0172_the set-up of a state of the art hyperthermia clinic.pdf

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Front i ers o f Rad ia tion Therapy and Onco logyEditor: J. M.Vaeth, San Francisco, Calif.Publishers: S. Karger, BaselReprint (Printed in Switzerland)

Front. Radiat. Ther. Onc., vol. 18, pp, 153-161 (Karger, Basel 1984)

The Set-Up of a State, of the ArtHyperthermia Clinic - Therapeutic,Ethical and Practical ConsiderationsHaira L BicherW estern Tumor Medical Group and Valley Cancer Institute, Van Nuys, Calif., USA

Hy perthermia is past the stage of experimental laboratory techniqueand in som e aspects well into phase II clinical trials. Mech anism s of action(direct cell kill with or without radiation [2], microdrculation changes [3],and pH shift [3] are being established, and even in the face of developingequipment and changing protocols, its value as an adjuvant in cancertreatment is not being disputed in the rapidly increasing amount ofpublished clinical results [2-9].In view of these facts; and provided that all the ethical, scientific andm edical caveats are properly considered, the creation of a Hy perthermiaClinic within the framework of an existing radiation therapy facilitybecomes feasible. Results will be presented to show that the samepercentages of tumor response and favorable therapeutic indices have beenm aintained at our W estern Hy perthermia Clinic as com pared with previ-ously pu blished clinical experiences including our own .Recent studies [1, 2, 5, 6, 7, 8, 9] involving a combination ofhyperthermia and X-irradiation have made a serious effort to measure anddocument the hyperthermia treatments more accurately, in most cases acomparison with radiation alone controls is made. K i m et al. [7] havetreated 50 patients with a variety of cutaneous tum ors. Imp roved results arereported for both the radiosensitive (i. e. mycosis fungoides) and radioresis-tant (i. e. melanoma) tumors with the combined hyperthermia and radia-tion treatment as com pared to either of the m odalities used alone. Theseauthors report com pl.ete disappearance of m ultiple recurrent melanom anodules without unusual normal skin reactions. However, combinationtherapy did produce enhanced skin reactions in patients whose treated


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areas included either a skin graft or heavily scarred skin from extensivesurgery.H o rn b a ck et al. [5] treated 72 patients w ith advanced cancer using the

combined therapy. Of the patients treated with hyperthermia prior toradiation therapy, 53 % experienced complete remission of symptomswhile in the group of patients treated with heat following radiotherapy,92 % showed com plete remission. Again there was no set protocol and theradiation doses varied from 500 to 60 0 rad/day w ith total doses from 3,000to 6,500 rad. Heat treatments were given using 433.92 MH z m icrowaves.Although the authors mention measuring tumor temperatures in thepatients there is no mention of temperatures achieved.M a n n i n g et al. [8] reported a very limited study combining localizedheat and radiation. The response rate for heat.radiation combination was80-90 % com pared with 50 % response rate for heat alone and radiationalone groups. The authors suggest a beneficial therapeutic ratio andminimal side effects from the combined treatments.Another limited study [9] treated two groups of patients withradiotherapy alone, hyperthermia alone, and combined treatment. Onegroup of patients received 20 0-600 rad fractions, 2-5 times per we ek to atotal of 1,800-2,400 rad in 5-14 fractions. The other group of patientsreceived the combined thermoradiotherapy treatments only, radiationfractions of 200-600 rad, 2-5 times a w eek to a total of 2,000-4,800 rad in6-20 fractions. Hy perthermic treatments for both groups was 42-44"C , 2-3tim es per week to a m aximum of 10 sessions in 4 weeks. Hyperthermiatreatm ents were given using either 2,450 or 915 MHz m icrowaves. Of thefirst group of ~ patients -6 experienced complete regression of lesionstreated with radiation plus hyp ertherm ia within 1 m onth of therapy. N oneof the tumors treated with hyperthermia alone regressed completely. In thesecond group of patients, 73 % showed tumor regression. Melanomaregressed completely in 2/4 cases. No adverse side effects were observed onnormal tissue from the combined treatment.Another interesting study was reported by Arc a n gel i et al. [1]. In 15patients with m ultiple neck node m etastases from head and neck cancertreated w ith either radiation alone or in com bination w ith hyperthermia, atotal of 33 neck nodes were treated, 12 with radiation alone and the restwith the combination. The radiation schedule resulted in 46 % completeresponse which was enhanced to 85 % com plete response when com binedwith hyperthermia, the rem aining 15 % showed partial response. It shouldbe noted that in the treatm ent schedule, when radiation was com bined with


