CAGLIARI – 23/24 giugno 2005
CHEMIO-IPERTERMIA:
primi risultati clinici su 100
casi con lesioni epatiche
avanzate
GIAMMARIA FIORENTINI,
DIPARTIMENTO ONCOLOGICO
OSPEDALE S.GIUSEPPE – ANTICA SEDE
EMPOLI (ITALY)
Hyperthermia effects summary
Direct heat-necrosis (relatively high temperatures)
Blood-perfusion decrease in tumors, hypoxia
Blood-perfusion increase in healthy tissue
ATP decrease in cells, energy deprivation
Lactic acid forming, acidosis
Radio- and chemo-sensitizing, synergy
Suppressing the adoption mechanisms
HSP membrane expression, gain of the
apoptotic signal
Micro-embolization, angiogenetic block
Developing lactic acid (acidosis)
pH
Decreasing ATP
ATP/CELL (M)
Temp. Change (°C)
Relative change in blood flow
Decreasing blood perfusion
Temperature
(°C)
Angio-block by electro
hyperthermia
University Witter-Herdecker, Dr. Sahimbas
May 22, 2000
May 24, 2000
May 25, 2000
+
Membrane shielding
for electric field
4-5 nm, 50-90 mV
[ 1*107 - 9*107 V/m ]
Cell-membrane
cell (2- 10
+
m)
Cell-membrane
E
[ 500 V/m = 5 V/cm  5 mV/cell ]
Cell membrane “encapsulation”
Selective conduction behavior
Extracellular heating
Extra-cellular
liquid
(conducts current)
Intra-cellular
liquid
(“encapsulated”
electrolyte)
current
current
Healthy tissue
Characteristically 2-8 m
Current lines
Tumor heating
Conductivity of tumor-tissue is
considerable higher
Tumor tissue
Self-focusing
Healthy tissue
Polarizing energy absorption
disordered
Conductivity of tumor-tissue is
considerable higher
Current lines
ordered
Tumor tissue
Good absorption
No absorption
Patient-like
dielectrics
Tumor-like
dielectrics
External field
Complex
impedance
selects
et
Active
electrode
e
Passive
Condenser arrangement
electrode
Electro-hyperthermia effects
120.00
Tumor-cell activity [%]
100.00
80.00
60.00
no electrohyperthermia no chemo
40.00
CDDP alone
electrohyperthemia alone no chemo
CDDP with electrohyperthermia
20.00
0.00
0.00
2.00
4.00
6.00
8.00
10.00
time [h]
12.00
14.00
16.00
18.00
EHY action
Increasing radio-sensitivity
Survival
1.0
10-1
radiation only
10-2
Rad.+ heat
10-3
Heat + rad.
10-4
0
4
Dose (Gy)
8
12
Indice Terapeutico dei tumori
CHEMIO
Cell. ossigenate +++
Cell. ipossiche
+
Endotelio vasi
+
Stroma
+
Microcircolo
SCORE
6+
RADIO
+++
++
+
+
7+
HT
+
+++
++
+
++
9+
IPERTERMIA DIELETTRICA
SECONDO LE VEEN
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
SECONDO LE VEEN 2
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
SECONDO LE VEEN 3
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
SECONDO LE VEEN 4
Gli elettrodi sono modificati mediante serpentina di
rame o sacche di plastica raffreddate con
circolazione ad acqua.
Questo accorgimento permette di elevare del 2030% 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)
COMPARISON OF RT ALONE WITH RT PLUS
HYPERTHERMIA IN PELVIC TUMORS: A
PROSPECTIVE, RANDOMIZED,
MULTICENTRE TRIAL
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
METHODS
358 pts included in a
prospective randomized trial
from 1990 to 1996.
Bladder ca. stages T2, T3 or T4
N0 M0
Cervical ca. FIGO IIB, IIIB, IV
Rectal ca. stages M0 – 1
METHODS 2
Pts randomly assigned to RT
alone (n=176) or RT plus
Hyperthermia (n=182).
Primary endpoints: complete
response and duration to local
control.
FINDINGS
CR rates were 39% after RT
and 55% after RT plus
Hyperthermia (p<0.001).
The duration of local control
was longer with RT+HT than
with RT alone (p=0.04)
FINDINGS 2
The addition of HT seemed to be
most important for cervical ca., for
wich CR rate with RT+ HT was
83% compared with 57% after RT
alone (p=0.003).
3-year overall survival was 27% in
RT group and 51% in RT+HT
group.
INTERPRETATION
HT in addition to RT may be useful in
advanced cervical tumors.
In our istitutions RT+HT is now the
treatment of choice in cervical ca. FIGO
stage IIB-IVA.
