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Vol. 9, p. I 125 1134 0360-3016/83 /081125 1053 .00/0Copyright 1983 Pergamon Prcss lad.

Original Contribution

TUMOR CONTROL AND THERAPEUTIC GAIN WITH DIFFERENTSCHEDULES OF COM~BINED RADIOTHERAPY AND LOCAL EXTERNAL.HYPERTHERMIA IN HUMAN CANCER

GIORGIOAR C AN G ELI , M. D ., AN N A C IV 1D A LLI , D . S C . , C A R LO N ER V ~, M. D oAND G1OVANNI CRETON, M.D.l s t i tuto Medico e d i Rice rca Sc ien t if ica , 00184 Rom e, I ta ly

GIORGIO LOVlSOLO AND FRANCESCO MAURO, D.Sc.Comitato Nazionale per lEnergia Nucleare, 00060 Roma, Italy

Tumor co n tro l and the rape ut ic ga in have been eva lua ted in a se r ies of s tud ies on pa t ien ts with mul t ip le l e s ionsem ploying d i ffe ren t pro tocols of combined rad io therapy (RT) and loca l ex te rna l hyper thermia (HT). Tumo r responsehas been evaluated during a follow-up ranging 6 to 18 m onths. Therapeutic enhancem ent factor (TEF) was defined asthe ra t io of the rmal enha ncem ent (TE) of tumors to TE o f skin , where TE was c l in ica l ly eva lua ted as the ra t io ofpercent response ( i .e . , complete tumor c lea rance and mois t desquamat ion, respec t ively) a fter combined mod a l i ty topercent respon se a f ter RT a lone. Loca l tum or cont ro l was constant ly bet ter in les ions t rea ted wi th any com binedmo dali t ies in com parison with RT alone. The use of high RT dose per fract ion appeared to increase tumo r control onlyin the combined modali t ies groups, the immediate (so called "simultaneous") schedule (HT at 42.5~C/45 rain, appliedimm edia te ly af te r each RT f rac t ion , twice a week) be ing m ore effec t ive than the de layed (so ca l l ed "sequent ia l")t rea tment (HT a t 42 .5C /45 m in , de l ive red 4 h af te r each RT f rac t ion , twice a week). The com bina t ion of h igh RTdose per fract ion with high temperature HT (45C for 30 min) achieved the best tumor control . No increased radiat ionskin reac t ion was observed when a conve nt iona l f rac t ion s ize of RT was used (3 da i ly f rac tions of 1 .5-2 Gy, 4 hin terva l between frac t ions) in a ssoc ia t ion wi th HT (42 .5C/45 m in, every o ther day , im m edia te ly a f ter the secon ddaily RT fraction). A rem arkable enhancem ent of skin reaction was observed, howev er, when using high RT doses perfrac tion in a ssoc ia t ion wi th 42 .5C HT, espec ia l ly wi th the imm edia te t rea tment sched ule . No en hancem ent of sk inreac t ion was obta ined a f ter h igh RT doses p er f rac t ions and 45C HT because an ac t ive sk in coo l ing by m eans ofcirculat ing cold water was used in these cases. Con sequently, a good TEF (1.58) was obtained when conven tional RTdoses per fract ion were used in associat ion with 42.5C HT. TEF values of 1.40 and 1.15 were o bserved when high R Tdoses pe r f rac t ion were employed in as soc ia t ion with the de layed and immedia te 42 .5C HT, respec t ive ly . HT a t45C can be safe ly em ployed on ly when tumors can be hea ted se lec t ive ly or a t l eas t prefe ren t ia lly in com par i son wi thnorm al t issue; in the lesions treated with such a schedule a TEF of 2.10 was obtained.Hyper thermia , Com bined hea t and radia t ion

INTRODUCTIONt o f the recen t c l in i ca l s tudies on h yper the rmia hav e

t he c l i n i ca l demo ns t r a ti on of t he po t en t i a l benef itf over 60 clinical studiesn m ore t han 3000 pa t i en t s i n t he la s t 5 yea r s ,wo- thi rds conce rn the use of local hyper therm ia inon wi th rad io the rapy , and only f ew s tudies have46124 37~5 They demo nstrate that percent complete

average of abou t 30%herapy a lone to an average o f about 70% after

com bined rad ia tion and hea t .3 8 However, the variabilityof i nc reased r ad i a ti on r esponse by hea t , r ang ing f rom 9 t o70%, is probably related to the fact that total andfractional radiation dose, temperature and heating time,as wel l as in t e rva l be tween the two mo dal i t i e s and the i rsequence, are very different am ong the se s tudies .Fur the rmore , i n co nt ras t wi th the re su l ts f rom exper i -menta l investigations2 29 34 36 3v 42 43 an increased skinrad ia t ion reac t ion has neve r been repo r t ed excep t in onepaper ,3 7 although in most clinical studies hyperthermiahas been d e l ivered im me dia t e ly a f t e r o r i n c lose sequencewith rad ia t ion .Information on long term response of comparable

Reprint requests to : Dr . Giorgio Arcang el i , Is ti tu to M edico edi ~Z.icerca Scientifica, Clinica Piccola Compagnia di Maria,Via ~ . S te f a n o R o ton d o 6 , 0 0 18 4 R o m a , I t a l y .Accepted for publication 15 March 1983.

