0186_CLINICAL THERMORADIOTHERAPY - 07.pdf

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Henri,. Ford Hosp M edVol 29, No 1, 1981

Clinical Therm oradiotherapyHI Bicher, MD, PhD,* TS San dhu, PhD,* and FW Hetzel , PhD*

A clinical trial is currently in progress to determine theefficacy of combined fractions of hyperthermia and radia-tion. The protoc ol consists of two pa rts. First, four fractionsof microwave-induced hyperthermia 45.0 ,- 0.5C) areapplied for 11/2 hours to the volume encompassing thetumor, each separated by 72 hours. After a one-week rest, asecond series of four fractions is adm inistered again a t 72-hour intervals Each fraction consists of a 400 tad dose ofradiation followed within 20 minutes by hyperthermia(42._5 -,- 0.5C) for 1 1/~ hours.

Currently, we have treated 62 patients with 82 fields with amean follow-up time of six months to date Total regressiowas observed in 60% of all cases, and p artial regression in33 ~ ; no response was seen in only 6 % of all those treated.Five local and three marginal recurrences have been observed. This paper discusses detai ls of response based onsite, histology, and classification.

The failure of conventional radiotherapy to control asignificant num ber of tumors without any extensive ad verseeffects on the surrounding normal tissue is mainly at-tributed to the presence of a viable hypoxic fraction of cellsin these tumors. As far back a s 1909 Schwa rz (1) showedthat if blood circulation was restricted by limiting oxygensupply, human skin become rad ioresistam. Beca use of theheterogeneous structure of tumors in general, there areregions containing closely packed cells, remote from bloodvessels, that are hypoxic (2). If even a very sma ll fraction ofhypoxic cells exists, radiotherapy will not be able to con-trol the tumor.To overcome this problem, many different approacheshave been tried. One early solution was to give the totalradiation doses in several fractions. During the course offractionated treatments, the resistant hypoxic cells becomeoxygen sen sitive, at least d uring later doses. Howe ver, i t ispossible that some tumors do not reoxygenate com pletelyso that some hypoxic cells still survive and cause a recur-

* Radiobiology Division, Departmenl of Therapeutic Radiology, HenryFord HospilalAddress reprinl requests to Dr. Bicher, Radiobiological Sciences, Depart-ment of l herapeulic Radiology, Henry Ford Hospital, 2799 W Grand Blvd,Detroit, MI 48202

rence. Even a few hypoxic cells would constitute a seriousproblem. To compensate for this limitation, one solutionhas b een to use high linear energy transfer (LET ) radiatioinstead of ordinary x- and "y-rays, so that the tumor re-sponse does not depend on the presence or absence omolecular oxygen. The ideal radiation that will have oxygen enhancem ent (OER) of unity, such as 2Me Va pa rticles,is incapable of penetratinl] tissue deeply enough to beuseful. The best that can be ac hieved is through the use oneutrons, pions, or high-energy heavy ions. These optiontend to be very expensive, a nd l imited clinical tr ials are sti lgoing on.In another approach, the patient is placed in an environment of pure oxygen at a pressure of 2 to 3 atmospheresbefore radiotherapy begins in an attempt to increase theavailability of oxygen to tumors. This technique has notproduced any significant improvement in tumor control,although a few centers around the world are still conduct-ing clinical trials.In recent years there ha s been increas ing interest in hyper-thermia to treat cancer, used either alone or in combinationwith radiation. Although reports on its use date ba ck to186 6 (3 ), research on hyperthermia has been stimulated inthe past two d eca des by se veral interesting findings inthermoradiobiological studies.

