GIAMMARIA FIORENTINI,

DIPARTIMENTO ONCOLOGICO

OSPEDALE S.GIUSEPPE – ANTICA SEDE

EMPOLI (ITALY)

CAGLIARI – 23/24 giugno 2005CAGLIARI – 23/24 giugno 2005

CHEMIO-IPERTERMIA: CHEMIO-IPERTERMIA: primi risultati clinici su primi risultati clinici su

100 casi con lesioni 100 casi con lesioni epatiche avanzateepatiche avanzate

Direct heat-necrosis (relatively high temperatures)

ATP decrease in cells, energy deprivation

Lactic acid forming, acidosis

Blood-perfusion decrease in tumors, hypoxia

Radio- and chemo-sensitizing, synergy

Suppressing the adoption mechanisms

Blood-perfusion increase in healthy tissue

Hyperthermia effects summaryHyperthermia effects summary

Micro-embolization, angiogenetic block

HSP membrane expression, gain of the apoptotic signal

pHR

EL

AT

IVE

SU

RV

IVA

L

Developing lactic acid (acidosis) Developing lactic acid (acidosis)

ATP/CELL (M)S

UR

VIV

ING

FR

AC

TIO

N

Decreasing ATPDecreasing ATP

Temperature (°C)

Rel

ativ

e ch

ange

in b

lood

flo

w

Tem

p. C

hang

e (°

C)

Decreasing blood perfusionDecreasing blood perfusion

University Witter-Herdecker, Dr. Sahimbas

May 22, 2000 May 24, 2000 May 25, 2000

Angio-block by electro Angio-block by electro hyperthermiahyperthermia

E

+

[ 500 V/m = 5 V/cm 5 mV/cell ]

cell (2- 10 m)

4-5 nm, 50-90 mV [ 1*107 - 9*107 V/m ]

+

Cell-membrane

Cell-membrane

Cell membrane “encapsulation”

Membrane shielding Membrane shielding for electric fieldfor electric field

Extra-cellularliquid

(conducts current)Intra-cellular

liquid(“encapsulated”

electrolyte)

Characteristically 2-8 m

current current

Extracellular heating

Tumor heating

Healthy tissue

Tumor tissue

Current lines

Conductivity of tumor-tissue is considerable higher

Selective conduction Selective conduction behaviorbehavior

Polarizing energy absorption

disordered ordered

Good absorption No absorption

External field

tt

Condenser arrangement

Patient-like dielectricsTumor-like

dielectrics

Active electrode Passive

electrode

Healthy tissue

Tumor tissue

Current lines

Conductivity of tumor-tissue is considerable higher

Complex impedance

selects

Self-focusingSelf-focusing

0.00

20.00

40.00

60.00

80.00

100.00

120.00

0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00time [h]

no electrohyperthermia no chemo

CDDP alone

electrohyperthemia alone no chemo

CDDP with electrohyperthermia

Tu

mor

-cel

l act

ivit

y [%

]

Electro-hyperthermia effectsElectro-hyperthermia effects

1.0

10-1

10-2

10-3

10-40 4 8 12

radiation only

Rad.+ heat

Heat + rad.

Sur

viva

l

Dose (Gy)

EHY action EHY action Increasing radio-sensitivity Increasing radio-sensitivity

Indice Terapeutico dei tumoriIndice Terapeutico dei tumori

CHEMIO CHEMIO RADIORADIO HTHT

Cell. ossigenate +++ +++ +

Cell. ipossiche + - +++

Endotelio vasi + ++ ++

Stroma + + +

Microcircolo - + ++

SCORE 6+ 7+ 9+

Un generatore di radiofrequenze a 13.56 Mhz produce ipertermia selettiva dei

tumori profondi fra i 46 e i 50°C mentre la T° dei tessuti sani rimane 40°C. le

frequenze vengono inviate all’organismo mediante applicatori e piastre parallele applicate sulla cute.

IPERTERMIA DIELETTRICA IPERTERMIA DIELETTRICA SECONDO LE VEENSECONDO LE VEEN

Il fascio di radiofrequenza è perpendicolare alla superficie dell’elettrodo/applicatore.

