0153_magnetic-induction hyperthermia.pdf

8/14/2019 0153_MAGNETIC-INDUCTION HYPERTHERMIA.pdf

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Ma gnetic Induction Hype rthermia

R esults of a 5 Year Multi Institutional National CooperativeTrial in Adv anced Cancer Patients

F. KRISTIAN STORM,-MD, HARVlEY W. BAKER, MD, EE WARD F. SCANLON, ~D, HENRY P. PLENK, MD,

P~AUL M. MEADOWS, ME , STEPHEIN C. COHEN, MD, CARL E. OLSON, MD, JOHN W. THOMSON, MD,JANARDAN, D. KHANDEKAR, MD, DENISE ROE, MS, ANNE NlZZE, PAC, AND DONALD L. MORTON, MD

Nine US institutions performed 14,807 Phase 1-1I treatments of magnetic-induction: (Magnetr0de[Henry Medical Electronics, Inc., Los Angeles, CA]) hyperthermia in 1170 adults. All had advanced

tumors: 20% had untreated inoperable cancer or disease progression despite surgery (10%), iadiationtherapy (XRT) (3%), chemotherapy (27%), or combinations (40%); 67% had pain; and 73% had reducedactivity. Eighteen percent were advanced primaries, 26% were recurrent, and 56% metastatic tumors inthe head and neck (7%), body wall (7%), extremity (4%), abdominal cavity (17%), pelvis (17~, lung(15%), or liver (30%); 36% were _5 cm. Treatments were to safe tolerance for 30 to

60 minutes for five or more treatments. Results in 960 evaluable patients were c.omplete~.....~r~sp_o_n~e_~(1-34 months; median, 7 months), partial response 18% (1-39 months; median, 4 months), minimalresponse 10% (1-15 months; median, 3 months), and no change 33% (1-32 months; median, 3 months),with decreased pain in 30% and improved activity in 21%, in-d ependent of histologic type or site.Regression was dependent on treatment type and minimum temperature: heat only, 23%; heat + XRT,60%; heat + less-than-standard XRT because of prior XRT failure, 39%, heat + intravenous (IV)chemotherapy, 28%; heat + same previously failed IV chemotherapy, 20%; heat + intraarterial (IA)chemotherapy, 28%; heat + same previously failed IA chemotherapy, 15%; heat + standard XRT+ chemotherapy, 58%; heat + less-than-standard XRT + chemotherapy, 47%; 47C, 100%. There were 49 (0.33%) skin burns and 2 systemicinjuries (stomach ulcer at 1 month; lung fibrosis at 9 months). This trial indicates that localizedhyperthermia has a significant role in palliation of human advanced solid cancer.

Cancer 55:2677-2687, 1985.

From the Division of Surgical Oncology, John Wayne Clinic,Jonsson Comprehensive Cancer Center, UCL A S chool of Medicine,Los Ang eles, California.

Supported by the Department of Health and Human Services,National Cancer Institute, grants no. P01-CA2 9605 (D.L.M .), N01-CM 1 17523 (H.P.P.), R01-CA 24883 (F.K.S.); Radiation TherapyOncology G roup grant no. 2UI0-CA 17906 (H.P.P.); American CancerSociety Clinical Fellowship (F.K.S.); the Fraternal Order of the Eagles

(P.M.M .); the Cohen Foundation for Oncologic Research (S.C.C.);Nancy and Carroll OConnor (F.K.S.); Michael A. Wayne and theJohn Wayne family (D.L.M. and F.K.S.); the Committee to CureCancer through Immunization (D.L.M); the Norman Sprague Jr.,M.D., Foundation (F.K.S.)~ the C harles Al~right Foundation (F.K.S.);the Charles Fabrikant Foundation (F.K.S.); and a Phi Beta Psi Sororitygrant (F.K.S.).

Address for reprints: F. Kristian Storm, MD, Division of SurgicalOncology, 9th Floor Louis Factor Building, UCLA School of Medicine,Los Angeles, CA 90024.

The authors thank the following: oncologic surgeons--Harvey W.Baker, MD , Richard Berk, MD , Constantine Hatzitheofilou, MD, C.Edwin Irish, MD, Larry R. Kaiser, MD, David H. Krag, M D, DonaldL. Morton, MD, Kenneth P. Ramming, MD, Edward F. Scanlon,MD , Allan W. Silberman, MD, Ph ilip A. S nedecor, MD, F. Kristian