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Clinical Thermoradiot herapy ~

RationaleRecent, extensive radiobiological and limited clinical stud-ies show that hyperthermia combined with radiation has asynergistic cell-killing ~ffect. Both in vitro (3-6) and in vivo(7-11} studies sl~ow that thermal enhancement depends no tonly on the sequenc e of the two treatments, but also on ce llcycle effects. The synergistic effect is most pronounced forradioresistant S-phase cells (12,2). Clinically, the most im-portant observation is that the hypoxic cells may beequally or more sensitive to hyperthermia than aerobiccells (3,10,13,14). The rationale for using hyperthermiaabove 43C in combination with ionizing radiation is thatthe viable hypoxic tumor cells, which are radioresistant,will be destroyed at these tempe ratures. Mild hyperthermia(40-42~) also introduces a significant change in tumorblood f low. It has been show n both in mouse tumo r studiesand in clinicaltrials (15) that hyperthermia in the 40-42Crange increases the blood flow with a conc omitant increasein oxygenation. It will effectively sensitize the otherwiseradioresistant hypoxic cells in the tumor. Dramaticchanges in cell survival during hyperthermia have alsobeen obse ~:ved when the pH of c ells is only slightly altered(16). Although there are no in vitro data to indicate differen-tial response or sensitization of tumor cells as opposed tonormal tissue cells, the cellular environment in the twocases is expecte.d to be q uite different in vivo. For exam ple,several studies (17-20) indicate that the pH of fluid inhuman and rodent solid tumors is lower than the normalpH of 7.4. This will result in differential tumor cell killingthat spares normal tissue. Other studies (21,22) show thatsome tumors have a sluggish blood flow as compared tonormal tissue. This finding suggests that under similarheating condit ions tumors a re not able to dissipate heat a sefficiently as the normal tissue. These findings about thedifferent microenvironments in tumors and normal tissueregarding pH, blood flow, and nutritional state probably ledearlier investigators (23-26)to conclude that hyperthermiaselectively, killed the tumor cells.Based on the above in vitro and in vivo r~diobiologicalfindings, several groups of investigators (15,21,25,27-29)are using a combination of hyperthermia and ionizingradiation in clinical studies. The clinical goals, methodol-ogy, and results of some of these studies are discussed inthe following section.

Clinical ThermoradiotherapyClinical applications of combined hyperthermia and radia-tion treatment date back to the beginning of the century,but early reports are anecdotal. Most reported only anattempt to treat human tumors and did not document the

temperatures to which tumors and surrounding normalt issues were h eated. This imprecision, along with the lackof radiation controls alone, makes it very difficult to drawany quantitative con clusions or eve n to establish that tumortemperature was raised a t all.The earliest reported combination of hyperthermia andionizing radiation is that of Schmidt (30) in 1909. Heproposed to treat malignancies by using diathermy forlocalized heating of tissue in combination with ionizingradiation. Some ye ars later, Arons and Sokoloff (31) usedradiofrequency (RF) c urrents for hyperthermic treatments ofintrathoracic and intra-abdominal tumors. However, sincethey made no temperature measurements, it is difficult toestablish whether they were able to raise the tissue tem-perature to a therapeutic range. Woeber (32) used ultra-sound with simultaneous x-irradiation to treat 20 patientswith cutaneous malignancies. He reported that tumorscould be controlled with a 40% reduction in radiation doseand tha t reactions of normal tissues were also diminished.Crockett, et al (33), following some experimental work onnormal dog bladders, treated seven elderly patients whohad incurable advanced bladder carcinomas with a com-bination of local hyperthermia and regional radiotherapy.The radiation dose varied from 4500 to 5500 rad. Theseauthors reported that the treatment produced a strikingreduction in tumor size without any serious adverse effects.Although they suggested that hyperthermia enhanced thetumor response, they did not attempt to determine heatdistribution within the bladder. Recently,, Hall (34) alsoreported regression of bladder papillomatosis without anycomplications. Each patients bladder was irrigated forthree hours a t a time with wa ter heated to 42-45C for 5-14sessions.Hartman and Crile (35) treated osteogenic sarcoma in fivechildren with microwave heating and various doses oradiation. Two of the five were alive five years later andwere sti l l able to use their l imbs. On e wa s a se ven-year-oldgirl with osteogenic sa rcoma in the right mid-t ibia, and theother was a 16-year-old with osteoblastic and osteolyticlesions of the meta physis of the distal part of the left radius.The other three children survived six to 17 months a nd diedof metastatic disease.Stehlin (36} reported a 67% five-year survival rate for 3patients he treated by using heated blood to perfuse theextremities, followe.~J by x-irradiation several weeks later.He found that at tissue temperatures of 40C patientstolerated the treatment very well for several hours, buwhen the extremities were perfused with blood heated to46C, c omplications resulted.In the past few ye ars several prospec tive clinical tr ials havebeen sta rted. We a re reporting the results of the Henry FordHospital trial.