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12 6 R a di at io n On c ol og y B io lo g y Q P hy si cs A u g us t 1 9 83 , V o lu m e 9 , N um b e r 8lesions after single or combined modalities have beenrarely repor ted , probably because mo st c l in ical t r ia ls havebeen done on very advanced lesions, and the presentknowledge about the potent ia l usefulness of hyper thermiaas an adjuvant to radiotherapy i s sparse and i t deserves tobe mo re carefully focused.This repor t out l ines the resul t s of d i fferent protocols ofcombined heat and radiation on patients with multiplelesions.

M E T H O D S A N D M A T E R I A L SPatients se lec tion and treatment protocolsSince 1977 microwave or radiofrequency hyper thermiahas been em ployed in our ins t i tu t ion in com bina t ion wi thradiation to treat several types of tumors. Over 100patients have been treated.This repor t conce rns only the resul t on 57 pat ients wi that leas t 2 les ions , but occas ionally with 3 les ions for a to talof 123 lesions. This allows a direct comparison, in thesam e pat ient , of the resul t s after radia t ion a lone and aftercombined m oda l i ty : Dur ing t he l a s t 5 yea r s 3 ma in s tud i eshave been c arr ied out on these pat ients:1 . Con vent iona l f rac t ion s ize o f rad ia t ion com bined wi thmoderate hyperthermia. This study was done on 26pa t i en t s wi th a to t a l o f 52 m ul tip le neck node m e tas-tases from head and n eck cancer . Radia t ion was givento the whole neck, according to a multiple dailyf rac ti ona t i on schem e repor t ed e l sewhere 34 of three

fractions of 2.0 + 1.5 + 1.5 Gy/day, 4 h intervalbe tween f rac t ions , 5 d ays /week, up to a to t a l dose o f60 Gy .Heat , at a tem perature of 42.5C for 45 m inutes was

applied to only 1 lesion per patient, each other day,imm edia te ly af te r t he 2nd da i ly f rac tion o f i r rad ia t ion ,for a total of 7 sessions.2 . High f rac t ion s ize o f rad ia tion com bined wi th mod er -ate hyperthermia. This study was carried out on 16patients with a total of 41 lesions. The lesions weremelanom a recu r rences of sk in and lymp h node s , cu ta -neous ches t wall recurrences from breas t cancer , necknode m etas ta ses f rom head and n eck tumo rs , skin andlymph no de m e tas t ases from carc inom a of the vulva ,skin and scalp nodules from undifferent ia ted tumors ofthe lung and tumo rs of unknown or igin . Radia t ion wasgiven only to involved areas, at a dose of 5 Gy perfract ion, twice-a-week, a t in tervals of 72-96 h , up to ato tal dose of 40 Gy.Heat, at a temperature of 42.5C for 45 minutes,was appl ied in connect ion wi th each radia t ion fract ion,e i the r imm edia te ly af te r i r rad ia t ion ( imm edia te t rea t -m ent ) o r 4 h l a t e r (de l ayed t r ea tmen t ) .3. High fraction size of radiation combined with hight emp era ture hyper the rm ia : 15 pa t i en t s wi th a to t a l o f30 lesions have been accrued in th is group. The lesionswere m isce l laneous but main ly s im i la r to those o f the2r id group.

Five fract ions of 6 Gy were given , twice-a-wintervals of 72-96 h, up to a total dose of 30 Gheat, at a temperature of 45C for 30 minutesapp l i ed imm edia te ly af te r each rad ia t ion f rac t i

A summ ary of t he h i s t o log i es , s it es , number of and lesions accrued in these trials is given in TaMany of these tumors were failures to conventreatments, including radiotherapy, and most owere advanced and/or disseminated. The procew e r e e x p l a in e d t o t h e p a t i e n t s a n d f a m i l y m e m b ethe op t ion of a l ternat ive therapies was ful ly discuss

Tumor response was simply recorded as a failsuccess (total disappearance of lesion) at the et rea tment or soo n after .Recurrences were reco rded dur ing a fo l low-up ranging from 6 to 18 months. The acute skin radreaction was evaluated according to a 4 degree sca le , comm only used by most c l in i c i ans: mi ld e rs t rong er i them a , d ry desquamat ion , and moi s t desqtion. Thermal damage has been evaluated as peoccurrence o f blis ters or necros is .RadiotherapyRadiation was given with a 5.7 MeV photonlinear accelerator. All fields were covered with am ater ia l of approp r ia te th ickness to secure a ful l bon the s k in . The f ie ld s ize ranged f rom 5 5 to 1cm acco rding to the target area . Total tumor doses rfrom 60 Gy/36 fractions/16 days to 30 Gy/5 frac15 day s , acco rd ing to the d i f fe ren t t r ea tmen t p ro tSkin doses were s imi lar to tumo r doses.Hyperthermia