Il tessuto adiposo,muscolare, osseo e tumorale si riscaldano diversamente a seconda del contenuto in acqua, sali

minerali e intrinseche proprietà elettriche e vascolari del tessuto.

IPERTERMIA DIELETTRICA IPERTERMIA DIELETTRICA SECONDO LE VEEN 2SECONDO LE VEEN 2

La penetrazione del fascio si correla alla superficie cutanea riscaldata:

Più questa è ampia più in profondità giunge il fascio.

Collegando il generatore ad un amplificatore della potenza di 1 Kilowatt si raggiunge

una profondità maggiore.

IPERTERMIA DIELETTRICA IPERTERMIA DIELETTRICA SECONDO LE VEEN 3SECONDO LE VEEN 3

Gli elettrodi sono modificati mediante serpentina di rame o sacche di plastica raffreddate con circolazione ad

acqua.Questo accorgimento permette di elevare del 20-30%

l’emissione del generatore con innalzamento della T° nei tessuti sottostanti lo strato adiposo evitando ustioni.

L’energia necessaria alla distruzione cellulare per azione diretta del calore è di 120-145 Kcal/mole.

In associazione con farmaci e/o radioterapia questa energia si riduce a 20-40 kcal/mole (TER: Thermal

Enhancenment Ratio)

IPERTERMIA DIELETTRICA IPERTERMIA DIELETTRICA SECONDO LE VEEN 4SECONDO LE VEEN 4

Jacoba van der Zee, Dionisio Gonzalez Gonzalez, Gerard C van Rhoon, Jan D P van Dijk, Wim L J van Putten, Augustinus A M Hart.

On behalf of the Dutch Deep Hyperthermia Group

THE LANCET •Vol 355 •April 1, 2000

COMPARISON OF RT ALONE WITH RT PLUS COMPARISON OF RT ALONE WITH RT PLUS HYPERTHERMIA IN PELVIC TUMORS: A HYPERTHERMIA IN PELVIC TUMORS: A

PROSPECTIVE, RANDOMIZED, PROSPECTIVE, RANDOMIZED, MULTICENTRE TRIALMULTICENTRE TRIAL

METHODSMETHODS

358 pts included in a 358 pts included in a prospective randomized trial prospective randomized trial

from 1990 to 1996.from 1990 to 1996.Bladder ca. stages T2, T3 or T4 Bladder ca. stages T2, T3 or T4

N0 M0N0 M0Cervical ca. FIGO IIB, IIIB, IV Cervical ca. FIGO IIB, IIIB, IV

Rectal ca. stages M0 – 1Rectal ca. stages M0 – 1

METHODS 2METHODS 2

Pts randomly assigned to RT Pts randomly assigned to RT alone (n=176) or RT plus alone (n=176) or RT plus Hyperthermia (n=182).Hyperthermia (n=182).

Primary endpoints: complete Primary endpoints: complete response and duration to local response and duration to local

control. control.

FINDINGSFINDINGS

CR rates were 39% after RT CR rates were 39% after RT and 55% after RT plus and 55% after RT plus

Hyperthermia (pHyperthermia (p<0.001).<0.001).The duration of local control The duration of local control was longer with RT+HT than was longer with RT+HT than

with RT alone (p=0.04)with RT alone (p=0.04)

FINDINGS 2FINDINGS 2

The addition of HT seemed to be The addition of HT seemed to be most important for cervical ca., for most important for cervical ca., for wich CR rate with RT+ HT was 83% wich CR rate with RT+ HT was 83% compared with 57% after RT alone compared with 57% after RT alone

(p=0.003).(p=0.003).3-year overall survival was 27% in 3-year overall survival was 27% in

RT group and 51% in RT+HT RT group and 51% in RT+HT group. group.

INTERPRETATIONINTERPRETATION

HT in addition to RT may be useful in HT in addition to RT may be useful in advanced cervical tumors.advanced cervical tumors.