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Materials and MelhodsIn this sludy we designed a fractionalion scheme thatcombined hyperthermia and radiation with a curative in-lent. The protocol is summarized below.

I. Hyperlhermia only: 4 Ireatments at 45C for 90 min-utes (skin 36C or below), at 72-hour intervals;

2. R est one week; response to heat alone evalualed;3. Radiation therapy and hyperlhermia: 4 trealments at

42C for 90 minutes; heat follows radiation (20-minute intervals); RT: 400 tad fractions for eachtreatment;

Total: 8 hyperthermia treatments + 1600 rad/2 weeks/4fractions.

This protocol has been designed to take advantage of theknown effects of hyperthermia either alone or combinedwith radiation. Skin cooling was implemented to preventnormal tissue damage. We chose the number of fractionsand duration of each treatment at random, taking intoacc ount such factors as the patients compliance a nd com-fort and possible biological factors such as ther-motolerance, vascular response, and repair. In addition,the total dose of radiation was low enough to allow pre-viously irradiated areas to be treated more than once.Localized hyperthermia was induced in all patients bymicrowave radiation that used direct contact applicators(37). The tumor size, location, and depth determine theexac t type and size of applicator to be used as w ell as themicrowave frequency (915 or 300 MHz).* Heat is initiallyapplied to the tumor in four fractions of 1 I/2 hours each at72-hour intervals. The temperature is monitored with con-ventional (Bailey) or ultramicrothermocouples (Medtra Inc)to ma intain the tumor tempe rature at 45c C __. 0.5C, whilethe overlying, normal skin is simultaneously air cooled ator below 36C. After these four fractions have been ap-plied, the patient rests for one week an d then receives fourmore fractions of hyperthermia, this time in combinationwith radiation. Each of these four treatments consists ofdoses of 400 tad to the tumor followed immediately (20minutes) by hyperthermia at a temperature of 42.0_0.5C, again at 72-hour intervals. As before, skin cooling isused to maintain a temperature of 36cC or lower at thesurface.The m icrowave hyperthermia wa s induced with directcontac t applicators, which are essentially square or rec-tangular cross-section waveguides.* We used two types ofmicrowave ap plicators: 1} a square or rectangular cross-section waveguide completely loaded with a low-loss di-electric ma terial and excited in TE,o mo de (37 ); 2) a All equipment l)y Medlra In(, Ek, lroit, MI

parlially filled rectangular waveguide excited in the TEMmode. The second applicator distributes heat better thanthe first one. Thermometry was accomplished by insertingone or two ultramicrothermocouples* in the tumor tissue,depending upon the size and location.

ResultsTo date, 62 patients have been treated with 82 field(Tables I and II). A total response was observed in 4treatment f ields, a pa rt ial response in 27 , and n o responsein only 6 fields. These included one ea ch of squam ous celcarcinoma,adenocarcinoma, and sarcoma. The only complications that could be directly attributed to treatment

TABLE ITreatment Results

82 Fields Treated 62 patientsTotal R e s p o n s ePartial ResponseNo Response

49 (60 )27 (33%)6 (7%)

RecurrenceLocal:Marginal:

ComplicationsSkin burns:Tongue and pharynx burns:Grand seizure:

53

2 (completely healed)2 (completely healed)1 (epileptic patient)

TABLE IINo, ofHistology Fields Response Follow-up

Malignant melanoma 17 8 Total 2 mo-1 yr6 P artial3 N o responseMalignant lymphoma 8 8 Total 2-7 moSquamous cell carcinoma 19 7 Total 2-6 mo11 Partial1 No responseAdenocarcinoma 33 24 Total 2-7 mo

8 Pa rtial1 No response t h e r(transitional cell, 5 2 Total 2-9 mobasal cell, glioma, sarcoma 3 PartialSummary 82 49 Total 2 mo-I yr

27 Partial6 No responseTotal Response: No tumor at two months follow-up and thereafter.Partial Response: Tumor decrea.sed in size Io half or less at lwo months

follow-up.

