0123_further experience with regional radiofrequency hyperthermia.pdf

8/14/2019 0123_FURTHER EXPERIENCE WITH REGIONAL RADIOFREQUENCY HYPERTHERMIA.pdf

1/5

Further Experience With Regional Radiofrequen cyHyperthermia and ytotoxic hem otherapy for

Un resectable Hep atic Neo plasiaFREDERICK L. MOFFAT, MD, FRC S (C), TOMAS GILAS, MD, FRCS (C), KEVIN CALHOU N, MD,MICHAEL FALK, RICHARD DA LFEN, BSC, LOFINE E. ROTSTEIN, MD, FRCS (C),LEONARD MAKOW KA, MD, PHD, VICTORIA HOWAR D, RN, DAVID LAING,

DAVID VENTURI, BSC, JACOB C. I .ANGER, MD, JUDITH A. FALK, BSC,AND RUDO LF E. FALK, MD, FRCS (C)The authors report on 178 patients with unresectable hepatic tumors who hav e been treated with 1 to25 (median, 6) courses of radiofrequency hyperthermia (RFHT) nad chemotherapy. In 137 patients,the hepatic tumors consisted of metastases from colorectal adenocarcinoms. For patients who had noprevious therapy and who had olorec~al metastases with no ex trahepatic disease, cumulative survivalat 52 weeks follow-up was 80.5% and partial tumor regression was seen in 78.4%. Among the 69patients who previously had conventional treatment for their h~patic disease, partial regression wasaecu in 43.5%. W e are no longer monitoring tumor core temperature routinely, as the invasive methodscurrently in use yield irreproducibie results; the risks to the patient cannot be justified in view of thequestionable relevance of the data obtained. A prospective ramiomized study of systemic chem otherapywith or withou t RFHT in patients with colorectal hepatic metastases is in progress.

CAmcer 55:1291-1295, 1985.

U NRESECTABLE HEPATIC MALIGNANCIES have anominous prognosis irrespective of the type oftherapy used. Systemic chemotherapy produces objectivetumor responses in 7% to 45% of patients thustreated.~.2 Although the response rate is higher withhepatic artery infusional (HAl) chemotherapy, this is aninvasive technique and its effect on survival is as yetunclear.~-~ External or interstitial radiotherapy to thefiver may provide some palliation for patients withsymptomatic hepatic neoplasia, but it has no effect onsurvival or objective response and can cause seriousmorbidityf -6.~ Interruption of the hepatic arterial circu-lation is of questionable benefit)~A Phase II clinical study of regional capacitive ra-diofmquency hy perthermia (RFHT) in com bination withcytotoxic chemotherapy has been in progress at theToronto General Hospital since August 1981. The lit-erature is replete with reports of the antineoplastic effectof thermotherapy both in vitro and i n v i vo .8-~ Further-more, locally and regionally applied hyperthermia using

Pre=nted at the Joint Meeting of the Society of Surgical Oncoiogyand the Society of Head and Neck Surgeons. New York, New York,May 13-17, 1984.From the Toronto General Hospital, Toronto, Ontario.Address for reprints: R. E. Fatk, MD, FRCS, 1-046 Mulock LarkinWing, Toronto G eneral Hospital, 101 College Street, Toronto, Ontario,MSG IL7.Accepted for publication August 9, 1984.

noninvasive technology produces only infrequent adverseeffects in humans when employed with chemother-apy.~6"~8-23 Our preliminary results with chemotherapyand FlIT in the treatment of hepatic neoplasia havebeen pub lished previouslY-|9 Our experience with thisregimen in patients with unresectable liver tumors isupdated in this report.Patients and M ethods

To date, 847 patients with tumors of various typeshave been treated with RFHT and chemotherapy at thiscenter. Of 291 patients treated for hepatic neoplasia,113 were excluded from this analysis: 59 were moribundwhen initially seen (anticipated survival less than 2weeks), 35 have been lost to follow-up, and 19 did notcomplete even a tingle treatment course. The remairfing178 patients included 99 men and 79 women rangingin age from 28 to 80 years (median, 57 years). Sites oforigin of hepatic neoplasia in these patients are sum-marized in Table 1.The apparatus and treatment protocol used have be endescribed in d etail elsewhere,t9 Briefly, the capacitiveRFH T m achines in use at this center produce radiofre-quency energ3, of 13.56 MHz through three channelswith up to 500 W of power per channel. One or allchannels may be employed in the treatment of a singlepatient as described by LeVeen et al.The output from