Storm, MD; medical oncologists--Elmer Brestan, MD, Stephen C.Cohen, MD , Philip B. Dreisbach, MD, William P. Galen, MD, RobertGoslin, MD, Charles M. Haskell, MD, Jamardan D. Kh andekar, MD,Allen Patton, MD, Gregory Sarna, MD; radiation therapists--NellBowie, MD , Donald Eads, MD, John J. Gallucci, MD, Raphael M.Garces, MD, Irving J. Horowitz, MD , Paul M. Meadows, MD , CarlE. Olson, MD, Henry P. Plenk, MD, Marcia J. S. Richards, MD,Robert Ring III, MD, William T. Sause, MD, John W. Thomson,MD; engineers and physicists--Doug Brewer, YuKong Chan, PhD,Charles Deal, Robert S. Elliott, Phl)~ William H. Harrison, BA, Dav idC. Matthes, MS; RN s/technicians--Lisa A1-Hashimi, RN, Milzi Benz,RN, Mary Ann Bright, RN, Dinah Celmin, CRT, Beverly Drury, RN,Lupe Ettinger, RN, C aron Finn, RN, Jane Foard, RN, Robin Foley,RN, Kathy Duggan Holmes, RN, Patricia Leprich, RN, Sonja Maxwell,RTT, Connie Mueller, RN, Jan McNitt, RN, Claudia Ongley, RN,Ann Packard, RN, Linda Peham, RN, Kim Raja, RN, Carla Rich,RTT, Helen Rowell, RTT, Karen Stickel, RN, B arbara Sosaya, RN;statisticians--Ed Korn, P hD, D enise Roe, MS, K enneth Pringle, SeniorProgrammer;, data-entry personnel--Stephen Conti, AA, Dan Greene,MSPH, Mindy lllingsworth, J. Anne Nizze, PAC, and Jamie Quintero,MPH.

Accepted for publication October 17, 1984.

2677


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2678 CANCERJune 1 1985 Vo

S U B S TA N T I A L B O D Y o fin vitro, in vivo, and clinicalevidence indicates that hyperthermia has significant

anti-cancer activity, particularly when combined withradiation therapy or chemotherapy.~ Hyperthermia hasbeen produced by water baths, perfusion, enshroudmentin water-circulating suits, extracorporeal heat exchang e,and electromagnetic or.acoustic waves, namely, short-waves, microwaves, or ultrasound.

We performed a comprehensive Phase I-II investiga-tion of localized hyperthermia in patients with advancedsolid cancer, particularly deep-seated visceral malignancy.Localized hyperthermia is not focused, and treats theregion of the bod y that contains the tumor; this approachassumes that tumors heat as well as normal tissue andthat in many cases tumors selectively retain higher levelsof heat due to relatively poor blood flow and inadequate

vasoregulation.2Patients were also treated w ith localized hyperthermia

combined with standard doses of radiation therapy orchemotherapy, based upon the premise of an additiveor synergistic response. 3-6 Patients whose disease pro-gressed after radiation therapy w ere subsequently treatedwith additional low doses of radiation combined withheat. Similarly, patients who had failed the best knownchemotherapy for their disease were treated with thesame ineffective agent(s) plus hyperthermia, in the hopesof bringing about a secondary response.

This cooperative study was desig.ned to answer severalimportant, clinically relevant questions, ts hyperthermiaas a single agent benefidial, or is it best employed asadjuvant treatment with radiation therapy or chemo-

therapy? Wo ullll standard doses of these agents becomeprohibitively toxic when combined with heat? Doesresponse depend upofi tumor histologic type, size~ orlocation, within .the body, or upon the absolute tumortemperfiture achieved? Finally, could localized hyper-thermia be l~r(orme~lshfely by Well-trained physiciansand nurses, given a standard clinical setting, withoutextensive on-site engineering expertise7

Conduct and Methods of Study

Institutions and Principal Investigators

Nine institutions participated in this study: UCLASchoo l of Medicine, Los A ngeles, California--F. KristianStorm, MD, Sponsor; Good Samaritan Hospital, Port-land, Oregon (University of Oregon affiliate)--HarveyW. Baker, MD; Evanston Hospital, Evanston, Illinois(Northwestern U niversity affiliate)--Edw ard F. Scanlon,MD ; LDS Hospital, Salt Lake City, Utah (University ofUtah affiliate)--Henry P. Plenk, MD, and John W.Thomson, MD; Baptist Hospital, Pensacola, Florida(University of South Alabama affiliate)--Paul M. Mead-ows, MD: Baptist Hospital, San Antonio, Texas (Uni-

versity of T exas affiliate)--Stephen C. C ohen, M DMarys Hospital, Milwaukee, Wisconsin (University ofWisconsin affiliate)--Carl E. Olson, MD; Desert Hos-pital, Palm Springs, California (University of SouthernCalifornia afflliate)--Philip B. Dreisbach, MD; anmona Valley Corrgnunity Hospital, Pomona, Cali(Loma Linda University affiliate)--Robert Ring, M

Study Dates

Patients were entered into the cooperative studya 5-year period from 1977 through 1983.

Subject Selection Criteria

AII patients had histologic proof of malignancy, was locally advan ced primary, recurrent, or metasdisease for which standard therapy offered little or noreasonable chance of cure. Candidates included thosewith advanced cancer for which no standard or potially beneficial therapy ex ists. Hyperthermia and dard therapy were used together during initial treatof advanced tumors where an additive or synergisticbeneficial effect was expected.3-6 No proven.method ofcancer therapy was withheld becau se of this investiga

Patients had a projec ted life expectancy of at leamonth. All treated tumors were measurable in at leastone plane. Any histologic type was accepted, as lonthe lesion fulfilled size and accessibility requirements

for evaluation. Patient accrual was by nonsolicited in-tramural and extramural referral.

Pretreatment Evaluation

Tumors were carefully measured using calipers, andthe measurements were recorded in millimeters. Whenan accurate depth measurement was impossible, anestinaate of tumor depth was made from the skin surface.