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were two skin burns caused by inadeq uate surface coo lingand two tongue and pharynx burns; all healed completely.One p atient with a history of epilepsy experienced a gratedmal seizure when being treated for a neck tumor. Threemarginal recurrences and five local recurrences have beennoted. Although it should be empha sized that great care isneeded during the initial planning and set-up for the pa-tient, it is possible to obtain actual thermometry for everytreatment of every field with minimal patient discomfort.Table II summarizes histological results. Among our pa-tients, malignant lymphoma was most responsive to thiscombination treatment. It should be pointed out that tumorregression after treatment ends is very slow and requiresapproximately two months before the total effect is ob-served. We also discovered during these treatments that them~crowave power required to maintain the desired treat-ment temperatures declines after the first or second treat-ment of a given field. These two phenomena are probablyrelated to heat-induced physiological changes within thetumor that affect its ultimate destruction. Further phys-iological studies are currently in progress.Another interesting outcome of this study concerns thepossible significance of the three margnal recurrences;they ma\, indicate that this combined modality effectivelytreats microscopic disease. M ore time is neede d for follow-up, and more patients must be treated before the clinicalefficacy of this protocol can be fully evaluated.

DiscussionRecent studies (15,21,25,2~,28,38,39) involving a com-bination of hyperthermia and x-irradiation have attem ptedto measure and document hyperthermia treatments moreaccurately. In most cases, these studies compared theirtreatment methods with radiation controls alone. Kim, et al(25) treated 50 patients who had a variety of cutaneoustumors. They reported mproved results for~both the ra-diosensitive (i.e., mycosis fungoides) and radioresistant(i.e., melanoma) tumors with the combined hyperthermiaand radiation treatment as compared to either modalityused al(~ne. Their overall tumor control rate was 78 aftercombined therapy as compared with 26~ after radiationalone. Multiple re~:urrent melanoma nodules completelydisappeared without unusual normal skin reactions. How-ever, combination therapy did intensify skin reactions inpatients whose treated areas included either a skin graft orheavily scarred s kin from extensive surgery.These investigators used two heating methods. Some pa-tients with tumors on extremities were heated by immer-sion in waterbath, while the rest of the patients were treatedwith RF (27.12 MI4z) inductive heating. In their study, there