1291


2/5

1 2 9 2 C^~cEa M arch l 1985 VolTAB LE i. Primary Tumors in 178 Patienls Treated With RFHT andChemotherapy for U nrer~ctable Hepatic Neoplasia

N o . o fI~tientsA d e n o e a _ ~ n o m a

C o l o r e c t a lB l ~ a S tP a n c r c a sG a l l b l a d d e rS l o m a c hUnknown primaryE s o p h a g u sDuodenum

M a l i g n a n t m e l a n o m aC u t a n e o u sO c u l a rMalignant gastrinoma (pancreatic)Malignant carcinoid (small bowel)PrimaryH e p a t o c a r c i n o m aCholangiocarcinomaAngiosarcoma

1 3 7655442lI32

3

1 7 8

with comfort for each patient. This ranged from 58360 W (median, 145 W).Medications administered during thermotherapycluded mild sedatives or analgesics as necessary, mronidazole and cytotoxic chemotherapy. Metronidazothree oral or intravenous doses of 500 rag per da

RFHT session, has been administered routinely sinApril 1982. This drug appears to facilitate tumor heatby RFHT)s Chemotherapy was administered concomtantly to all but three patients (Table 2). Forty-nipatients received HA l chemotherapy following a standaprotocol,~ 83 patients received systemic (intravenchemotherapy, and the remaining 43 patients receivcytotoxic agents by both routes during different coursof RFHT . Of those receiving HA l chemotherapy, laprotomies performed for various unrelated indications22 patients provided an opportunity for insertion ofindwelling silastic hepatic artery catheter with a subctaneous injection po rt (Port-A-C ath, Pharmacia, Pisctaway, N J). These patients were treated thereafter on anoutpatient basis.

RFHT: radiofrequency hypcnhermia.

each channel is delivered to the patient through twoflexible planar electrodes placed on the body surfaceopposite and facing one another so that the tumor liesbetween them. For the last 15 months we have beentreating patients using only one m achine channel, as wehave found that this is the best method of treatmentwith the electrodes currently in use.

Tumor core tempe rature was monitored in 38 selectedpatients with hepatic tumors in the early months of theRFH T program. Twenty-seven of these are among the178 patients analyzed here. Two electronic thermometrysystems were used, both of which require percutaneousinsertion of a wire thermistor or fluoroptic heat-sensitiveprobe into the tumor mass being treated,m9 Systemictemperature was measured orally or rectally before andat the end of each days RFH T treatment.Informed consent was obtained from all patientsbefore admission to the RFHT program, and the pro-visions of the Hlsinki Declaration (1975) were observed.Treatments were given on an outpatient basis except forpatients undergoing hepatic artery infusion (HAI) che-motherapy via transfemoral angiographic catheter orrequiring admission to hospital for other reasons.

To date, patients have received 1 to 25 treatmentcourses (median, 6 courses) of RFI-IT and chemotherapy.Each treatment course consisted of one to five consec-utive daily sessions of 75 to 120 minutes of thermo-therapy. Total time on RFHT in each treatment courseranged from 80 to 565 minutes (median, 271 minutes).Machine power w as set at the maximum level compatible

ResultsThe results of tumor core temperature measuremen

in the 38 monitored patients have been published prviously)9 Systemic temperature in all 178 patients creased by only 0.6 _.+ 0.3C during thermotherapy,clinically negligible increment.Pat ient Groups

For analysis, the patients were stratified by extent disease and previous therapy into four groups.Group I : Group I com prised 51 patients with advancedisease whose expected survival was less than 8 weeks.Group II: Group II comprised 69 patients whosexpected survival was greater than 8 weeks and who hafailed to respond to the best available chemotherapy fotheir tumors before coming to hy perthermia.G r o u p I I 1: Group III comprised 58 patients withnewly diagnosed and as yet untreated hepatic neoplasisome of whom had extrahepatic disease.G r o u p I V: Group IV comprised 37 patients fromGroup III with colorectal adenocarcinoma metastatic tthe liver, but with no extrahep atic disease.