Heat was delivered using various microwaveMH z, 2450 M Hz) or r ad iof requency (27 .12 M Hz) na l app l i ca to r s .At the beginning, 500 MHz applicators of vshape and size were used. An illustration of the these applicators, as well as their isothermal mphan tom , has been presen t ed and d i scussed i n a p repape r] They were able to del iver a useful heat ing u

Table 1 . Si tes an d his to logiesN

Histology Site lesS qua mo us ce ll H ea d a nd ne ck, ly m ph no de sc a rc ino m a Vulva , skin and lymp h nodesAdenocarc inoma Breast, skin recurrencesLung, skin and lymph nodesrecurrencesM elano m a Rec urren c es o f skin an dlymph nodesUndifferent ia ted Lung, skin and scalpcel l ca rc inoma metastasesUnknown, skin metas tases


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t

Tumor control after combined heat and radiation @ G. ARCANGEL et at. 1127

depth of about 3 cm . For deeper les ions , a conv entional 27MH z dia the rmia uni t was used . Each l e s ion was hea tedby p lac ing a sm al l app l ica to r ove r the tu ,mor a rea and ala rge r app l i ca to r on the opposi t e s i t e a t a l a rge r d i s t ancef rom the sk in , so tha t p re fe ren t ia l hea t could be g iven tothe tum or. In some instances, these elect rodes were usedin couples a t r ight or var ious angles to increase the s ize ofthe heated surface and the depth of penetration. Thethermal distribution in phantom and in vivo by theseappl icators has been descr ibed in a previous paper . 2 Theywere able to deliver useful heat ing up to a depth o f about 4cm.Because superfic ia l burnings rela ted to power leakageand applicator over-heating was not infrequent, theabove hea t ing p r ocedur es wer e abandoned .The cur ren t app roac h fo r the t rea tme nt o f superf ic i a llesions is the use of a 2450 MHz generator with newlydes igned non co ntac t o r contac t app l i ca to rs o f app rop r i -ate length and size. A preliminary illustration of theseappl i ca to rs wi th t he i r iso therma l m aps has been r epor t edelsewhere.5 They are able to de liver useful heat ing up to adepth of 2-3 cm. An array of contact applicators iscurrently employed to treat lesions of larger extent ordepth.5 A c o m p l e te p h a n t o m a n d in v ivo animal dos ime-t ry wi th t he use of d i fferen t number and pos i t ion of t heseapplicators will be published in a separate paper (Ar-c a n g e l i et al. u n p u n i sh e d d a t a , 1 9 8 3 ) .Temperature was monitored at the regular intervals,with the power o f f , by inse r t ing an 18 g auge con s tan tancopper thermocouple wire inside the plastic lumen of as t andard in t raca th p robe p rev iously p laced a t t he base o fthe lesion.Occasional ly, other thermocouples were placedat several dep ths from the surface (usually from 0.5 to 2 .5cm depths). The thermocouples were then connected to amultichannel electronic thermometer for temperaturereading.Recen t ly , wi th the in t roduct ion o f 2450 M Hz app l i ca-tors, we have used microthermocouples, imbedded insu ture with a d iam ete r o f 100 + 5 microns,* that do notin teract wi th elect rom agne t ic field . They were inser ted indepth by m eans of a specia l ly designed need le that can beeas i ly wi thd rawn, l eav ing t he t herm ocouples i n p l ace . A l lthermocouples were then connected to a multi-channel.Hec t ron i c t hermo meter so t ha t a con t i nuous t emp era ture~onitoring could be obtained in different sites of thehea ted v o lume. Dur ing the t rea tme nt , the l eve l o f in t e r -ference with the electromagnetic field could be deter-mined by comparing the temperature reading afterswitching the power off. A treatment temperature of42.5C for 45 minutes and of 45C for 30 minutes wasattempted in the first two and in the third trial, respec-t i ve ly , but f luc tua t ion o f +0.5 could n o t be av o ided whencont inuous t empera ture mon i to r ing was no t used . Hea t -i ng t ime was t he effec ti ve t ime a t t he t r ea tme n t t empera -

L id

W

@ RT HT 0 RT

5

;9/26

7/ 7

~0/14 ~

12 MONTHS

Fig. 1o Local control ra tes of the lesions treated in the first tr ia l:O Rt alone: 60 Gy/36 F/ 16 days; Combined modality: HT =42.5C/45 min , each o ther day, immedia te ly af te r the 2nd da i lyradia t ion frac t ion.

ture. In the third trial, in which a temperature of 45Cwas attempted, the normal skin surrounding the lesionswas ac t ive ly coo led by m eans o f c i rcu la t ing co ld wate r ,while no skin cool ing wa s used in the f i rs t two t r ia ls .R E S U L T S

In analyzing the resul t s , a main conside ra t ion should beout lined: eve ry pa t i en t had a t l eas t 2 l e s ions , one o f themwas t rea t ed on ly wi th rad ia t ion and was , t he re fo re , usedas an inner control. Statistical significance has beenattempted by means of the chi square test, although, int h i s i ns t ance , eve ry d i f fe rence sh ould be cons ide red s ig-n i f ican t as the re sp onse to d i ffe ren t schedules conce rn sthe same tumor in the same patient, the only possiblevar ia t ion being the s ize of lesions.Tumor control