In our istitutions RT+HT is now the In our istitutions RT+HT is now the treatment of choice in cervical ca. FIGO treatment of choice in cervical ca. FIGO

stage IIB-IVA.stage IIB-IVA.For the other tumor sites, evidence is For the other tumor sites, evidence is required from trials with more patients required from trials with more patients

before practical recommendations can be before practical recommendations can be mademade

EHY

NON-INVASIVE

Treating area: REGIONAL (Deep seated tumors)

Invasivity:

Electro-Hyperthermia Electro-Hyperthermia TherapyTherapy

MATHERIALS AND MATHERIALS AND METHODSMETHODS

•Hyperthermia delivered by EHY 2000 machine

•Treating schedule: 60 – 80 minutes for 8 sessions for 2 times

•Energy delivered: 100-120 Watt corresponding to 22000-35000 KJ

every session•CDDP 20-30 mg total dose

administered before HTH on day 1-3-5-7-9 as bolus i.v.

•CT control every 60 days for 3 times

PATIENTS SELECTIONPATIENTS SELECTION

112112 pts proposed with liver metastases from colo-rectal cancer

and hepatoca.

1212 excluded for:4 far advanced disease

4 body conformation and obesity3 cardiac pace makers

1 implanted electronic pump

PATIENTS SELECTION PATIENTS SELECTION 22

78 78 pts with liver metastases from colo-rectal cancer: stage II/III (30/48) Pettavel

classification.

AllAll pts treated with at least 3 lines of chemo

6666 received also RFA

5252 underwent surgical excision

2222 pts with hepatoca: 2222 Child C., Okuda stage II/III (15/7)

PATIENTS SELECTION PATIENTS SELECTION 33

22 pts with hepatoca: 22 Child C., Okuda stage II/III (15/7)

AllAll pts treated with different chemotherapy

18 received RFA 8 underwent surgical excision

RESULTS AND TOXICITYRESULTS AND TOXICITY

Liver metastases from CRC:2 CR, 11 PR, 2 CR, 11 PR, 13 RR = 16.6%13 RR = 16.6%

20 SD = 25.6% 20 SD = 25.6%

TTP = 14 (5 – 22) wksTTP = 14 (5 – 22) wks

ST = 20 (16 – 33) wksST = 20 (16 – 33) wks 39 PD = 50%39 PD = 50%

ST = 12 (4 – 16) wksST = 12 (4 – 16) wks

Better QoL = 48 (61.5%)Better QoL = 48 (61.5%)

RESULTS AND TOXICITY RESULTS AND TOXICITY 22

Hepato Cellular Carcinoma:2 CR, 6 PR, 2 CR, 6 PR, 8 RR = 36.4%8 RR = 36.4%

4 SD = 18.2% 4 SD = 18.2%

TTP = 18 (7 – 36) wksTTP = 18 (7 – 36) wks

ST = 27 (9 – 41) wks ST = 27 (9 – 41) wks

10 PD = 45.4%10 PD = 45.4%

ST = 16 (5 – 21) wksST = 16 (5 – 21) wks

Better QoL = 16 (68.2%)Better QoL = 16 (68.2%)

RESULTS AND TOXICITY RESULTS AND TOXICITY 33

•SKIN BURNS: 2 CASESSKIN BURNS: 2 CASES•LOCAL PAIN/RUSH/OEDEMA: 4/3/1 LOCAL PAIN/RUSH/OEDEMA: 4/3/1

CASESCASES•NEUROPATHY G 2-3: 6 CASESNEUROPATHY G 2-3: 6 CASES

•MYELOSOPPRESSION G 2: 8 CASES MYELOSOPPRESSION G 2: 8 CASES •NEFROPATHY G 3: 2 CASESNEFROPATHY G 3: 2 CASES

•CHANGE OF BEHAVIOUR: 1 CASECHANGE OF BEHAVIOUR: 1 CASE•ALOPECIA: 1 CASEALOPECIA: 1 CASE

CONCLUSIONSCONCLUSIONS

1.1. Evidence of responses in Evidence of responses in pretreated ptspretreated pts

2.2. Increase of QoL also in pts Increase of QoL also in pts without responsewithout response

3.3. Good compliance Good compliance

4.4. Feasibility on out patient clinic Feasibility on out patient clinic basisbasis

5.5. Low cost treatment Low cost treatment

6.6. Low toxicityLow toxicity

No pain

Before treatment (%)