was a great variation in both the radiation dose and thelength of hyperthermia treatment as well as in the numberof fractions. The radiation doses varied from 800 tad in twofractions for melanoma to 2400 rad in eight fractions forKarposi sarcoma. Similarly, hyperthermia (43.5C) treat-ments varied from two fractions of 30 minutes formelanoma to 5 fractions of 60 minutes for mycosisfungoides. The hyperthermia treatments immediately fol-lowed the radiation treatments in all cases. While thesedata d o not suggest any pa rticular treatment schedule for aparticular tumor, they do demo nstrate the greater effective-ness of combined thermoradiotherapy as compared tohyperthermia or radiation alone.Hornbac k, et al (27) used the com bined therapy to treat 72patients who had advanced cancer. Of those treated withhyperthermia before radiation therapy, 53% experiencedcomplete remission of symptoms, while of those treatedwith heat following radiotherapy, 92~7~ showed completeremission. Again, there was no set protocol and the radia-tion doses varied from 50 to 600 rad per da~; with totaldoses from 3000 to 6 500 tad. Heat treatments used 433 .92MHz microwaves. Although the authors mention that theyattempted to measure tumor temperature during thesetreatments, tumor temperatures in the patients are notg~ven.Johnson, et al (28; conducted a pilot study to evaluatenormal skin and melanoma tumor thermal enhancementratios of 41.5-42C hy perthermia with radia tion. Th eymea sured the response of normal skin to treatment byevaluating the degree of erythema acc ording to a numeri-cal scoring system. Tumor response was assessed by mea -sur.ing tumor diameter. Although the study was notconclusive about the thermal enha ncement ra tio, it didhighlight some of the problems in obtaining useful clinicaldata.The study involved patients with multiple metastaticmelanoma lesions. At least three lesions were chosen oneach patient, all of whom were divided into three groupsand given one, three, or four fractions, with a minimum 72-hour interval between each fraction. R adiation dose perfraction for different lesions varied from 500 to 900 tad. r~some cases, they used single fractions of 1000, 1100, 1200,or 1300 rad. In all patients one lesion was heated imme-diately after radiation therapy, and was then used for com-parison with other lesions treated with radiation a lone.Hyperthermia treatments, which varied between 1 and 2hours a t 41.5-42C, were a dministered w ith 915 MH zdirect contact microwave applicators (3~7).Because of the lack of follow-up data, skin enhancementratio (SER) and tumor enhancement ratio (TER) could beevaluated for only a few patients. SER values varied from

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1.2 to 1.7, while TER values in most cases were 1.3. Thisstudy demo nstrated, however, that superficial tumors of upto 4 cm wide and 2 cm deep could be heated with anaccuracy of __. 0.5C either during or after radiation with915 MHz microwaves.Manning, et al (29) reported on a very limited study thatcombined heat and radiation. Of 40 patients treated withhyperthermia, four were treated in combination with radia-tion. Each had a minimum of three nodules. One nodulereceived a heat treatment of 43C for 40 minutes withradio-frequency currents. Another nodule received radia-tion alone from two radium needles to a dose of 4000 ta din 100 hours. A third lesion received the same dose inaddition to heat to 43C for 40 minutes simultaneously,with radium needles used as heating electrodes.The response rate for the heat-radiation combination was80-90~ compared with a 50~ response rate for heat aloneand radiation alone. These authors suggest a beneficialtherapeutic ratio and minimal side effects from the com-bined treatment.Another limited study (39) treated two groups of patientseither with radiotherapy alone, hyperthermia alone, orcombined treatment. One group received 200-600 tadfractions, 2-5 times per week for a total of 1800-4200 tadin 5-14 fractions. The other group received combinedthermoradiotherapy treatments only, radiation fractions of200-600 rad, 2-5 times a we ek, for a total of 2000-4800 tadin 6-20 fractions. Both groups received hyperthermic treat-ments (42-44cC) 2-3 times per week to a maximum of 10sessions in 4 weeks. Either 2450 or 915 MHz microwaveswere used for the treatments. In the first group of eightpatients, lesions in six patients regressed com pletely afterthey were treated with radiation and hyperthermia withinone month of therapy. None of the tumors treated withhyperthermia alone regressed completely. In the secondgroup of patients, 73~ showed tumor regression.Melanoma regressed completely in two of four cases. Noadverse side effects on normal tissue were observed fromthe combined treatments.Arcangeli, et al (21) reported that 15 patients with multipleneck node metastases from head and neck were treatedeither with radiation alone or radiation combined withhyperthermia. A total of 33 neck nodes were treated, 12with radiation alone, and 21 with the combination. Hyper-thermia was induced by 500 MHz microwaves with a non-contact applicator.These investigators used a very interesting fractionalscheme. Described as a multiple daily fractiona (MDF)scheme, it consists of 200 + 150 + 150 tad/day, with 4-5hour intervals between fractions, for 5 days per week, and

up to a total of 4000/7000 tad. All lesions were irradiatedwith the same total dose, whether or not they receivedhyperthermia.The MDF schedule resulted in a 46 complete responsewhich was enhanced to 85% complete response whencombined with hyperthermia; the remaining 15% showedpartial response. It should he noted that when MDF wascombined with hyperthermia, heat was applied immediately after the second daily fraction. The authors did noobserve any abnormal reactions in areas that received thecombined treatment.In the study reported here, we have obtained an overatotal response rate of 60~. Although further study andfollow-up are necessary a nd other protocols must be examined, it is clear from these results that regardless of ana tomical location and tumor histology, hyperthermia a ppears tobe an e ffective mod ality to treat malignant disease.