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Hyperthermia Clinic - Therapeutic Considerations h y p e r t h e r m i a , h e a t w a s a p p l ie d i m m e d i a t e ly a f t e r t h e s e c o n d d a i ly f r a c -t ion . The authors d id no t obs . erve any abnorm a l reac t ions in areas that w eret r e a t e d w it h c o m b i n e d t h e r a p y .In a pr e l iminar y p ubl i c a t ion [2 ] we r e po r te d an e f f e c t ive f r ac t iona t ionr e g ime n us ing 45 C r e g iona l hype r th e r mia c ombine d wi th l ow dose (1 ,600tad) X- i r r adia t ion , y i e ld ing an ove r a l l to ta l r e spo nse r a te o f 65 . Th e ser e s u l ts a r e n o w e x p a n d e d t o i n c l u d e a n e n l a r g e d s e r i e s a s w e l l a s i n t r o d u c -ing an intr ac av i tar y and inte r s t i t i a l a i r - c oo l e d de v i c e for the t r e a tme nt o fde e p- se ate d tumor s .T h e a b o v e -m e n t i o n e d c l in i c a l s tu d i e s a r e b o t h i n t e r e st in g a n dencou ra ging. In add i t ion , recent phys io logica l ev idence sho ws a d i f f erent ia l b r e a k in g p o i n t in b l o o d f lo w i n t u m o r s a s c o m p a r e d t o n o r m a l t is s u e sw h i c h r e s u l t s i n d r a m a t i c s h i ft s i n i n t r a tu m o r p H [ 3 ]. T h e s e o b s e r v a t i o n smay , in part , exp la in t he resu l t s of t he c l in ica l t r ia l s we are repo rt ing here .

M ethodsAir-cooled m~crowave applicators (PDM, Inc., Van Nuys, Calif.) for use in hyperther-mic treatment of tumors in several regions of the body have been designed and tested both forphysical characteristics, heat distribution in phantom s and treatm ent fields in patients.Homogeneity of temperatures and minimum leakage levels were determined and foundsatisfactory. Routinely, treatment temperatures of 44-45"C were obtained at tum or depthwhile surface was kept at 37"C. U sing 300 MH z increased the effective penetration beyond5 cm, the blood flow acting as hom ogenizing factor.Similar results were obtained using intracavitary antennae, typically introduced in themouth, pharynx, esophagus or rectum. R egional temperatures of 44-45"C could be routinely

achieved in the treated area, with a minim um of reaction from the hollow viscera containingthe device. Again, the use of 300M Hz gave an extended treatment field. Furthermore, asystem for interstitial radiotherapy with hy perthermia has also been devised using m icrowave-induced heat delivered through a s eries of interstitial antennae introduced into the plasticcarriers that are a normal com ponent of the Syed-N eblitt device and other implant applicators.According to the volume of implantation r~quired the system can operate at 915 or300 MH z, the lower frequency being used when more penetration of the microwave is desiredeither because of a larger imp lant volume or bigger interantannae spacing. Another specialfeature of the system is air cooling of the antennae jackets which avoid hot spot formationaround them. Th is is progressively important as the interantenna spacing increases.Com plete thermom etry was performed during every patient treatment em ployingm icrothermocouples (100~m ). The microtherm ocouples were im planted in the tum or(whenever possible) and in surrounding or overlying normal tissues. Throughout treatment,temperature readings were taken at 5-rain intervals under power off conditions to eliminateany possible interference artifacts. Temperatures were recorded using a modified Apple IIcom puter with a special interface which also controlled the microwave on-off cycle. A


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i c h e r

T abl e L ProtocolPrevious radiation therapy Treatment

< 5,000 rador 5,000 rad more than 1 year ago ~ 2 0 / 1 0>5,000rador 5,000rad less than 1 year ago I0/i0