-For inaccessible lesions, special studies, such as radio-graphs, angiograms, ultrasound, or compuierized to-mography (CT) scans, assessed thq pretreatrncnt size,depth, and location of the. tumor: Volume calculation

was made whe~re feasible.Adequate evaluation of the patients general health,extent of disease, and capacity to undergo treatment

included: (1) history, physical examination, and .appro-priate laboratory studies; (2) activity status---~rank 0= fully active (Karnofsky 90-100), rank 1 = restrictedbut ambulatory and able to carry out light work (Kar-nofsky 70-80), rank 2 = out of bed more than half ofworking hours and capable of self care but ufiable towork (Karnoffsky 50-60), rank 3 = limited to self carewith more than half of waking hours confined to bed orchair (Karnofsky 30-40), and rank 4 = completely bed-ridden (Karnofsky (10-20): and (3) pain status--rank


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No. 11 MAGNETIC-INDUCTION HYPERTHERMIA Storm el a]. 2679

0 = pain-free, rank 1 = nonnarcotic analgesics required,rank 2 = oral narcotics required, rank 3 = oral and/orintramuscular narcotics required, and rank 4 - intra-venous narcotics required.

Hyperthermia Equiprnent and Training ofPrincipl Jnvestigators

We used unaltered, nonmodified original generatorsand standard electrodes supplied by Henry MedicalElectronics. Inc., Los A ngeles, California (M agnetrodeSystem Hyperthermia~ Devic~l.

This ~ystem creates electromagnetic energy in theform of shortwave-band radiowaves at the ISM (indus-tnal-scientific-amedical) frequency of 13.56 MHz, andemploys either capacitive or inductive applicators toprovide noninvasive, localized hyperthermia. 7 The ca-pacitor electrode heating method uses a pair of cooled

contact conductive plates suitably arranged on eitherside of the volume being treated. On tissues with a hig hwater content, such as muscle, internal organs, or tumors,effectiveness is reduced by excessive h eating of overlayingsubcutaneous fat. For tumors located subdermally withless than 1 cm of overlaying normal skin and subcuta-neous tissue, specific tumor heating was accomplishedby incident wave contouring using various-shaped contactelectrodes, as well as surface cooling (3% of cases).

Magnetic-loop applicators are self-resonant, noncon-tact circular structures with built-in impedance matchingcircuitry. The coil is a single turn of a rolled conductingsheet that overlaps in a nonconductive manner. Thearea of the overlap and the gap distance provide theproper amount of capacitance. The element param eterswere selected to produce very large circulating currentsin the loop structure. These currents create a strongelectromagnetic field into which the body or limb isimmersed; this provides localized hyperthermia withrutexcessive heating of surface tissues. With deep internaltumors and normal overlaying skin and subcutaneoustissues of 1 cm or greater thickness, magnetic-loopelectrodes were used. S ince different body parts (thorax,abdom en, neck) were treated by this method , electrodesof different sizes were employed (97% of cases).

Patients were treated in a standard clinical setting,without a screen room, Faraday cag e, or other shielding.The hyp erthermia system meets or exceeds Federal

Communications Commission (FCC~ and AmericanNation~.l Standards Institute (ANS I) standards for per-sonnel safety. Pursuant to Med ical Device Amendmentsof 1976 and 1981, this device was classified as "inves-tigational and was used for human subjects under aClinical Investigations Exemption approved by the Foodand Drug A dministration (FDA ).

All principal investigators (or their representatives)

were fully trained at the UCLA Medical Center in theprinciples and application of this device, ensuring uni-form hyperthermia delivery according to the methodsof the study. None could deviate from or modify thesemethods, or the standard equipment, without exclusion.All were required to attest to the conformity of treatmentsat their facility and to abide by Department of Healthand Human Services (DHHS) regulations for humansubject protection.

Thermometry Equipment

All investigators used c~]ibrated thermocouples orthermistors reliable to _+ 0.1C- read serially throughouttreatment during brief periods of radiofrequency (RF)-wave interruption, or nonperturbing fiberoptic sensorsreliable to _+0.1C read continuous~l~ d ...u~riffg-ireatment.Acceptable protocol probes included B.ajley Microther-mocouples, Model N os. MT 23-29 and IT 14z23"(BaileyInstrument Co., Saddlebrook, N J); YSI needle thermis-tors, Series No. 500 (Yellow Springs-Ilastyument Com-pany, Yellow Springs, OH); gallium-arse~de by Clini-

,therm, Inc. (Dallas, TX); and phosphor Fluoroptic (Lux-tron, Inc., Mountain View, CA-).

Treatment Temperature Monitoring

Norma l tissues:Skin and/or subcutaneous tissue, aswell as oral and/or rectal core temperatures, were mea-

~fured in all patients to assure that normal tissues re-mained w ithin their physiologic thermal tolerance range.

~ tlt~lOrS. Tumor temperatures were assessed wheneversafely possible. In each case, individual risk was weigh edagainst potential knowledge gained. Ideal tumor-tem-perature monitoring included the normal tissue-tumorinterface, as well as radial depths within the tumor,including its peripheral and central regions. Sterile needle,wire, or fiberoptic thermometers, with or without sterilelocating tubes, were placed aseptically using local anes-thetic (1% xylocaine without epinephrine), or surgicallyin and about accessible tumors to be treated.

The highest recorded temperature throughout thetumor that was sustained throughout therapy(i.e., theminimum tumor time-at-temperature) was entered into

our data as the tumor heating capacity.

