with local microwave hyperthermia. Int. J. RadiÃ¢t.Oncol. Biol.Phys., 7:615-619, 1981.

24. Magin, R. L. Hyperthermia and chemotherapy: when will they be used in theclinical treatment of cancer? Eur. J. Clin. Oncol., 79: 1655-1658,1983.

25. Manning, M. R., Cetas, T. C., Miller, R. C., Oteson, J. R., Connor, W. G., andGemer, E. W. Clinical hyperthermia: results of a Phase 1 trial employinghyperthermia alone or in combination with external beam or interstitial radiotherapy. Cancer (Phila.), 49: 205-216, 1982.

26. Marmor, J. B., Pounds, D., Postic, T. B., and Hahn, G. M. Treatment ofsuperficial human neoplasms by local hyperthermia induced by ultrasound.Cancer (Phila.), 43:188-197,1979.

27. Overgaard, J. Ultrastructure of a murine mammary carcinoma exposed tohyperthermia in vivo. Cancer Res., 36: 983-995,1976.

28. Overgaard, J. Fractionated radiation and hyperthermia: experimental and clinical studies. Cancer (Phila.), 48:1116-1123,1981.

29. Parks, L. C., Minaberry, P., Smith, D. P., and Neely, W. A. Treatment of far-advanced bronchogenic carcinoma by extracorporeally induced systemic hyperthermia. J. Thorac. Cardiovasc. Surg., 78: 883-892, 1979.

30. Perez, C. A., Nussbaum, G., Emami, B., and Von Gerichten, D. Clinical resultsof irradiation combined with local hyperthermia. Cancer (Phila.), 52: 1597-

1603,1983.31. Peters, L. J., and Fletcher, G. H. Causes of failure of radiotherapy in head and

neck cancer. Radiother. Oncol., 7: 53-63, 1983.

32. Pettigrew, R. T., Galt, J. M., Ludgate, C. M., Horn, D. B., and Smith, A. N.Circulatory and biochemical effects of whole body hyperthermia. Br. J. Surg.,67:727-730,1974.

33. Rege, V. B., Leone, L. A., Soderberg, C. H., Jr., Coteman, G. V., Robidoux,H. J., Fijman, R., and Brown, J. Hyperthermic adjuvant perfusion chemotherapyfor Stage 1 malignant melanoma of the extremity with literature review. Cancer(Phila.), 52: 2033-2039,1983.

34. Robinson, J. E., Wizenberg, M. J., and McCready, W. A. Radiation andhyperthermal response of normal tissues in situ. Radiology, 773: 195-198,1974.

35. Rubin, P., Cowen, R. B., and Rubin, D. J. Hyperthermia. Int. J. RadiÃ¢t.Oncol.Biol. Phys., 5:701-726,1979.

36. Scott, R. S., Johnson, R. J. R., Kowal, H., Krishnamsetty, R. M., Story, K.,and Clay, L. Hyperthermia in combination with radiotherapy: a review of fiveyears experience in the treatment of superficial tumors. Int. J. RadiÃ¢t.Oncol.Bid. Phys., 9: 1327-1333,1983.

37. Scott, R. S., Johnson, R. J., Krishnamsetty, R., Story, K., Wojtas, F., and Clay,L. Extended follow-up of patients treated with hyperthermia and radiation for

superficial malignancies. Am. J. Clin. Oncol., 5: 138,1982.38. Stehlin, J. S. Hyperthermic perfusion for melanoma of the extremities: experi

ence with 165 patients, 1967 to 1979. Ann. NY Acad. Sci., 335: 352-355,1980.

39. Storm, F. K., Kaiser, L. R., Goodnight, J. E., Harrison, W. H., Elliott, R. S.,Gomes, H. I., and Morton, D. L. Thermochemotherapy for melanoma metastasis in liver. Cancer (Phila.), 49:1243-1248,1982.

40. Suit, H. D., Radiation biology: the conceptual and practical impact on radiationtherapy. RadiÃ¢t.Res., 94:10-40, 1983.

41. Suit, H. D. Potential for improving survival rates for the cancer patient byincreasing the efficacy of treatment of the primary lesion. Cancer (Phila.), 50:1227-1234,1984.

42. Suit, H. D., and Shwayder, M. Hyperthermia: potential as an antitumor agent.Cancer (Phila.), 34:122-129,1974.

43. Thrall, D. E., Gillette, E. L., and Dewey, W. C. Effect of heat and ionizingradiation on normal and neoplastic tissue of the C3H mouse. RadiÃ¢t.Res., 63:363-377,1975.

44. Till, J. E., McNeil, B. J., and Bush, R. S. Measurement of multiple componentsof quality of life. In: The Interdisciplinary Program for Radiation OncologyResearch, Cancer Treatment Symposia, Vd. 1, pp. 177-181. U. S. Departmentof Health and Human Services, 1984.

45. U, R., Noell, T., Woodward, K. T., Worde, B. T., Fishbum, R. I., and Miller, L.S. Microwave-induced local hyperthermia in combination with radiotherapy ofhuman malignant tumors. Cancer (Phila.), 45: 638-646, 1980.

46. van der Zee, J., van Rhoon, G. C., Wike-Hodey, J. L., Faithfull, N. S., andReinhold, H. S. Whole-body hyperthermia in cancer therapy: a report of aPhase l-ll study. Eur. J. Cancer Clin. Oncol., 79: 1189-1200,1983.

47. Wheldon, T. E., Michalowsky, A. S., and Kirk, J. The effect of irradiation onfunction in self-renewing normal tissues with differing proliferative organisation.Br. J. Radiol., 55: 759-766, 1982.

48. Withers, H. R., and Peters, L. J. Biological aspects of radiation therapy. In: G.H. Fletcher (ed.), Textbook of Radiotherapy, pp. 103-180. Philadelphia: Lea &Febiger, 1980.

49. Withers, H. R., Thames, H. D., and Peters, L. J. Differences in the fracttonationresponse of acutely and late-responding tissues. In: K. H. Kircher, H. D.Kegelnik, and G. Reinartz (eds.), Progress in Radto-Oncdogy II, pp. 287-296.New York: Raven Press, 1982.

OCTOBER 1984 4841s



1984;44:4836s-4841s. Cancer Res Edward L. Gillette Hyperthermia Combined with Radiation or DrugsClinical Use of Thermal Enhancement and Therapeutic Gain for

Updated version

http://cancerres.aacrjournals.org/content/44/10_Supplement/4836s

Access the most recent version of this article at:

E-mail alerts related to this article or journal.Sign up to receive free email-alerts

Subscriptions

Reprints and

[email protected] at

To order reprints of this article or to subscribe to the journal, contact the AACR Publications

Permissions

Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://cancerres.aacrjournals.org/content/44/10_Supplement/4836sTo request permission to re-use all or part of this article, use this link



http://cancerres.aacrjournals.org/cgi/alerts

mailto:[email protected]



clinical use of thermal enhancement and therapeutic gain ... · clinical use of thermal enhancement...

Documents