Surv iv al an d R e spo n seAs of April 1984, 86 patients have died, havin

survived 3 to 76 weeks (median, 26 weeks) from thdate of initial treatment with RFHT. The other 9patients have been followed for 3 to 107 weeks (median36.5 weeks). Survival and follow-up by patient grouare summarized in Table 3.


3/5

No. 6 RFHT AND CHEMOTHERAPY FOR HEPATIC NEOPLASMS Moffat et al . 1293TAB LE 2 . Concomitant C~otoxic C"l~moth~mpy in 178 Paticnt~ Treated With RFHT for Unres~ble Hepatic Neoplasia

Chemotherapy

Priimaw tumors (n = 178) 5-FU MT X MITOSyslemlc

CCNU VC R VBL PC B DO X HA lAdenoca~notr~sColorc~tum (n = 137) 86 12 93 31 44Breast (n = 6) 3 1 3 i

P a n c r e a s ( n = 5 ) l 2 2 2Gallbladder (n = 5) 2 5 2 4S t o m a c h ( n = 4 ) 3 3 I IU n k n o w n I ( n = 4 ) 2 l 2 ILun$ (n = 2 2 2 2 IEsophagus (n = 1) i I IOvary (n = 1) l i 1Duodenum (n = I) i 1 IMelanoma (n -- 5) 2 4 3 2

G a s l r i n o m a ( n = I ) I I l IC a r c i n o i d ( n = I )Hepatocarcinoma n = 3) 2 2 ICholangiocaminoma n = ) I 1 Angiosarcoma (n ffi I)

To~ 106 19 119RFHT: radiofrequency hyperthermia: 5-FU: 5-fluorouracil: MTX:

methotmxaze: MITO: mitomycin C; CLNU: cis-chloroni~rosourca: VCR:

522II

7332i3

22

44 3 62 I I 92

vincristine: VBL: vinblastin~ P C B : procarbazine; IX)X : doxorubicin;HAl: hepatic artery infusional.Cu m ulative survival is shown in Figure 1. It is apparentthat patients as yet untreated for their hepatic disease(G roups III and IV) have fared sub stantially b etter thanthose who pre viously had fai led conventional therapy( G r o u p I I ) o r p a t i e n t s w i th f a r a d v a n c e d h e p a t i c n e o p l a s i a

(G roup I ) . In par t icu lar , G roup IV patients have donevery w ell: 11 patients have bee n followed for 52 w eeksor longer. Cu m ulative surv ival at 52 weeks is 80.5% forG r o u p IV .

Objective r e s p o n s e w a s assessed using the criteriaout l ined by Moertel .24 In al l cases the assessm ent wasmade by at least one of the following methods: hepaticangiography, computerized transaxial tomography, ab-dominal ultrasonography and/or scintigraphic hepaticscan. Response rate and duration are given for eachgroup in Table 4. In Groups lit and IV, partial tumorregression wasseen in 67.2% and 78.4% of patients,

r~ctively, and the median duration of these responseswas 32 weeks. Even in patients who had previouslyfailed chemotherapy (Group II), partial tumor regressionoccurred in 43.5% (median duration, 2 6 weeks).There were no differences in survival or objectivetumor response between patients who received chemo-therapy by hepatic artery infusion and those treatedsystemically.Toxici ty

The adverse effects related to tumor core temperaturemonitoring have been reported previously,t9 Briefly, twopatients developed local peritonitis and fever as a resultof thermistors being inserted into the iive~, both c o m -plications were managed con servatively. In one otherpatient, a thermistor broke off and was retained in 4heliver with no ill effect.

No.Patients

Percent

T A B L E 3. Follow Up and Survival b y Group: April, 1984Mortalities Cur~ntly living

Survival (wk) Patients Follow-up (wk)M _ ~ l _ i a n (Range) No. Percent Median (Ranse)

Group(n = 51) 37 ( 7 2 . 5 % )G r o u p I In 69) 33 (47.8%)Group I11(n = 58) 16 (27.6%)G~oup IVn 37) ~ (13.5%)

20 (3-37) 14 (27.5%) 14 (4-39)35 (9-73i 36 (52.2%) 23 (3-74)40 (13-76) 42 (72.4%) 35 ( 3 - 1 0 7 )39 ( 1 0 - 6 4 ) 32 ( 8 6 . 5 % ) 36 ( 3 - 1 0 7 )


4/5

9 4 March 5 1985 V o ~

FIG. . Cumulative survival for 178 patients mated with RFHTand chemotherapy for unresectable hepatic cancer. Patients hav~ beens~ratified by extent of disease and previous therapy into four groups(l-IV) as described in text.