Dose and Treatment Schedule

Hyperthermia application (all categories):Patients weretreated within the physiologic norm al tissue-temperature

range, to com fortable tolerance. Treatments were for 30to 60 m inutes at tumor-treatment temperature per treat-ment application, no more than once per day, at 24- to72-ho ur intervals. On ly awake, responsive patients weretreated, with or without mild sedation.


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Radiation therapy application:Hyperthermia was givenwithin 4 hours of radiation therapy (XRT), at 24- to72-hour intervals, throughout the course of XRT. Stan-

dard applicable doses and fractions of XRT were em-ployed in accordance with acceptable and commoncommunity practice, and were given only to patientswho had not received larior XRT to the field of treatment.The total XRT dose varied according to the organ beingtreated, but did not exceed the standard recommendeddosage for that organ.

Less-than-standard-dose XRT was employed in ac-cordance with abceptable and common communitypractice in patients who had failed prior standard-doseXRT for their disease, and where additional XRT wassafely feasible. Additional XRT doses varied accordingto the organ being treated, but did not exceed .standardrecommended dosage for that organ. All radiation ther-apy was ad ministered by a qualified radiation therapist.

Chemotherapy application:Drugs were administeredimmediately before or simultaneously with hyperthermia.Only FDA-approved chemotherapeutic agents, doses,and schedules were used, in accordance w ith acceptableand common community practice. The chemotherapyin each case was an indicated agent(s) applicable to thecancer being treated, lnvestigational drugs and doseswere prohibited. Chemotherapy was administered underthe supervision of qualified physicians experienced inthe use of antineoplastic agents..

Evaluation During Hyperthermia

During h.~erthermia, all patients had their vital signs(pulse, respiration, and blood pressure) and core tem-peratures serially monitored. Any adverse symptomduring ltceatment was noted and investigated. Clinicalevaluation of~tiormal tissue in the treatment field wasmade se~ial13)-~lufihg~ treatment. If the 45C thermaltolerance limit of any normal tissue occurred, or if anyadverse reaction was observed, treatment was immedi-ately terminated, and appropriate supportive care wasinstituted as req uired.

Criteria Jb r Response

Patients evaluableJbr therapeutic response:Heat alone:patients completed five or more serial heat treatments,defined as one course of hyperthermia. Heat plusradiation therapy: patients completed the initial pre-scribed course of radiation therapy combined with hy-perthermia, defined as one course of thermoradiother-apy. Heat plus chemotherapy: patients completed fiveor more serial treatments of simultaneou s heat and drugadministration, defined as one course of thermochem-otherapy.

Tumor response.Complete response (CR) was deas the disappearance of all evidence of the treatedPartial response (PR) w as defined as a decrease o

or more in the size of the treated tumor. Minimaresponse (MR) was defined as a decrease of 25% ormore in the sizo~of the treated tum or. Stable diswas defined as no change,i.e., _+25%, in the size of thtreated tumor. Since nonviable tumor matrix may breplaced by scar after effective hyperthermia w ior no reduction in size, z growth arrest of a previousgrowing tumor was categorized as disease "stabiliProgression (P) was defined as greater than 25% inin the size of the treated tumor.

Pain response. Pain response was defined as impment by at least one pain rank.

Activity response:Activity response was definimprovem ent by at least one activity rank.

Duration of response.Duration of response wasculated from the time of initiation of hyperthermitherapy.

Treatment response exclusions:Patients unable tocomplete one course of therapy, for whatever reason,were considered nonevaluable (NE) for therapeusponse.

Assessment of Toxicity

Toxicity was evaluated during and after the comof a course of hyperthermia at serial intervals (2-4weeks). Evaluation included physical examination anappropriate blood chemistries for the organ(s) treated.Patients undergoing chemotherapy also had seriplete blood counts (CBC), differential prothrom(PT), partial prothrombin time (PTT), and platelecounts.

Data Collection and Analysis

All patients were entered into the comphterizebase. No patients or data were e~xcluded because of inadequote treatment or porr results.-tData-entrYpersonnel were trained.by the ~hief statistician (D.R.)

and data-entry coordinator (A.N.). Additionally, statis-ticians independently verified the accuracy of datafor 5% of the data forms. All analyses were condby statisticians not directly connected with~.the trial.Those patients who had one or more cours~ of thwere considered evaluable for treatment response, andall patients were considered evaluable for toxicity

Informed Consent

Patients understood the investigational nature of thisstudy and gave fully informed consent to participate, in


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accordance with all applicable institutional, state, andfederal guidelines. They could withdraw from the studywithout prejudice.

Patient and Tumor ProfileOne thousand, one hundred seventy adults, 55% of

whom weye male, ranging in age from younger than 20years t0 ~older than 80 years (70% 5 0-90 years), under-went 14,807 regional hyperthermia treatments. Patientsreceived a median of 10 treatments (average, 12.7:range, 1-160).

All patients had a~lvanced disease a] the time oftreatment~ Two hundred thirty (2~) had gad no priortherapy; the others~had had disease progression despitesurgery in tit (10%), radiation therapy in 40 (3%),chemotherapy in 306 (27%), or combination therapy in459 (40%). Seven hundred sixty-three patients (67q)had pretreatment pain, of Whom 568 (74%) required

narcotics and 911 (79% ) had restricted activity, of whom550 (60% ) had a Karnofsky rating of 50 to 60 or less.