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References1. 5chwarz G. U ber Dosensensibilisierung gegen RoetEens und R adiumStrahlen. Muench. Med W ochenschr 1909;56:1217-21.2. Thomlinson RH, Gray LH. The hislological slructure of some h u m a nlung canc er and lhe possible implicalions for radiotherapy. Br JCancer 1955;9:539-49.3 Kim SH, Kim IH, Hahn EW. The radiosensitization of hypoxic tumorcells by hyperthermia. Radiology 1975;114:727-28.4 Sapareto SA, Hopwood LE, Dewey WC. Com bined ef fects of x -i rradiation and hyperlhermia on CHO cells for various temperaturesand orders of applicat ions. Radiat R es 1978;73:221-23.5 Sapareto SA, Raaphorst PC. Dewey WC. Cell killing and the sequenc-ing of hyperthermia and radiation. Int J Radiol Oncol BIOl Phys

1979;5:343-47.6 Thrall DE , Gerweck LE Gillette EL, et al, Responses of c ells in-vitroand tissues in-vivo to hyperthermia and x-irradiation. In: Advances inradiation biology,; 3rd ed. New York: Academic Press, 1976;6:211-27.7 Gillette EL. Hyperthermia and therapeutic ratios. In: InternationalSymposium on Cancer Therapy by Hyperthermia and Radiation.Washington, DC, April 28-30, 1975.8. G illette EL, Er~sley BA. Int J Radiat O ncol Biol Phys 1979;5:209-13.9, Goldfeder A, Brown DM. Berger A Enhancement of radioresponse ofa mouse mammary carcinoma to combined treatments with hyper-

thermia and radiosensilizer misonidazole. Cancer Res 1979;39:2966-70.1 0 Robinson JE, Eizenberg MJ, McCready WA. R adiation and hyperther-m~a response of normal tissues in situ. Radiology 1974;113:195-98.1 1 Thrall DE, Gillette EL. Bauman CL. Effect of heat on the C~H mammaryadenocarc~noma evaluated in terms of tumor growth. Europ J Cancer1973;9:871-75.12 Gerweck LE, Gillette EL, Dewey WC. Effect of heat and radiation on

synchronous Chinese hamster cells: Killing and repair. Radiat Res1975;64:611-23.13 . Gerweck LE, Gillette EL, Dewey WC. Killin g of Chinese hamster cellsin-vitro by heating under hypoxic or aerobic conditions. Europ JCancer 1974:10:691-93.1 4 Schutman N. Ha ll El. Hyperthermia: Its effect on proliferative andplateau phase c ell cultures. Radiology 1974;113:207-09.15. Bicher HI, Sandhu TS, Hetzel FW. Hyperthermia and radiation ncombination. A clinical fractionation regime. Int J Radiat Oncol BiolPhys 1980;6:867-70.1 6 Gerweck LE. Modification of cell lethality at elevated temperatures.The pH effect. Radiat Res 1977;70:224-35.1 7 E d e n M . Haines B, Kahler H. The pHof rat tumors mea sured in-vivo. JNail Canc er Inst 1955;16:541-56.18. Gullino PM , Grantham FH . Smith SH, et al. Modif ications of the acid-

base status of the internal milieu of tumors. J Nall Cancer Insl1965:34:857-69.19. Meyer KA. Kam merling EM, Antman L, et a l. pH studies of malignantt issues m huma n beings Cancer Res 1948;8:513-18.20. Newsland I, Swenson KE. Investigations of the pH of malignanttumors n mice and humans after administration of glucose. AclaObstet Gynecol Scand 1953;32:359-67.21. Arcangeli G, Ba rni E, Dividall i A, et al. Effectiveness of microw avehyperthermia combined wilh ionizing radiation: Clinical resulls onneck node me tastases. Inl J Radial Oncol giol Phys 1980;6:143-48.