The results of the first trial (conventional fraction sizeof radiation combined with moderate hyperthermia) aregiven in Fig. 1. A complete response after radiation alonewas obtained in 42% lesions (l 1/26). Addition of heatresulted in an increased degree and speed of tumorcontrol, with 73% lesions (19/26) achieving completeregression. The higher effectiveness of combined oversingle treatment modality can be noticed during the wholeperiod of observation. The unexpected higher tumorcontrol rates at 18 months, 4/7 (57%) and 7/7 (100%)lesions treated with the single or combined modality,respectively, is probably related to the longterm survivalof those patients in whom almost all lesions, treated withdifferent modalities, have been controlled. Because of thehigh death rate of these patients during the follow-upperiod, the difference between the two treatment modali-ties is statistically significant (p _< 0.05) only at the end oftreatment.

Addition of heat did not result in an increased skin* M e d t ra , D e t ro i t, M ic h ig a n 4 8 20 2 .


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1128 Radiat ion Oncology Bio logy Physicsradiation reaction, moist desquamation occurring at thesame rate in the fields treated with either the single orc o m b i n e d m o d a l i ty ] A r e l a ti v e l y h i g h i n c i d e n c e o f t h e r -mal damage (7/26 blisters) occurring in these patientswas related to power leakage and over heating of theapplicators initially used in this study. ~Fig . 2 summ ar izes the re su l t s o f the second t r ia l (h ighf rac ti on s i ze of r ad i a ti on com bined wi th mod era t e hyper -thermia). Tumor control was obtained in 37% (6/16)lesions after radiotherapy alone. Combined modalitiesach i eved a be tt e r tumo r r esponse , espec i a l ly i n t he imm e-d i a te t r ea tmen t g roup i n which a com ple t e c l ea rance wasobtained in 77% (10/13) lesions, in comparison to 67%(8/12) complete responses obtained after the delayedt r e a tm e n t . T h e b e t te r r e sp o n se s w i th c o m b i n e d m o d a l i -ties persisted after a 6 month follow-up, immediatetreatment still being the most effective (71% or 5/ 7con t ro l led l es ions) i n com par i son t o t he de l ayed t r ea tme n t(57% or 4/7 controlled lesions), and with radiotherapyalone (33% or 3/9 cont rol led lesions). However , no s ta t i s-tically significant difference could be demonstratedamong these g roups .Addition of heat resulted also in an increased skinr a d i a ti o n r e a c t io n e sp e c i a ll y i n t h e i m m e d i a t e t re a t m e n tgroup.~ A rep resen ta t ive pa t i en t with mul t ip le me lanom anodules i s shown in F igure 3 ( a -b) and 4 ( a -b): a m arkedacute skin reaction after immediate treatment can beobserved in Figure 3a, in comparison with the slightpigmentation obtained after radiation alone (Figure 3b,lower part of the thigh) or after delayed treatment(Figure 3b, upper part of the thigh). Some months laterthe late skin damage after the immediate treatment isunaccep tably h ighe r (F igure 4a) in com par i son wi th tha tobta ined af t e r rad ia t ion a lone o r d e layed t rea tme nt (F ig .4b, lower and upper part of the thigh). A remarkably

100

5O

O J

10 /13~ 7

6 16

MONTHS6

Fig . 2 . Local con tro l ra tes of the l e s ions t rea ted in the secon dtrial: RT alone: 40 Gy/ 8F/ 25 days; [] Delayed treatment:HT = 42.5oC/45 min, 4 h after each radiation fraction; Immediate treatment: HT = 42o5OC/45 rain, immediately aftereach radia t ion frac t ion.

August 1983, Volume 9 , Number 8

Fig. 3. Acute skin reactions in a patient withme lanom a nodules t rea ted with different mo da l i t ies : ate treatment; b. Delayed treatment (upper part oRadia t ion a lone ( lower pa r t o f the th igh ) .

lower incidence of thermal damage in these gbl is ters over 31 t rea ted areas) was obta ined by emmore carefully designed applicators (see MethMater ia ls) .The results of the third trial (high fractionrad ia t ion com bined wi th h igh t empera ture hypera re r epor t ed i n F igure 5 . A comp le t e tumor r esponobta ined in 33% (5 /15) l e s ions af t e r rad io the rapand in 87% (13/15) lesions after combined modal irema rkably h ighe r re spo nse in the l a t t e r g roup palso after 6 month follow-up when 2/9 (22%) (89 ) lesions were still controlled after single o


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Tumor cont ro l aft e r combined hea t and radia t ion G. AR CANG ELI et al. 1129

t J

5O

@ RT0 RT+HT

13/15 S 9 _

5/15

MONTHS

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Fig. 5. Local control rates of the lesions treated in the thirdtrial: Rt alone: 30 Gy/5 F/15 days; Combined modality:HT 45C/30 rain, immediately after each radiation fraction.