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D e s c r i pt i o n o f t r e a t m e n t20 10 20 XRT fractions 200 rad 5 weeks 4 000 tad total10 A fractions 43 C 1 h twice weeHy10/10 10 XRT fractions 200 tad 5 weeks 2 ,0 0 0 r od t o t a l10 A fractions 43 C 1 h twice weekly

minimum of 4 probes were used in each treatment placed in the tumor, normal tissue at risk,surface at risk (usually skin) and a water bath (for control of system drift).Two different protocols were followed. In previous pu blications [2] w e described a low

radiation-hyperthermia combination (also recorded as RTOG protocol 78-06A). Briefly,treatment consisted of 4 fractions of hyperthermia alone followed after a 1 week rest by 4additional fractions of hyperthermia, this time immediately following irradiation. All treat-ments were separated by 72h following a Monday-Thursday or Tuesday -Friday pattern.Each hyperthermia treatment lasted 1 h at the prescribed temperature (450C alone; 42Cwith radiation) and each radiation dose was 400 rad. Therefore, treatment consisted o[ a totalof 8 hyperthermia treatments and 1,600 rad over a total period of 5 weeks. W e shall refer to thisprotocol in our previous results.

In our current series, the previous protocol was modified to include a higher dose ofradiation, as described in table I. Radiation dose was either 2,000 or 4,00 0 tad. Patients wereadjudicated to either category depending on the previous radiation dose. If this dose wasgreater than 5,000 rad or given less than 1 year ago, the patient received only 2,00 0 rad. Mostof the patients entered into these protocols had previously failed radiation therapy and/or hadno proven treatment alternative left to them.

ResultsIn our previous series [4] 178 patients were treated with a multim odal-

ity regimen involving hypertherrnia administered in multifraction fashion(8 hyperthermia treatments per field). Since many of these patients hadmultiple tumors, at least-250 tumors were treated (over 2,000 treatmentsessions). Not all of them fitted all criteria for inclusion in the specific


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Hypertharmia Clinic - Therapeutic Considerations 157TableIL Summ ary of results [from ref; 4, with perm ission]121 fields treated 82 patients

Total response 79 (65.5 )Partiat response 36 (29.7%)No response 6 (5.0%)ecur rence lo lmarg ina l ompl icat ions skin burnstongue and pharynx burnsgrand seizure

2 (completely healed)2(completely heated)I (neck treatment-epileptic patient)

ebleIlL Respong by radiation dose19fields 4,000 rad + ~ 15 total response 79 %4 partial response 21%12 fields 2,000 rad + ~ 7 total response 58 %5 partial response 42 %

protocol, but am ong evaluable results the following can be cited: 121 fields(tumors) were treated according to the 8.fraction protocol with 1,600 rad in4 fractions. The final results show no m ajor toxicity, and a rate of 65 % oftotal responses and 30 % partial response. A cute reactions after treatmentswere those due to radiation. Further analysis of this series is shown intablell.Current results at the W estern Hyp erthermia Clinic include 41 fields in38 patients treated during the last 8 months. 31 patients completed thetreatm ent and were evaluable. Of these, 74 % showed a total response and26 % a partial response (23 and 8, respectively), W hen considering thepercentage of respons~ by radiation, dose fields treated with 2,000 rad andhypertherm ia showed a 58 % total response (7/5) as com pared with 79 %total response on fields treated w ith 4,000 tad and hypertherm ia (15/4)(table II ). No major toxicity was noted ascribable to the hyperthermiaexcept for minor burns.


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Bicher 158Discuss ionThe fractionation regimen em ployed in this study (regional hyperther-m ia plus low dose radiation) shouldbe compared w ith those em ployed inother reported clinical trials. In their study, K i m et al. [7] repo~ 78 %overall tumor control rate after combined therapy as compared with 26 %after radiation alone. These investigators utilized two heati~ ng m ethods.Som e patients with tumors on extrem ities were heated by im m ersion in awater bath. The rest of the patients were treated using RF (27.12MHz)inductive heating. It should be pointed out that there is a great deal ofvariation in both the radiation d6se and the hyperthermia treatmentduration as well as in the num ber of fractions. The radiation dose em ployedvaried from 800 ~radin 2 fractions for m elanoma to 2,400 radin 8 fractions