There have been no mortalities or systemic effectsattributable to RFHT. Superficial partial thickness burnsto the skin underlying the electrodes occurred in 6patients (3.4%) and subcutaneous fat necrosis was seenin 18 patients (10.1%). All thermal injuries healedquickly and uneventfully. In patients with fat n e c r o s i s ,local induration persisted indefinitely but was of no~onsequence.19There were no adverse effects related to the adminis-tration of metronidazole. Chemotherapeutic toxicityconsisted of thrombocy topaenia in three patients whichTABLE 4. Objective Response to RFHT and C hemotherapy in 178Patients With Hepatic Neoplasia

P a t i e n t s D u r a t i o n ( w k )No. (Percent) Median (Range)

G r o u p I ( n = 5 1 )P a r t i a l r e g r e s s i o n ( 1 5 . 7 ~ ) 5S t a b l e 3 ( 5 . 9 % )Proton 37 ( 7 2 . 5 % )Indeterminate* 3Group I1 (n = 69)Pa~Jal regression 30 (43.5%) 26S t a b l e 9 (13.0%) 17P r o g r e s s i o n 24 (34.S )Indeterminate 6Group ii (n ffi 58)Partial regression 39 (67.2%) 32~able 3 (5.2%) 14Priori 14 ( 2 4 . 1 )lndelt~mina~ 2Group IV (n = 37)part~ regression 29 (78.4%) 32Stable 3 (8.1%) 14P r o g r e s s i o n 4 00.8 )I n d e t e r m i n a t e I

02-28)( I 1 - 3 7 )

(~-~))(18-19)

These patients have been followed for less ~han 10 weeks~ all are[~trrently alive.RFHT: radiofrequency hyl~rthermi&

resolved when the drugs were withheld. As reportedpreviously, two patients treated with HAl chemotherapyvia transfemoral catheters developed fevers and a thirdbecame septicemic. The patients recovered a~er removalof their catheters and treatment with antibiotics)9

DiscussionWe have been i m p ~ s s e d b y the l o w incidence oftoxicity associated with RFHT . The adverse effects s e e n

c o n s i s t o n l y o f m i n o r s e l f - l i m i t e d t h e r m a l i n j u r i e s t os u b c u t a n e o u s t i s s ue s a n d s k i n . W h e n u s e d i n c o m b i n a -t i o n w it h c h e m o t h e r a p y , R F H T p r o v i d e s g o o d p a l l i a t i o nf o r p a t i e n ts w i t h i nc u r a b l e h e p a t i c c a n c e r , p a r t i c u l a r l yp a t i e n ts w i t h n e w l y d i a g n o se d h e p a t i c m e t a s t a se s f r o mc o l o r e c t a l a d e n o c a r c i n o m a .

I n a r e v i e w o f t h e t h e r a p e u t i c o p t i o n s c u r r e n t l y a v a i l -a b l e f o r c o l o r e c t a l h e p a t i c m e t a s t a s e s th e i n c i d e n c e o ft u m o r r e s p o n s e t o s y s te m i c c h e m o t h e r a p y w a s f o u n d t or a n g e f r o m 7 % t o 2 1 % i n p a t i e n t s t r e a t e d w i t h a s i n g l ed r u g . a n d f r o m 3 0 % t o 4 3 % w h e n m u l t i p l e a g e n t s a r eused) Hepatic artery infusional chemotherapy producestumor regression in 40% to 60% of treated patients.2Balch et al. reporting on 81 patients who underwencontinuous 5-fluorodeoxyuridine (FUDR) infusion intothe hepatic artery using an implantable infusion pumpdevice, found that 88% of patients had a reduction of33% or more in their serum carcinoembryonic antigen(CEA ) levels. Survival was substantially improved overthat of 129 matched historical controls treated wi~hsystemic chemotherapy.2~

We have show n that when chemotherapy administeredby either route is combined with RFI-IT, the responserate in patients with previously untreated colorectalmetastases confined to the liver is over 75 . Althoughour results do not permit conclusions to be drawnconcerning the influence of RFHT and chemotherapyon survival, the data from patients in Groups HI andIV suggest that ihere m ay be a substantial positive effect.The q uality of life in patients who respond to therapyis excellent; in almost all cases these patients are morefunctional than they had been before entering the RFHTprogramme. Dramatic reduction in pain and fatiguabilitywas reported by all patients responding to treatmentand by most of those whose tumors were stabilized bythis regimen. In patients whose tumors did not respondto RFHT, the quality of life was not compromised bythe treatment protocol.