0

10

20

30

40

50

60

70

%

Moderate pain Severe pain

3 month after treatment (%)

Pain-reduction, higher life quality Pain-reduction, higher life quality

HCC vg PR lasting 24 HCC vg PR lasting 24 weeksweeks

Metastases from CRC: Metastases from CRC: CR lasting 20 weeksCR lasting 20 weeks

Metastases from CRC: Metastases from CRC: CR lasting 24 weeksCR lasting 24 weeks

DEEP ELECTRO-DEEP ELECTRO-HYPERTHERMIA WITH HYPERTHERMIA WITH RADIOFREQUENCIES RADIOFREQUENCIES

COMBINED WITH COMBINED WITH THERMO-ACTIVE DRUGS THERMO-ACTIVE DRUGS

IN PATIENTS WITH IN PATIENTS WITH LIVER METASTASES LIVER METASTASES

FROM  COLORECTAL FROM  COLORECTAL CANCER:CANCER:

VERY GOOD PRVERY GOOD PR

(lasted 11 months)(lasted 11 months)

TREATMENT RESULTS OF THE FIRST 72 PATIENTS TREATED BY DR. J. BRENNER, Telhashomer Hosp. Israel, (1997-1999)

• COMPLETE RESPONSE: 4.2%COMPLETE RESPONSE: 4.2%

• PARTIAL RESPONSE: 11.1%PARTIAL RESPONSE: 11.1%

• MAJOR RESPONSE: 15.3% MAJOR RESPONSE: 15.3%

• MINOR RESPONSE:MINOR RESPONSE: 12.5% 12.5%

• STABLE DISEASE:STABLE DISEASE: 8.3% 8.3%

• OVERAL RESPONSE: 36.1%OVERAL RESPONSE: 36.1%

Only EHY for hopeless casesOnly EHY for hopeless cases

72 PATIENTS PROGRESSED AFTER CONVENTIONAL MEDICINE

NONE OF THE PATIENTS HAD OTHER THERAPIES AT THE SAME TIME WITH THE ELECTRO-HYPERTHERMIA

Diagnosis: GlioblastomaMale, 64 years, unable to walk, aphasia

Treatment: Local hyperthermia + ACNU 3 x 50 mg every 5 weeks

before treatment

after 3 cycles of treatment patient walks again, speaks fluently

(gently from Dr.A.Herzog, Benediktusquelle)

after treatment

Glioblastoma

ASTROCYTOMA relapsed(vg PR confirmed at 14 months)

JAN. ‘04 APR. ‘04

JAN. ‘04 APR. ‘04

ASTROCYTOMA relapsed(vg PR confirmed at 14 months)

Nodes relapsed from Nodes relapsed from sarcoma:sarcoma:

march 2004 sept. 2004march 2004 sept. 2004

liver and nodes metastases liver and nodes metastases from paraganglioma: vgPR from paraganglioma: vgPR

lasting 28 wks lasting 28 wks

Internal mammary relapse :Internal mammary relapse :before and after IPHT before and after IPHT ( march – august 2004)( march – august 2004)

The electro-hyperthermia is a new treatment modality for primary and secondary liver tumors

The combination of electro-hypertermia and CDDP is feasible on out-patient basis

HPT permits new applications in palliative fields

The hyperthermia methods are cost-effective

Hyperthermia conclusions 1Hyperthermia conclusions 1

Pain reduction, improving life quality

Warrant further well planned studies.

Hyperthermia conclusions 2Hyperthermia conclusions 2

ESHOESHOEuropean Society Hyperthermia Oncology

SITILOSITILOSocietà Italiana Terapie Integrate Locoregionali

in Oncologia

AIROAIROAssociazione Italiana Radioterapia Oncologica

ICHSICHSInternational Clinical Hyperthermia Society

International Clinical International Clinical Hyperthermia SocietyHyperthermia Society

XXVII ICHSXXVII ICHSCONFERENCECONFERENCE

FLORENCE FLORENCE 27/28 Oct. 27/28 Oct.

20052005Mark on your

Mark on your

calendar!!!

calendar!!!