for Kaposis sarcoma. Sim ilarly, hypertherm ia (43.5 C) treatments variedfrom 2 fractions of 30 m in for melanom a to 5 fractionsof 60 rain for my cosisfungoides. The hyperthermia treatments followed immediately the radia-tion treatments in all cases. This data does not suggest any particulartreatment schedule for a particular tumor. The study does, however,dem onstrate the imp roved effectiveness of com bined thermoradiotherapyas comp ared to hyperthermia or radiation alone.In the study by Ma n n i n g et al. [8], of the patients treated withhyperthermia, 4 were treated in combination with radiation. Each had am inimum of 3 nodules. One nodule received a heat treatm ent of 43"C for40 m in using radiofrequency currents. A nother nodule received radiationalone from two radium needles t0a dose of 4,000 rad in~100 h.A thirdlesionhad the same dose plus simultaneous heat to 43 * C for 40 m irl using~radiumneedles as heating electrodes.~ A 30 40 % increase in response wasobserved for the com bination therapy.A r c a n g e l i et al. [1] employed a rather unique technique in theirprotocol. Hyperthermia was induced by 500-MHz microwaves using anoncontact applicator. These investigators used a very fractional (MD F)schem e, it consisted of 200 + 1 50 + 150 rad/day, 4~5 h interval betweenfractions, 5 days/week, up to a total of 4,000-~ 7,000 fad. All the lesions wereirradiated with the sam e total dose, whether ornot they received hyp erther-m ia. Again a 40 % increase in response was seen for tl, fe comb inedmodalitytherapy.J o h n so n et aL [6] conducted a p ilot studyto evaluate norm al skin andm elanoma tum or therm al enhancem ent ratios of 41..5-420C hypeitherm iawith radiation. The response of norm al skin to the treatment w as m easured


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Hyperthermia Clinic - Therapeutic Considerations 159by evaluating the degree of erythema according to a numerical scoringsystem. Tumor response was assessed by measuring tumor diameter.Although the study was not conclusive about the thermal enhancementratio, it did bring to light some of the problems associated with obtaininguseful clinical data. The study involved patients with multiple metastaticm elanom a lesions. A t least three lesions were chosen on each p atient. Thepatients were divided into three groups and given 1, 3 or 4 fractions w ith aminimum of 72h interval between each fraction. Radiation dose perfraction for different lesions on a patient varied from 50 0 to 90 0 rad. Insome cases single fractions of 1,000 , 1,200 or 1,300 rad were used. On allpatients one lesion was heated im m ediately following radiation therapy andthe other two or more lesions treated with radiation alone were used forcomp arison. Hyperthermia treatments were adm inistered using 915-MH zdirect contact microwave applicators [6]. Duration of hyperthermia treat-m ents varied between 1 and 2h at 41.5-42.0C.Skin enhancem ent ratio (SER) and thermal enhancem ent ratio (TER)could be evaluated only for a lim ited num ber of patients because of lack offollow-up data. SER values varied for 1.2 to 1.7 while TER values in m ostcases were .3. This study dem onstrated, howev er, that superficial tum orsup to 4 cm in diameter and 2 cm in depth could be treated with an accuracyof + 0.5C either during, or after irradiation with 915-MH z m icrowaves.The study reported here as well as the results of other investigatorstend to indicate the relative effectiveness and lack of overall adverse effectsfrom combined hyperthermia and radiation. Further prospective, site-specific trials are now planned or in progress to further evaluate both thesafety and effectiveness of fractionated hyperthermia and radiation. Inaddition, the patients already treated will continue to be followed at2-m onth intervals.However, in certain clinical situations, it appears that hyperthermia isnot only a weapon of last resort, but one to be considered in the early stagesof treatment. Such is the case of m alignant deposits in previously heavilyradiated fields, or tumors of certain histologies sensitive to heat but notother methods of treatm ent. Melanoma and sarcoma, for exam ple, will fallunder this category. Also, in certain anatomical locations where heat iseasily applied and no side effects have been demonstrated even whencom bined w ith usually therapeutic radiation doses, the use of heat as anadjuvant in primary treatment under the auspices of prospective ran-domized, site-specific protocols should be considered specially in sites(esophagus, brain, etc.) where the possibility of cure is otherwise m inima l.