Two hundred fifteen (18%) patients had advancedprimary, tumors, 303 (26% ) had locally recurrent tumors,and 648 (56% ) had m etastatic disease. There were 707(61%) adenocarcinomas, 135 (12%) epidermoid carci-nomas, 130 (11% ) sarcomas, 137 (12% ) melanomas, 13(1%) lymphomas, and 45 (4%) other less common solidtumors. Five hundred twenty (63%) of the tumors were5 cm or larger in least dimension, and 302 {37%) wereless than 5 cm. -.

Treated tumors were lo{ated in the head and neck in77 (7% ) patients, the body wall in 79 (7%), an ex tremityin 42 (4%), a lung in 177 (15%), the liver in 351 (30%),the pelvis in 202 (17%), another intra-abdominal locationin 201 (17%), or another body site in 32 (3%). Ninehundred twenty-four (86%) of the tumors were considereddeep internal or visceral (below the body wall), and 152(14% ) were deemed superficial (on or in the body w all).

Production of Localized H yperthermia in TumorsHeating capacity was determined in 591 tumors; 409

(69%) had one site monitored and 182 (31%) had twoor more sites monitored. No injuries or deaths wereassociated with temperature monitoring. In nearly allcases monitoring occurred during the initial treatment.

Table 1 shows the overall result of localized hyper-hermia within tumors. It is emphasized that the datarepresent the highest temperature mg , asured throughouthe tumor, throughout treatment (i.e., the minimumumor time-at-temperature for 30--60 minutes). At theseumor temperatures, only, 2 of 924 (0.2%) patients hadskin temperatures ever recordedat 45C or high er, andonly 24 of 932 (3%) had subcutis at or above thisemperature. Tumor heating capacity did not appear to

TABL E 1. Production of Regional Hyperthermia in Tumors

Minimum tumortime-al-temperaturein C (30-60 min) No. (%)

_ 5 0 9 (2%)

be correlated with tumor histologic.type(Ta .ble2), locationwithin the body (Table 3), depth, dr- siid(Table 4.)~

Results

Of the 1170 patients entered on study, 960,completedat least one course of therapy and we]~evaluable fortumor response. Table 5 shows the overall response ofthe entird group. There were. 353 (37%) patients withobjective tumor regression (CR + PR + MR) for 1 to39 months, 313 (33%) with disease stabilization for 1 to32 months, and 294 (30%) with disease progression.Pain improved overall in 30% of patients, and activityin 21% (Table 6). Interestingly, not only did 228 of 651(35%) patients with tumor response have pain improve-ment but 49 of 287 (17% ) with disease progression alsohad improvement in pain status.

Overall response did not correlate with tumor histo-logic type (Table 7), location of the tumor within thebody (Table 8), or depth of the treated lesion (Table 9).Overall response did vary by the type of treatmentemployed (Table 10), as well as by minimum tumortemperature (Table 11). The incidence of regression washigher in those patients treated with combination ther-moradiotherapy or thermochemotherapy than in thosetreated with hyperthermia alone. The rare occurrencesof sustained minimum tumor temperatures of 46C orhigher produced a high response rate. When these twovariables (i.e., treatment type and minimum tumortemperature) were combined (Table 12), combinationtherapy and hig her temperaturgs seemed most beneficial.

Table 13 shows the overall toxicity in 14,807 treat-ments of localized hyperthermia and hyperthermia com-bination therapy. There were 49 (0.3%) surface tissueinjuries,of which on ly 6 resulted in focal areas of skinloss, and 2 (0.01%) systemic injuries. After 1 month ofthermoradiotherapy to the upper abdomen, one patientdeveloped a peptic ulcer, and 9 months after receiving


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Minimum Adenocatemp C n = 332

TABL E 2. Tumor Heating Capacity by Histologic Type

Epidermoid Ca Sarcoma Melanoman = 70 n = 90 n = 71

Lymphoman=9

- 4 521 (6%) 2 (3%)

~ ~(~p: temperature; adenoca: adenocarcinoma.

24 (27%) 18 (25%)29 (32%) 25 (35%)25 (28%) 17 (24%)

12 (13%) 11 (16%)

324

0

Othern=12

092

TAB LE 3. Tumor Heating Capacity by Location

Minimum Head, neck Body walltemp C n = 56 n = 70~

(:40 ~ 2b (36%) 21 (30%)40-41.9 24 (43%) 26 (38%)42-44.9 ~ 8 (14%) 15 (21%)

>_45 , 4 (7%) 8

Extremity lntrabdominal Pelvis Lung Livern = 36 n = 93 n = 119 n = 34 n = 161

9(25/,,) 11 (12%) 25(21%) 6(18%) 17(11%)10 (28%) 41 (44%) 46 (39%) "17 (50%) 73 (45%)10 (28%) 32 (34%) 44 (37%) 9 (26%) 58 (36%)7 (19%) 9 (10%) 4 (3%) 2 (6%) 13 (8%)

Othern=13

7060

temp: temperature.

thermoradiotherapy, one patient had areas of lung fibrosisexceeding that expected after radiation therapy alone.There was n o increase in chemotherapy tox icity reportedwith simultaneously administered localized hyperttker-mia. There were no treatment-related deaths.