22. LeVeen HH, Wapnick D, P iccone V, Falk G, Ahmed N. Tumoreradication by radio-frequency therapy. JAMA 19761235:2198-2200.23 . Chen 13, I.-leidelberger C. Quantitative studies on the malignanttransformation of mouse prostate cells by carcinogenic hydrocarbonsin-vitro. [nt J Cancer 1969;4:166-78.2 4 Giovanella BC, M organ AC, Stehlin JS, et al. Selective lethal effect ofsupranormal temperatures on mouse sarcoma cells. Cancer Res1973;33:2568-78.25. Kim JH, Hahn EW, Benjamin FJ. Treatment of superficial cancers bycombination hyperthermia and radiation therapy. Clin Bull

1979;9:13-16. 6

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30.3 1

3 2

3 3

Schrek R. Sensitivity of normal and leukemic lymphocytes and leuke-mic myloblasts to heat. J Natl Cancer Inst 1966:37:649-54.Hornback NB, Shupe RE, Homayon S, et al. Preliminary clinicalresults of combined 433 MHz microwave therapy and radiationtherapy on patients with advanced cancer. Cancer 1977;40:2854-63.Johnson RJR , Sandhu T S, Hetzel FW, Bicher HI, et al. A pilot study toinvestigate the therapeutic ratio of 41.5-42C hyperthermia and radia-tion. Int J Radiat ONcol Biol Phys 1979:5:947-53.Manning MR , Cetas T0 Boone MLM, Miller RC. Clinical hyperthermia:Results of the phase I clinical trial combining localized hyperthermiawith or without radiation (high dose rate and low dose rate;. ASTR21st, Annual Meeting. New Orleans, 1979.Schmidt HE. Z ur Rontgenbehandling tiefgelegener Tumoren. FortschrGeb Rontgenstrahlen 1909;14:134-36.Arons I, Sokoloff B. Combined roentgenotherapy and ultrashort-waveAm J Stay 1937;36:533-43.Woeber K. Die Bede ntung des U ltraschalls fur die Dermatelogie undsiene Anwendung bet Hauttumoren in Kombination mit Roent-genstrahlen. Strahlentherapie 1955;98:169-84.Crockett AT, Kazmin M, Nakamura R , et al. Enhance ment of regionalbladder megavoltage irradiat ion in bladder cancer using local bladderhyperthermia. J U ro11967;97:1034-37.

34. Hall R. In: International Symposium on Cancer Therapy by Hyper-thermia and Radiation. Washingtor DC, April 28-30, 1975.35. Hartman JR, Crile G, Jr. Heat treatment of osteogenic sarcoma. Reportof 5 cases. Clin Orthop 1968 ;61:269-76.36. Stehlin IS, Jr. Regional hyperthermia by perfusion. In: InternationalSymposium on Hyperthermia and Radiation. Washington DC, April28-30, 1975.37.3 8

Sandhu RS, Kowal HS, Johnson RJR. D evelopment of m~crowavehyperthermia applicators. Int J Radiat O ncol Biol Phys 1978;4:515-19.Manning MR, Cetas T0 Boone MLM, Miller RC. Clincia hyperthermia:Results of lhe phase I clinical Irial combining localized hyperthermiawith or without radiation. Inl J Radiat Oncol Biol Phys 1973,1979;5:S2 (abst).

39. U R, Noell KT, Woodward KT, Worde BT, Fishburn RI, Miller l..S.Microwave-induced local hyperthermia in combination with ra-diotherapy of human malignant tumors. Cancer 1980;4_5:638-46.

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0186_CLINICAL THERMORADIOTHERAPY - 07.pdf