For the other tumor sites, evidence is
required from trials with more patients
before practical recommendations can be
made
Electro-Hyperthermia
Therapy
EHY
Treating area:
Invasivity:
REGIONAL (Deep seated tumors)
NON-INVASIVE
MATHERIALS AND
METHODS
•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 SELECTION
112 pts proposed with liver metastases
from colo-rectal cancer and hepatoca.
12 excluded for:
4 far advanced disease
4 body conformation and obesity
3 cardiac pace makers
1 implanted electronic pump
PATIENTS SELECTION 2
78 pts with liver metastases from colo-rectal
cancer: stage II/III (30/48) Pettavel
classification.
All pts treated with at least 3 lines of chemo
66 received also RFA
52 underwent surgical excision
22 pts with hepatoca: 22 Child C., Okuda stage
II/III (15/7)
PATIENTS SELECTION 3
22 pts with hepatoca: 22 Child C., Okuda stage
II/III (15/7)
All pts treated with different chemotherapy
18 received RFA
8 underwent surgical excision
RESULTS AND TOXICITY
Liver metastases from CRC:
2 CR, 11 PR, 13 RR = 16.6%
20 SD = 25.6%
TTP = 14 (5 – 22) wks
ST = 20 (16 – 33) wks
39 PD = 50%
ST = 12 (4 – 16) wks
Better QoL = 48 (61.5%)
RESULTS AND TOXICITY 2
Hepato Cellular Carcinoma:
2 CR, 6 PR, 8 RR = 36.4%
4 SD = 18.2%
TTP = 18 (7 – 36) wks
ST = 27 (9 – 41) wks
10 PD = 45.4%
ST = 16 (5 – 21) wks
Better QoL = 16 (68.2%)
RESULTS AND TOXICITY 3
•SKIN BURNS: 2 CASES
•LOCAL PAIN/RUSH/OEDEMA: 4/3/1
CASES
•NEUROPATHY G 2-3: 6 CASES
•MYELOSOPPRESSION G 2: 8 CASES
•NEFROPATHY G 3: 2 CASES
•CHANGE OF BEHAVIOUR: 1 CASE
•ALOPECIA: 1 CASE
CONCLUSIONS
1. Evidence of responses in pretreated
pts
2. Increase of QoL also in pts without
response
3. Good compliance
4. Feasibility on out patient clinic basis
5. Low cost treatment
6. Low toxicity
Pain-reduction, higher life quality
70
60
50
%
40
3 month after
treatment (%)
30
20
Before treatment (%)
10
0
No pain
Moderate pain
Severe pain
HCC vg PR lasting 24 weeks
Metastases from CRC:
CR lasting 20 weeks
Metastases from CRC:
CR lasting 24 weeks
DEEP ELECTROHYPERTHERMIA WITH
RADIOFREQUENCIES
COMBINED WITH
THERMO-ACTIVE DRUGS
IN PATIENTS WITH
LIVER METASTASES
FROM COLORECTAL
CANCER:
VERY GOOD PR
(lasted 11 months)
Only 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
• COMPLETE RESPONSE: 4.2%
• PARTIAL RESPONSE:
11.1%
• MAJOR RESPONSE:
15.3%
• MINOR RESPONSE:
12.5%
• STABLE DISEASE:
8.3%
• OVERAL RESPONSE:
36.1%
TREATMENT RESULTS OF THE FIRST 72 PATIENTS TREATED BY
DR. J. BRENNER, Telhashomer Hosp. Israel, (1997-1999)
Glioblastoma
Diagnosis: Glioblastoma
Male, 64 years, unable to walk, aphasia
Treatment: Local hyperthermia + ACNU 3 x 50 mg every 5 weeks
before treatment
after treatment
after 3 cycles of treatment patient walks again, speaks fluently
(gently from Dr.A.Herzog, Benediktusquelle)
JAN. ‘04
APR. ‘04
ASTROCYTOMA relapsed
(vg PR confirmed at 14 months)
JAN. ‘04
APR. ‘04
ASTROCYTOMA relapsed
(vg PR confirmed at 14 months)
Nodes relapsed from sarcoma:
march 2004 sept. 2004
liver and nodes metastases from
paraganglioma: vgPR lasting 28
wks
Internal mammary relapse :
before and after IPHT
( march – august 2004)
Hyperthermia conclusions 1
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
Pain reduction, improving life quality
Warrant further well planned studies.
Hyperthermia conclusions 2
ESHO
European Society Hyperthermia Oncology
SITILO
Società Italiana Terapie Integrate Locoregionali
in Oncologia
AIRO
Associazione Italiana Radioterapia Oncologica
ICHS
International Clinical Hyperthermia Society
International Clinical
Hyperthermia Society
XXVII ICHS
CONFERENCE
FLORENCE
27/28 Oct.
2005