Discussion

Hyperthermia has a long and interesting history datingto before the year 1900, and several excellent reviewtexts are currently available. ~,s,9 Over the last decade,convincing evidence for the tumoricidal effect of heathas come from basic science laboratories throughout the

world. Unfortunately, few trials have evaluated theclinical effectiveness and toxicity of localized h yperther-

TAB LE 4. Tumor Heating Capacity by Depth and Size

Depth Size

Minimum Superficial Deep -5 cmtemp C n = 135 n = 410 n = 122 n = 395


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No. 11 MAGN ETIC INDUCTION HYPERTH ERMIA Storm et a 2683

TAB LE 7. Response by Tumor Histologic Type

Histologic type CR PR MR S P

Adenoca 44 (6%) 96 (16%) 62 (11%) 207 (35%)178 (30%)

Epidermoid C a 22 (19%) 31 (27%) 14 (12%) 29 (26%) 17 (15%)Sarcoma 2 (2%) 21 (21%) 8 (8%) 31 (31%) 37 (37%)Melanoma 15 (13%) 16 (14%) 5 (4%) 27(23%) 54 (46%)Lymphoma 0 1 1 5 3Other 2 ~6%) 8 (25%) 3 (9%) 14 (44%) 5 (16%)

CR: complete regression; PR: partial regression; MR: minimum regression; S: stabilization; P: progression; A denoca: adenocarcinoma;Ca: carcinoma.

TAm-E 8. Response by Tumor L ocation

Location CR PR MR S P

Head and neck 19 (29%) 19 (29%) 4 (6%) 13 (20%) 11 (17%)Body wall I1 (17%) 15 (23%) 5 (8%) 13 (20%) 20 (31%)Extremity 7 (21%) 10 (30%) 4 ( 2%) 4 (12%) 8 (24%)

Lung 9 (6%) 15 (10%) 23 (16%) 57 (39%) 43 (29%)Liver 8 (3%) 32 (11%) 19 (6%) 117 (38%) 128 (42%)Intraabdominal 9 (6%) 30 (19%) 21 (13%) 44 (28%) 52 (33%)Pelvis 17 (11%) 44 (28%) 16 (10%) 56 (36%) 23 (15%)Other 3 (t2% ) 7 (28%) 2 (8%) 6 (24%) 7 (28%)

CR: com plete regression; PR: partial regression; MR : minimum reg ression; S: stabilization; P: progression.

the majority of treatments were administered on anoutpatient basis.

Since this trial was designed to test a new treatmentmodality, only patients with locally advanced primary,recurrent, metastatic, or refractory disease were included.This was with full knowledge that such a population ofpatients would unfavorably bias response against the

treatment. Although , principal investigators could choosewhether to use hyperthermia alone or in combinationwith radiation therapy and/or chemotherapy based upontheir best clinical judgement, no proven method ofcancer therapy was withheld because of this study.

Patients understood the investigational nature of thetrial, and gave fully informed consen t to participatein

TABLE 9. Response by Tumor Depth and Size

"CR PR MR S P

~ ~ 2 . ~ . ( 9 % i 28 (23%) 26 (21%) 35 (28%)-49 (6%) 125 (17%) 274 (36%) 238 (31%)

Depth ..-~ [ ~Superficial , ~ , 11 (9%)Deep - - 70 (9%)

Size-5 cm 36 (7%) 95 (18%) 64 (12%) 177 (34%) 146, (28%)

CR: com plete regression: PR: partial reg~ression: MR: minimum regression: S: stabilization; P: progression.

TAB LE 10. Response by Treatment Type

Treatment type CR PR MR S P

Heat alone n = 142 4 (3%) 16 (11%) 12 (9%) 27 (19%) 83 (58%)Heat + STD XRT n = 227 48 (21%) 53 (23%) 36 (16%) 71 (31%) 19Heat +


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2684 CANCERJune 1 1985 Vo k 5 5

TABLE I 1. Response by Minimum Tumor Temperature

Minimum temp C CR PR MR S P


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tutional status (pain and activity), with no new lesionsin the treated field, may be an important criteria ofresponse to hyperthermia. It is recognized that somepatients with advanced cancer treated with radiationtherapy or chemotherapy do not respond, even thoughtheir tumor growth seem s to stabilize, either because of

decreased growth as the tumor increases in volumealonK.~v~e Gompertzian curve or for other unknownreasons. However, in contrast, the patients reported inthis study who had temporary disease stabilization sub-sequently did demonstrate tumor growth and]or a sig-nificant decline in constitutional status, indicating that

-their tumors were still in th~)ogarithm ic phase of tumorgrowth) T hus, the313 (33%) incidences of disease sta-bilization, for l~ to 32 months (median, 3 months)probably elobs not reflect a placebo effect, and m ay beclinically important when using hyperthermia.

The 30% incidence of improvement in pain and 21 %improvement in activity (Table 6) were also gratifying,particularly considering that 74% of the patients withpain required narcotics and 60% of the patients withrestricted activity had a Karnofsk y status of 50 to 60 orless. Interestingly, despite continued tum or progressionand lack of an objective tumor response to treatment,49 of 287 (17%) such patients with pain and 23 of 290(8%) such patients with restricted activity also hadimprovement in sym ptoms. The reason for this surprisingsubjective response in the absence of objective tumorregression or stabilization is unknown.