We abandoned tumor temperature monitoring as aroutine procedure in the early stages of the RFHTp r o g r a m for several r e a s o n s . A s reported previOusly, w~found that tumo r temperature measurements in patientswith hepatic cancers were irreproducible from one daysRFHT treatment session to the next. We also foundthat the tumor temperatures recorded ha d no relationship


5/5

RFHT AND ~-IEMOTHERAPY FOR HEPATIC NEOPLASMS Mo ffat et a i . 1295to the machine power used or to the objective tumorresponses observed.~ These findings are n ot surprisinsin view of the methods currently available for measmingtemperature ~ deeply situated tumo rs and the difficultyin placing one or more thermistors or probes in exactlythe ~ame positions in a tumor over several successiveRFHT treatments.The architecture of a malignant neoplasm is veryheterogeneous: areas with excellent blood supply areinterspersed with areas of poor tissue perfusion andregions of frank necrosis. The distribution of heat withina tumor undergoing RFHT is therefore very uneven andprobably changes over time as the lesions size andarchitecture change. Therefore, it is unreasonable tosuggest that measurements obtained with a single probeinserted at the start of each RFH session would havemuch relevance with t~et to the efficacy of therapy.The use of multiple probes would only yield a largerquantity of data of equally dubious significance.Furthermore, the insertion of temperature probes intodeeply situated tumors is associated with potentiallyserious complications, as our experience dem onstrates.The use of m ultiple probes can only increase the risk ofserious mishap to the patient. Although there have beenclaims that multiple probes can be inserted with impunityinto tumors of the pancreas, liver or pelvis, we suggestthat this practice will eventually result in major m orbidityor even mortality. We contend that the routine use ofinvasive tumor temperature monitoring in patients un-dergoing thermotherapy is unjtistifmble given the ques-tionable quality of the information obtained and thereal potential for serious misadventure with these meth-ods. Invasive mon~ing should be largely confined tothe animal laboratory currently. When noninvasivetechnology for measuring temperature in deep tumorsbecomes available, the current methods could justifiablybe used in selected low-risk patients in an attempt tocorroborate the results obtained with the newer system s.

In view of the shortcomings and risks of invasivetumor temperature monitoring~ the efficacy of RFHTas a treatment m0dality for malignant neoplasia mustbe determined by carefully designed Phase lIl efinicaltrials. Since February 1983 we have been enteringpatients with eolorectal hepatic metastases into a pro-Sleeve randomized study of RFHT and systemic che-motherapy. Patients are treated with systemic chemo-therapy alone (5-fluorouracil and mitomycin C) or sys-temic chemotherapy plus FLIT. Patients who failtherapy are put on the HAl chem otherapeutic regimen3with or without RFHT as determined by the initialrandomization. We hope to complete this trial withinthe next 18 to 24 months.

R F R N S. ]tyler . A critical mhew of lhe treatment of coloreetal liverm e lm lm ~ C li n O n co i 1982; 8:149-1~.2. I.ilbtdale CI, Sherlock P. M anagement of metastatic liver disease.