Fig. 4 Late skin reactions in the same patient as Figure 3: a.Immediate treatment: b Dela3ed treatment ~upper part of the, . h i . Radia t ion a lon e ( lower pa r t o f the th igh} .

bined modality, respectively. Again. this difference isstatistically significant tp = 0.01~ only at the end oft rea tment .No incr eased inc idence o f sk in m o is t desquamat ion wasobserved in the combined versus single modality group,probably because o f the ac t ive sk in coo l ing an d/o r lowertotal doses of radiation employed in this trial.~ H o w e v e r ,t h e r e w a s a n i n c r e a se d i n c i d e n c e o f th e r m a l d a m a g e o nuncoo led sk in a reas (7 /11 necros i s) as a consequence o fthe necrotic process induced by the high temperatureheating in tumor cells which were grossly involved theo v e r l a y i n g sk i n .~ The representat ive example of a pat ient

wi th 2 m elanom a l es ions (F igure 6 a -b ), shows t he sha rphea t - i nduced nec ros i s conf ined t o t he tumo r a rea t r ea t edwith com bined m odal i ty ( .upper nodule ) in cont ras t wi ththe rem arkable , but incom ple te , r egress ion o f the l e s iont r ea t ed wi th r ad io therapy a lone .Patterns of failure

Figure 7a shows the failure pattern of the lesionstreated with the first protocol. During the follow-upperiod, percent total failure after radiation alonei nc reases from 58% a t t he end of t rea tmen t t o 85% a t 18m onths; wi th com bined mo dal i ty , howev er , a ft e r a smal lincrease , i t r emains a lmost a t a p la t eau l eve l o f 35 38%.Therefore , t he add i t ion of hea t seem s to be no t on ly m oreef fec t ive in ach iev ing more num erous tum or c lea rancesbut also in maintaining the control of lesions during thefol low-up per iod. This i s m ore c lear ly suggested by Figure7b in which the com bined to s ing le m odat i ty f a ilure ra t iois plotted as a function of the observation period. Thisr a t io r epresen t s t he ac tua l therma l en hancem en t of tumorre sponse to rad ia t ion as d i ff e ren t l e s ions were t rea t ed inthe same patient with different modalities. It can beobserved that th is ra t io has a c onstant value of about 0 .46t h rough the who le fo l low-up pe r iod , i nd ica t ing tha t , dur -ing this period, in more than a half of the patients,r ecu r rences o ccur red o n ly i n t he g roup of l es ions t r ea tedwi th r ad io therapy a lone .Figure 8a shows the failure pattern of the lesionst rea ted in the sec ond t r ia l . Percent tota l fa i lure, a t the en dof t r ea tme n t and a t 6 m on ths , r anges f rom 23 t o 31%wi ththe immediate treatment, and from 33 to 50% with thedelayed schedule, while this range is 62 to 81% afterradiotherapy alone. The combined to single modalityfa i lure ra t io s (F igure 8b) in th i s t r i a l , r ange f rom 0 .53 to0.62 for the delayed, and from 0.37 to 0.38 for the


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1130 Radiat ion Oncology Bio logy O Ph ysics August 1983, Volume 9 , Number 8 RT H T RT

7 26 ~

12

Fig. 6 . a . Pa t ient wi th 2 m elanom a nodules , before t rea tme nt : b.The heat induced necrosis is sharply confined to tumor areat rea ted wi th combined m oda l i ty (upper les ion) in cont ra s t wi ththe rem arkable , but incomp le te , regress ion of the lower l e s iont rea ted wi th radio therapy a lone.immediate treatment, thus indicating the higher effec-t i veness of t h i s l a s t schedu le i n con t ro ll i ng tumors .The fa i lure pat tern of the las t t r ia l i s repor ted in Figure9a. A fter radiotherap y a lone, the fa i lure ra te ranges from67 a t t he end of t r ea tmen t t o 87% a t 6 m on ths , whi le on ly13% les ions f a i led the com bined mod al i ty and n o l e s ionsrecurs during the follow-up period. Consequently, thecombined to single modality failure ratio tends tod e c r e a se f r o m 0 . 1 9 a t t h e e n d o f t re a t m e n t t o 0 . 1 5 a t 6m onths , as shown in F igure 9b , thus ind ica t ing ag a in the

o

\w0.5

0 6 12 18

M O NFig. 7. a. Failure rates of the lesions of the 1s t trial: O R Combined m odali ty , b. Combined to s ingle m odaratio.higher e f fec t iveness o f the combined over s ing lment modal i ty .The e ffec t i veness of t he va r ious t herapeu t i c schcan be evaluated from Figure 10 in which the comsingle modality failure ratios are summarized. t i ve ly h igh ra t io ( tha t i s a re la t ive ly low ef fec t iveobta ined wi th the p ro toco l em ploy ing conv ent iont ion frac t ion s ize and m odera te hyper the rm ia . Hoth is ra t io seem s to rema in a t a pla teau level t i ll 18 i nd ica t ing a cons tan t e f fec t iveness o f the com bint he s i ng l e t r ea tmen t m oda l i ty d u r ing t he fo l low-upsecond trial (high radiation fraction size and mhype r the rm ia) , t he ra t io af t e r de layed t rea tm ent ih ighe r an d t ends to increase fur the r with t ime , reaat 6 months, a value well above that obtained wprevious protocol. However, with the immediatment, the ratio is constantly lower and remainplateau level during follow-up. With the third pthe ratio is the lowest and tends to decrease withthus appearing to be the most effective schedcont ro l l ing tumors .Tkerapeutic gainThe ef fec t o f the d i ffe ren t schedules o f com bines i n g l e t r e a tm e n t m o d a l it y o n t u m o r s a n d t h e i r su ring norm al t issue, i s shown in Figure I 1, in which ptumor re sponse and mo is t desquama t ion a re p lo tt e