Table 7 shows the response to treatment by tumorhistologic type. Tumor regressions were observed in all

major tumor types: adenocarcinoma (35% ), epidermoidcarcinoma (59%), sarcoma (31%), melanoma (31%),lymphoma (20%), and other solid tumors (40%). Epi-dermoid carcinoma seem ed to be particularly responsiveto treatment. The overall response to treatment wasindependent of the location of the tumor within thebody, as well as the depth or size of the lesion (Tables8 and 9). This was probably due more to the heatdelivery system employed than to the specific character-istics of the tumor site or to the tumor dimension. Twoof the authors (J.D.K. and E.F.S.) recently reported anaverage temperature of 43.9C using this heating systemfor tumors of the pancreas,~2 the most centrally located

organ evaluated to date.Overall response varied by the type of treatment

employed (Table 10). With h eat alone, there were 32 of142 (.23% ) tumor regressions; the response to combinedstandard-dose radiation therapy or chemotherapy was137 of 227 (60%) and 55 of 194 (28%), respectively.Even more significantly, subsequent tumor regressionoccurred in 35 of 90 (39%) patients treated with heat

TAB LE 1 3. Treatment Toxicity

Toxicity Incidence

LocalFirst-degree burn 17Second-degree burn 26 49/14,807 (0.3%)Third-degree burn 6

SystemicPeptic ulcer 1 2/14,807 (0.01%)Lung fibrosis 1

Deaths (treatment-related) 0/14,807 (0%)

combined w ith less-than-standard-dose radiation therapyafter they failed standard-dose radiation alone, and in40 of 21 1 (19% ) patients who were secondarily treatedwith combination thermochemotherap~-after docu-mented disease progression, o~ "th~tt S~rfi~ chemothera-peutic agent(s) alone. These results i~icate ibmt" hyper-thermia may be a useful clinicgl adjuvant to radiationtherapy and chemotherapy where a syuergistic or additiveresponse has been predicted.34 Unfortu~l~ely, the resultsof this Phase 1-11 study do not shed further light on themechanism(s) of interaction of these treatment modali-ties. Moreover, since patients received a variety of thecommonly em ployed chemotherapeutic agents most ap-propriate for their disease, including single drug andcombinations of doxorubicin, cisplatin, bleomycin, ni-trosoureas, 5-fluorouracil, cytoxan, low- and high-dosemethotrexate, mitom ycin C, velban, vincristine, imidizo,lp:carboximide, phenylalanine mustard, and others, ad-

ministered by various oral (PO), intravenous (IV), andintra-arterial (IA) routes in many different types oftumors, no specific conclusions could be drawn regardingthe efficacy of any specific thermochemotherapy regimen.

As previously predicted in a large number ofin vitro,in vivo,and pilot clinical investigations, ~~9 tumor re-sponse correlated with the minimum tumor temperatureachieved (Table 11). At 40 to 45C, the overall incidenceof tumor regression ranged from about 40% to 50%.There seemed to be a break in response at 46C andabove, with more than 80% tumor regression at suchhigh temperatures. Most interestingly, an unexpectedand significant incidence of tumor regression was ob-

served at minimum tumor temperatures of less than40C (Tables 11 and 12). Analyzing this group separately,less than 40C alone resulted in 2 of 16 (13%) tumorregressions, less than 40C heat plus radiation therapyresulted in 19 of 46 (41%) regressions, less than 40Cheat plus chemotherapy resulted in 3 of 17 (18%)regressions, and less than 40C heat plus radiationtherapy and chemotherapy resulted in 4 of 12 (33%)


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2686 CANCER

regressions. Thus, hyperthermia treatment should notbe abandoned based upon some preconceived desirabletumor temperature, since clinical responses may occur

at quite low temperatures.Tumor response was evaluated by both the type oftreatment employed and the minimum tumor temper-ature achieved (Table, 12). These results show thatalthough hyperthermia alone may be beneficial (partic-ularly in the rare incidences of superheating), mostfavorable responses occurred when localized hyperther-mia was combined with radiation therapy or chemo-therapy.

Of special importance is the fact that combinationlocalized hyperthermia treatment was so well toleratedby these sick patients with such advanced disease. Table13 shows the rare treatment-related complications. Sig-

nificant surface-tissue injury occurred in only six (0.04% )patients, and systemic injuries in two (0.01%). Bothsystemic injuries occurred in patients receiving com binedthermoradiotherapy: After l month of treatment, onepatient developed a peptic ulcer that healed withoutsequellae after discontinuing treatment; 9 months aftertreatment, one patient with a lung tumor manifestedareas of lung fibrosis considered more sev ere than thatexpected from radiation therapy alone. In the 14,807treatments administered at nine institutions, there wereno treatment-related deaths. However, it should beemphasized that although all of the patients in this trialhad ad vanced or refractory cancer, this study group wasa selected population based upon knownpotentiallypredictable side effects of h eat therapy in certain situa-tions. For ex~t~ple, patients with any of the followingconditions werenot treated: (l) circulatory compromisein the treatment field with impaired or damag ed normaltissue ,~va~regulafion, and a reduced capacity to augmentblood~10w and~dissiI~ate hbat that could result in normaltissue injury (incl~dihg extensive surgical scarring,brawny edema, vascular disease, radiation fibrosis, andsplit-thickness or pedicle skin grafts); (2) significanttumor fistulae communicating with the aerodigestivetract, where massive tumor necrosis could potentially

result in fistula enlargement or increased infection; (3)impaired tissue sensation from disease, heavy sedation,or anesthesia, since burns could occur without patientawareness; and (4) cardiac pacemak ers or large ferrous(iron-containing) metal prostheses i.e., total joints, fem-oral rods, etc.). This study, however, confirmed thatnonferrous metals in the field of treatment, includingcommonly employed small internal surgical vascularclips and implantable chemotherapy infusion pumps e.g., Infusaid, Infusaid Corp., Norwood, M A) could besafely treated.