Pro~ L i~ r Dis 1982; 7.-649-662.3. Falk RE, ~ P, Makowka L e~ a/. Intermittent percutaneousinfusion into the hel~tic artery of c~totoxic drugs for hepatic tumour~C ~ m . /S ~ g 1 9 8 2 ; 2 5 : 4 " /- 5 0 .4. Sundqvist K, ~m LO, Jousson PEet al. Treatment of livercancer with regional intra-arterial 5-FU infusion. A m J S u r g 1978; 3 6 : 3 2 8 - 3 3 1 .5. Pall YZ, Wallace S, Fmireich EJ et aL The palliative role ofbe~atic arterial infusion and arterial occlusion in colorectal carcinoma~ to the liver. Lancet 1981; 1:349-351.( ~ . ~ B o r g e l t B B , G e l b e r R , B r a d y L W e t a t. T h e p a l f i a ti o n o f h e p a t i cm~ta.qases: Results of the Radiation Therapy Oncology Group PilotS t u d y I n l J R a d i a t O n c o l B i o i P h y s 1 9 8 1 ; 7 : 5 8 7 - 5 9 1 .7. Grady ED. Internal radiation therapy of hepatic cancer. D isCo/on Re~um 1979; 22:371-375._8~D~nik Z , Falk RE, Howard V, Makowka L, Venturi D.H~rthermia as a treatment for neoplasia~ C a n J S u r g 1982; 25:603-6 0 8 .9. Giovanella BC, Stehlin JS, Morgan AC. Selective lethal effect ofmpranormal ~-mperatures on human neoplastic cells. C a n c e r1 9 7 6 ; 3 6 : 3 9 4 4 - 3 9 5 0 .10. Muclde DS, Dickson JA. The selective inhibitory effect ofhYlXrthennia on the metabolism and growth of malignant cells. Br JC a n c e r 1 9 7 1 ; 2 5 : 7 7 1 -7 7 8 .i l. Dickson JA, Shah Sa, W aggott D, Whalley WB. Tumoureradication in the rabbit by radiofrequency heating. C a n c e r R e s 1977;37:2162-2169.12. Siotman GJ, Milazzo J, Jain K~ Swaminathan AP, Rush BF.The effect of radiofrequency hyperthermia on the C a755 routinea d e n o c a r c i n o m a . C a n c e r 1 9 8 0 ~ 4 6 : 1 9 9 2 -1 9 9 5 .1 3 . B a k ~ H W , S n e d e c o r P A , G o s s J C e t a t . R e g i o n a l h y p e r th e r m i af o r c a n c e r . A m J S u r g 1 9 8 2 ; 1 4 3 : 5 8 6 - 5 9 0 .14. LeVeen HH. W apnick S, Piccone V, Falk G, Ahm edT u r n o u t e r a d i c a ti o ~ o f r a d i o fr ~ l u e n c y t h e ra p y . J A M A 1 9 7 6 ; 2 3 5 ~ 2 1 9 8 -2 2 0 0 .15. LeVeen HH, OBrien P, Wallace KM. Radiofrequency ther-

~Or~s~O r c a n c e r . J S C M e d A s so c 1 9 8 0 ; " / 6 : 5 - 9 .

oma metastases in liver. Cancer 1982; 49:1243-12 -12~--.I:K, Harrison WH, Eiliott RS, Morton DL. Hyperthermictherapy for lmman mmOasms: Thermal death time. Cancer 1980,46~9-1854.a ~ k R E , M o l r a t F t . , C _ ~ o u n K e t a t . T h e ~ . o f ra a i o f r~ . . u e .n ~hyl~.tlhermia on human neoplasms when used vath metromdazole.S~)9 Gyneco/O~uet 1983; 157:505-512. .~ FL, F~ik RE, C~houn K e~ a~. TI~ eff~t of r~fio~hyi~e~erm~ m~d ~-motherapy on primary and secondar7 liverneoplasms when reed with adjuvant metronidazole. S~e~ 1983;

he~d and neck cancer with radiofrequenc~ hyperthermm and cy~..tox~c~ o w a ly. Can J Sur~ 1984; 27:3&-~1.CD, B e~ino ~R. Pmsib~e benefits of hyperthermia tochU-1~o_ t l~apy. Cancer Res 1979; 39:22 85-2289. .~l-l~im GM. Potential. for therapy for drags and h~pe~-rmia.~ armeS 979; 39:2264-226~.or ~B. Intemctious of h~bermia and chemotherapy inCancer Res 1979; 39:2269-2 2" /6.24. btce~el 03. Chem otherapy of co|o~-tal canc~. In: CaandmannE, ed. Co, on Cancer. New Yo~k: Gu~v Fischer Verlag, 1978; 20?-2~6.25. ~ CM, Urist MM, Soong S~, McG~gor M. A prospectiveph~s~ r~ clinical trial of continuous FUD R regional chemotherapF foreolorectal metasta~s to the liver using a to~ll~ implantable druginfusion ~mp. Ann S u r ~ 1983; ~98:567-573.

0123_further experience with regional radiofrequency hyperthermia.pdf

Documents