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Tumor control af ter combined heat and radiat ion G. A RCANGELI et al. 1131

1

5

1 16

4 123/13

MONTHS

--

ONT SFig. 8. a. Failure rates of the lesions of the 2nd trial: RTalone; [] Delayed treatment; Immediate treatment, b. Com-bined to single modality failure ratio: [] Delayed treatment;A I m m e d ia te t r e a tm e n t .

RT100 O RT HT

~ O

1 0 / 1 5

2/1500

MONTHS

2/15

o

MONTHSFig. 9. a. Failure rates of the lesions of the 3rd protocol: RTalone; o Combined modality, b. Combined to single modalityfa i lure ra t io .

func t ion o f the rad ia t ion f rac t ion s ize . Pe rcen t com ple teresponse increases with fraction size after immediatet rea tment whi le, because of the lower tota l doses adm inis-tered when a high fraction size was used, it tends todecrease after radiation alone. For the same reason, aqight decrease of tumor control rate can be observedwhen the de l ayed t r ea tmen t was employed . On the o therh a n d , a f t e r c o m b in e d m o d a l i ti e s , p e r c e n t m o i s t d e sq u a -mation increases too with fraction size, the highesti nc rease occur r ing wi th the immedia te t rea tment , whi lean in terme diate var ia t ion of skin react ion can be observedw i th t h e d e l a y e d s c h e d u l e . N o t h e r m a l e n h a n c e m e n t o fsk in reac t ion i s obse rved in the l e s ions t rea t ed wi th h ighradiation fraction size combined with high temperaturehyperthermia because of the skin cooling and/or lowert o t a l rad ia t ion doses e mp loyed in th i s t r i a l .F r o m t _h . e r e su lt s r e p o r te d a b o v e a n d o n a p r e v i o u spaper~ we attempted to estimate the TherapeuticEnh ancem ent Fac to r (TEF) , usua l ly def ined as the ra t io

o

\wO.5

1 2 18MONTHS

~ig. 10. Summary of the combined to single modality failurera t ios obta ined wi th different schedules: O Conv ent iona l radia -t ion frac t ion s ize and m odera te hy per therm ia ; [] High radia t ionf ra ct ion s iz e a n d m od e ra te h ype r th e rm ia ( d e l aye d t r e a tm e n t ) ; , High radiation fraction size and moderate hyperthermia( Immedia te t rea tment) ; High rad ia t ion f rac t ion s ize and h ighte m pe ra tu re h ype r th e rm ia .


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Tumor control af ter combined heat an d radiat ion G. ARC ANGELI et al. I133(TE = 1 .78), un less tumors can be p re fe ren t i a l ly hea tedas i n t he t h i rd t r i a l, by m eans of an ac t i ve sk in coo l ing .

The delayed application of HT and high radiationf ra c t io n s i z e s i n d u c e d a l o w e r t h e r m a l e n h a n c e m e n t o nb o t h tu m o r a n d sk in ; h o w e v e r , t h e e n h a n c e m e n t o n t h eskin was lower than on the tumors, so that a goodtherapeutic enhancement could be obtained (TEF =1.40).The combination of conventional fraction sizes ofradiation and moderate heat did not increase the skinreaction, whereas the enhancement induced in tumorswas still significant resulting in a good therapeuticenhan cem ent (TEF = 1 .58) .The immediate therapy is based on a hyperthermicsensitization of the radiation effect, the mechanism ofaction being mainly based on a decreased repair ofsu b le t h a l r a d i a ti o n d a m a g e o t h e r t h a n o n a d i r e c t ra d i o -sensitization and on an enhanced killing of cells inrelatively radioresistant phases of the cell cy-e l e .7 1 2 1 3 1 9 2 8 3 0 3 5 3 6 4 4