June 1 1985 Vo

It should also be understood that the principal inves-tigators participating in this study were highly trainedin the application of hyp erthermia using thi~ heat d

system. Whether the low toxicity observed in thican occur with other hyperthermia delivery systeunknown. ~,

This Phase I-II trial clearly indicates that localizedhyperthermia has a role in the palliative treatment ofhuman advanced solid cancer, particularly when com-bined with radiation therapy or chemotherapy. In suchpatients, hyperthermia treatment with this techniqueshould no longer be considered investigational. Hosince this treatment modality is not as yet known to becurative, and as responses have generally been temp(range, 1-39 months; median, 3-7 months), localizedhyperthermia should not be used in place of estabpotentially curative methods of cancer therai~y. over, although implied by these results, it remains to bedetermined in a prospective randomized Phase III trialwhether localized hyperthermia in combination withradiation therapy or chemotherapy is more effectivethan these mo dalities alone. The ou tcome of this institutional national cooperative Phase I-II study nowwarrants such com parative treatment .ffials, as thmoricidal effects of localized hy perth~rmia appeand potentially important in the palliative treatment ofhuman solid cancer.

ConclusionsLocalized hyperthermia alone or in combinatio

radiation therapy or chemotherapy was administe1170 patients during 14,807 treatments at nine institu-tions in a national cooperative trial. In the study popu-lation, comprised of patients with advanced primary,recurrent, metastatic, or refractory solid cancer, themajority of whom had failed one or mo re prior theof 960 evaluable patients, the overall response wascomplete regression in 85 (9%), partia.I regreksion (18%), minimal regression in 9,5~ (10%), arid growthstabilization in 313 (33~o.). Tumor response occurred

from 1 to 39 months (median, 3-7 months) and wasassociated with improvement in pain and abtivity in asignificant number of patients. Tumor regressionsmore frequent with combination thermoradiotherthermochemotherapy than with hyperth~rnrf~i alone.Moreover, a significant number of tumor regressionswere observed at low temperatures (


11/11

11MAGNETIC-INDUCTION HYPERTHERMIAStorm el al. 2687

This Phase I-II trial shows that localized hyperthermiang the Magnetrode System Hyperthermia Device isand palliative in a substantial number of patients

th advanced cancer. W hether this form of treatmentquivalent to or better than other forms of palliativeapy was not the object of the study. However, the

erall result of this trial indicates that localized hyper-ermia using-this heat delivery system should no longerregarded as investigational, and that Phase 111 trials

e now warranted.

REFERENCgS

1. Storm FK, ed. Hyperthcrmia in Cancer Therapy. Bbston: GKll, ~983.2. Storm FK,Harrison ~WH, Elliott RS, Morton DL. Normal tissued solid tumor effects of hyperthermia in animal models and clinicalls. Cancer Res1979; 39:2245-2251.3. Kim JH, Antich P, Ahmed S, Hahn EW. Clinical experienceth radiofrequency hyperthermia.J Microwave Power1981; 16:193-4.

4. Overgaard J. Influence of sequence and interval on the biologicresponse to combined hyperthermia and radiation.Natl Cancer lnstMonogr1982; 61:325-332.

5. Hahn G. Potential for therapy for drugs and hyperthermia.Cancer Res1979; 39:2264-2268.

6. M armor JB. Interaetions of hyperthermia and chemotherapy inanimals. Cancer Res1979; 39:2269-2276.

7. Storm FK, Harrison WH, Ellion RS, Morton DL. Clinical RFhyperthermia: A new approach to cancer therapy. IEEE TransM771982; 30:1149-1158.

8. Hahn GM, ed. Hyperthermia and Cancer. New York: PlenumPress, 1982.

9. Hornbeck N, ed. Hyperthermia and Cancer: Human ClinicalTrial Experiences. Boca Raton, Horida: CRC Press, 1983.

10. Olch AJ, Kaiser LR, Silberman AW, Storm FK, Graham LS,Morton DL. Blood flow in human tumors during hyperthermiathera v: Dem onstration of vasoregulatio.~ and an applicable physiolog-ical ~:lel. J Surg Oncol1983; 23:125-" 132.

11. Parks LC, Smith GV. Systemic hyl~erthermia by extracorporialinduction: Techniques and results. In: Storm FK, ed. Hyper~hermia in.Cancer Therapy. Boston: GK Hall, 1983; 407-446.

12. Khanderkar JD, Scanlon EF, Garces RM, Prasad G, EawrenceGA . A Phase II study with radiofrequency hyperthermia,.radiation,and chemotherapy in carcinomas of the pafidr~as and- stomach (A bslr615). Proc Am Assoc Cancer Res1983:24:155.

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