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Bicher

T a b le I V . Caveats

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Treatonly under the aegis of p rotocols approved by a federally approved InternalRevue BoardComply with FDA rules and regulations for equipment- report everything promptlyProper physics supervision - 50 % FTEthermom etry, forms, field homogeneityEach treatment under close MD supervision (full-time M D required)

The caveats necessary to use a research m odality in the environment ofa community hospital are well defined and addressed constantly bychemotherapists and numbers of other specialities (cardiologists, nephr-ologists, etc.). Among others these include proper protocols approved byan Institutional Revue Board that meets federal standards, adherence toregulation and reporting required for the use of new m edical devices as setby the FD A , and careful scientific observation of each treatmen t and result.The setting up of such a clinic also demands proper physics and medicalsupervision. A physician versed in the use of the equipment shouldsupervise and interpret each hyperthermia treatment (table IV).

Data have been presented to show that all this is possible today.Although limited by the physics in the locations that can be treated, it isalready scientifically and financially feasible to bring this new form oftreatment to bear on certain cases of advanced cancer, to provide goodpalliation and collect the scientific data needed for the future developmentof this promising modality.

1 Arcangeli, G.; G arui, E.; Dividalli, A., et al.: Effeedveness of microwave hy pertherm iacombined with ionizing radiation: clinical results on neck node metutases. Int. J.Radiat. Oncol. Biol. Phys. 6:143-148 (1980).

2 Bicher, H. I.; Sandhu, T. S.; Hetzel, F. W.: Hyp erthermia and radiation in combination:a clinical fractionation regime. Int. J. Radiat. Oncol. Biol. Phys. 6:867-870 (1980).

3 Bicher, H. I.; Hetzel, F. W .; Sandhu, T. S., et al.: Effects of hypertherm ia on normal andtumor microenvironment. Radiology 137:523-530 (1980).4 Bicher, H.I.; Hetzel,.F.W.; Sandhu, T.S.: Results of a phase I/l] clinical trial offractionated hyperthermia in combination with low dose ionizing radiation; in Bicher,Bruley, Int. Hypertherm ia, pp. 87-97 (Plenum Pregs, New Y ork 1982).


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Hyperthermia Clinic - Therapeutic Considerations 1615 Hornback, N.B.; Shup e, R.E.; Hom ayon, S., et al.: Preliminary clinical results ofc o m b i n e d 4 3 3 M H z m i c r o w a v e t h e r a p y a n d r a d ia t io n t h e r a p y o n p a ti e n ts w i t h a d v a n c e d

cancer. Cancer 4 0 : 2 3 5 4 2 8 6 3 (1977).6 Johnson. R. J. R.; Sandhu, T. S.; Hetzel, F. W., et al.: A pilot study to investigate thetherapeutic ratio of 41.5-42.0C hyperthermia radiation. Int. L Radiat. Oncol. Biol.Phys, 5 : 9 4 7 9 5 3 (1979).7 Kim, J. H,; Hahn, E. W.; Benjamin, F.J.: Treatment of superficial cancers by combina-tion hyperthermia and radiation therapy. Clin. Bull. 9 : 1 3 1 6 1 9 7 9 ) .8 Manning, M.R.; Cetas, T.; Boone, M.L.M.; Miller, R.C.: Clinical hyperthermia:results of the phase I clinical trial combining localized hyperthermia with or withoutradiation (Abstract). Int. J. Radiat. Oncol. Biol. Phys. 5 : S 2 173 (1979).9 U, R.; Noell, K.T. , W oodward, K.T., et al.: Microwave-induced local hyperthermia incombination with radiotherapy of human malignant tumors. Cancer 4 5 : 6 3 8 6 4 6 I1980).

H. I. Bicher, MD, W estern Tumor Medical Group and Valley Cancer Institute,5522 Sepulveda Boulevard, Van Nuys, CA 91411 (USA)

0172_the set-up of a state of the art hyperthermia clinic.pdf

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