However, a differential effect on tumor and normalt i ssues can be obta ined by increasing the in terval betweenthe two m oda l i t ies o r by dec reas ing t he r ad i a t ion f r ac ti onsize. If heat is delivered 3 to 6 hours after radiation, atwhich t ime n o rmal t i ssues should have repa i red rad ia t iondam age, but tumo rs may have no t ,~~7 t hen hea t i ng co u ldbe expected to induce more damage in tumors than innormal tissues. Furthermore, as the radiation fractions ize i s reduced , m ore ce l l k i l li ng re su l t s f rom "s ing le -h i t"lethal events than from accumulated sublethal inju-ries.1446 Thus, the im pairment of sublethal dam age repairby heat is progressively decreased; then, the thermalenhancement of radiation response tends to be lower,w h e t h e r i m m e d i a t e o r d e l a y e d s c h e d u l e s a r e u se d . Th ethe rapeut i c ga in can be because o f ce l l ki l li ng in tum orsthat may still result from accumulated sublethal injuryrather than from single-hit event. On the other hand,by increas ing the in t e rva l be tween the two mod al i ti e s o rby decrea sing the f ract ion size of radiat ion, a different iale n h a n c e m e n t e f fe c t o n t u m o r s m a y s t i l l re su lt f ro m t h edirect hyperthermic cytotoxic destruction of the nutri-

t i ona l ly dep r ived , ac id ic and ch ronica l ly hy pox ic rad io re -s i s t a n t t u m o r cells.~3~s2735363941From the p resen t s tudy , som e useful b io log ic info rma-t ion can be de r ived an d used fo r des ign ing c l in i ca l t r ea t -m ent schedu les . An o p t ima l t r ea tm en t shou ld r esu lt f roma balance between heat and radiation, providing anadequate and hom ogeneous hea t depos i t ion and d i s t r ibu-tion is ensured. Local failure among potentially curablecancers is still a difficult problem for the oncologist,accoun t ing for one- thi rd to one-h alf of a l l cancer fa i luresi n seve ra l p r imary tumors . P a l l ia t ion o f d i f fused d i seasesand/or of recurrences in previously irradiated areas isa l so a rou t ine p roblem fo r the onco logi s t . I f rad io the rapyhas neve r been g iven before , an op t ima l t r ea tmen t shou ldresult by simply adding, once (or twice) a week, 5 to 7imm edia t e o r de l ayed sess ions of modera t e hyper thc rmia(43C/45 min) to a full conventional fractionation (orhyper f rac t iona t i on) r ad io therapy course . Wi th t h i s p ro to-co l , no i nc rease of r ad i a ti on dam age t o n orma l t i s sue and ,henc e , no decrease o f the rapeut ic ga in o r tumor cont ro la re expec ted . In he avi ly i r rad ia t ed t i ssues o r when fas tt rea tment s o f mul t ip le l e s ions a re requi red fo r pa l l i a tion ,an optimal treatment should result by delivering, twice-a-week, 5 to 7 fractions of 5-6 Gy in combination with5--7 hyper therm ic sess ions . I f the tumor can be select ivelyor preferentially heated in respect to normal tissue, animm edia t e app l ica t ion of m odera t e (43C) o r h igh (45C)temperature heating can be safely administered with asignificant probability of complete tumor response. Ont he con t ra ry , the de l ayed adm in i s tr a t ion of m odera t e hea t(43C) should provide an effect ive t rea tm ent wi th a lowerincidence of normal t i ssue damage.

In conc lus ion , t he p resen t s tudy g ives som e b io log ica linform at ion that i s useful in des igning c l in ical protoc ols indifferent clinical situations. The biologic phenomenainvolved in the in teract ion between heat and radia t ion canbe differently and alternatively exploited to obtain themaximum tumor sensitization and the minimum normaltissue damage. Further development of better heatingtechniques is now necessa ry to employ h yper therm ia in a llc l in i ca l s i tua t ions a s an adjuvant to rad io the rapy .

R F R N S1. Arcangeli, G.: Clinical exploitation of biological phenom-

ena in combined radiotherapy and local hyperthermia.Proc. 13th Intern. Cancer Congr. Seattle, September 8-15,1982 (In press.).

2. Arcangeli, G., Barni, E., Benassi, M., Cividalli, A., Creton,G., Lovisolo, G., Mauro, F., Nervi, C.: Heating patternsafter 27 MHz local hyperthermia. Comparative results inpiglet normal tissue and in phantom. In Hyperthemia inRadiation Oncology G. Arcangeli, F. Mauro (Eds.). Mila-no, Masson Italia Editori. I980, pp. 69-78.3. Arcangeli, G., Barni, E., Cividalli, A., Mauro, F., Morelli,D., Nervi, C., Span6, M., Tabocchini, A.: Effectiveness ofmicrowave hyperthermia combined with ionizing radiation:Clinical results on neck node metastases. Int. J. Radiat.Oncol. Biol. Phys. 6: 143-148, 1980.

4. Arcangeli, G., Barocas, A., Mauro, F., Nervi, C., Span6,M., Tabocchini, A.: Multiple daily fractionation (MDF)

radiotherapy in association with hyperthermia and/ormisonidazole : Experimenta l and c l in ica l resul ts . Cancer 45 :2707-2711, 1980.5. Arc ange l i , G. , Civ ida l l i , A. , Lovisolo , G. , Nerv i , C. : Cl in icaresu l ts a fter d ifferent p ro toco ls of combined loca l he a t andradiation. Strahlentherapie 159: 82-89, 1983.6. Bede, Z., Diwen, Z., Xiaoxiong, W.: Clinical effects ofradia t ion combined wi th radiofrequency dia thermy in b lad-der cancer: A preliminary report (Abstr. No. Fill 3).Presented at the 3rd International Symposium: CancerTherapy by Hyperthermia, Drugs and Radiation, FortCollins, Colorado, U.S.A., June 22-26, 1980.7. Ben Hur, E., Elkind, M.M., Bronk, B.V.: Thermallyenhanced rad ioresponse of cul tured C hinese ham ste r ce l l ., ;:Inh ib it i o n o f r ep a i r o f su ble tha l da m a ge a nd en ha nc em en tof lethal damage. Radiat. Res. 58:38-51, 1974.

8. Bicher, H.I., Sandhu, T.S., Hetzel, F.W.: Hyperthermia


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1134 Radiat ion Oncology Bio logy O Ph ysicsand radia t ion in com bina t ion: A c l in ica l frac t iona t ion regi -men. Int. J. Radiat. Oncol. Biol. Phys. 6: 867-870, 1980.9. Brenner, H.J., Yerushalmi, A.: Combined local hyperther-mia and X-irradiation in the treatment of metastatictumours. Br . J . C ance r 33: 91-95; 1975.

10. Corry, P., Barlogie, B., Spanos, W., Armour, E., Barkley,H., Gonzales, M.: Approaches to clinical application ofcombinations of nonionizing and ionizing radiations. InRadiation Biology in Cancer Research Meyn, R .E. andWithers, H.R. (Eds.). New York, Raven Press. 1980, pp.637-644.11 . Denekamp, J., Stewart, F.: Evidence for repair capacity inmo use tumours re la t ive to sk in . In t . J . Rad iat . Oncol . BioLPhys. 5: 2003-2010, 1979.

12 . Dewey, W.C., Freeman, M.L., Raaphorst, G.P., Clark,E.P. , Wong , R .S .L. , Highf ie ld , D.P. , Spiro , I . J. , Tomasov ic ,S .P. , Denm an, D.L. , Co ss , R .A. : Ce l l bio logy of hyperthe r-mia and radiation. In Radiation Biology in CancerResearch Meyn, R.E. and Withers, H.R. (Eds.). NewYork, Raven Press. 1980, pp. 589-621.13. Dewey, W.C., Hopwood, L.E., Sapareto, S.A., Gerweck,L. E . : Ce l lu l a r r e s pon s e s to c om bin a t ion s o f h ype r th e rm ia

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2 0 . Hill, S.A., Denekamp, J.: The response of six mousetumours to combined heat and X-rays: Implications fortherapy . Brit. J. Radiol. 52: 209-218, 1979.21. Hornback, N.B., Shupe, R., Shidnia, H., Tek, J.B., Sayoc,E., George, R., Marshall, C.: Radiation and microwavetherapy in the treatment of advanced cancer. Radiology

130: 459-464, 1979.2 2 . Johnson, R.J.R., Sandhu, T.S., Hetzel, F.W., Song, S.Y.,Bicher, H.I., Subjeck, J.R., Kowal, H.S.: A pilot study toi n v e s t ig a te s k in a n d tum or th e rm a l e n h a n c e m e n t r a t io s o f41.5-42.0C hyperthermia with radiation. Int. J. Radiat.On co l . B i o l . Phys . 5: 947-953, 1979.

23. Kim, J.H., Hahn, E.W.: Clinical and biological studies oflocalized hyperthermia. Cancer Res . 39:2258-226 I , 1979 .24. Kim, J.H., Hahn, E.W., Antich, P.P.: Radiofrequencyhyperthermia for clinical cancer therapy. J . Nat l . Can cerInst. Monog. 61: 33%342, 1982.

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30 . Li, G.C., Evans, R.S., Hahn, G.M.: Modificatiinhibition of repair of potentially lethal X-ray damah ype r th e rm ia . Radiat. Res. 67:491-501, 1976.31. Luk, K .H. : M ic rowa v e h ype r th e rm ia a t 245 0 a n d 91frequencies. Henry Ford Hosp . Med . J . 29:28-31, 1932. Manning, M.R., Cetas, T.C., Miller, R.C., OlesoConnor, W.G., Gerner, E.W.: Clinical hyperthR esu l ts o f a p ha se I t r i al em p lo y ing h y p e r the rm ia a loin com bina t ion wi th externa l beam or in tes t i t ia l radiopy. Cancer49: 205-216, 1982.3 3. M a rm o t , J .B . , H a hn , G . M . : C o m b ined r a d i a ti o n a nd thermia in superficial human tumors. Cancer 47: 1991 , 198 0 .3 4. Myers, R., Field, S.B.: The response of the rat tcombined hea t and X-rays . Brit. J. Radiol. 50: 5811977.3 5. Overgaa rd, J . : The effec t o f loca l hyper thermia a lone acombination with radiation, on solid tumors. In CTherapy by Hyperthermia and Radiat ion, C. Streffer et(Eds.), Baltimore, Munich, Urban and Schwarzem1978, pp. 49-61.36 . O v e rg a a rd , J .: S im ul ta n e ous a n d s e que n t ia l h ype r th eand radiation treatment of an experimental tumor asurrounding normal t i ssue in vivo. Int. J. Radiat. OnBiol. Phys. 6: 1 5 07- 1 5 1 7 , 1 9 80 .

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