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CAGLIARI – 23/24 giugno 2005 CHEMIO-IPERTERMIA: primi risultati clinici su 100 casi con lesioni 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 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

RELATIVE SURVIVAL Developing lactic acid (acidosis) p. H RELATIVE SURVIVAL Developing lactic acid (acidosis) p. H

SURVIVING FRACTION Decreasing ATP/CELL (M) SURVIVING FRACTION Decreasing ATP/CELL (M)

Temp. Change (°C) Relative change in blood flow Decreasing blood perfusion Temperature (°C) 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 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 m. V [ + Membrane shielding for electric field 4 -5 nm, 50 -90 m. V [ 1*107 - 9*107 V/m ] Cell-membrane cell (2 - 10 + m) Cell-membrane E [ 500 V/m = 5 V/cm 5 m. V/cell ] Cell membrane “encapsulation”

Selective conduction behavior Extracellular heating Healthy tissue Current lines Tumor heating Conductivity of tumor-tissue Selective conduction behavior Extracellular heating Healthy tissue 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 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 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 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. 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 + 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 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 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 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 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, COMPARISON OF RT ALONE WITH RT PLUS HYPERTHERMIA IN PELVIC TUMORS: A PROSPECTIVE, RANDOMIZED, MULTICENTRE TRIAL Jacoba van der Zee, Dionisio 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 METHODS 358 pts included in a prospective randomized trial from 1990 to 1996. Bladder ca. stages T 2, T 3 or T 4 N 0 M 0 Cervical ca. FIGO IIB, IV Rectal ca. stages M 0 – 1

METHODS 2 Pts randomly assigned to RT alone (n=176) or RT plus Hyperthermia (n=182). 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. 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. 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 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 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 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 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) 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 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 = 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 Qo. L = 48 (61. 5%)

RESULTS AND TOXICITY 2 Hepato Cellular Carcinoma: 2 CR, 6 PR, 8 RR = 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 Qo. L = 16 (68. 2%)

RESULTS AND TOXICITY 3 • SKIN BURNS: 2 CASES • LOCAL PAIN/RUSH/OEDEMA: 4/3/1 CASES 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 Qo. L also CONCLUSIONS 1. Evidence of responses in pretreated pts 2. Increase of Qo. L 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 (%) 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 HCC vg PR lasting 24 weeks

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

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

DEEP ELECTROHYPERTHERMIA WITH RADIOFREQUENCIES COMBINED WITH THERMO-ACTIVE DRUGS IN PATIENTS WITH LIVER METASTASES FROM 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 Only EHY for hopeless cases 72 PATIENTS PROGRESSED AFTER CONVENTIONAL MEDICINE NONE OF THE PATIENTS HAD OTHERAPIES 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 + Glioblastoma Diagnosis: Glioblastoma Male, 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)

JAN. ‘ 04 APR. ‘ 04 ASTROCYTOMA relapsed (vg PR confirmed at 14 months) JAN. ‘ 04 APR. ‘ 04 ASTROCYTOMA relapsed (vg PR confirmed at 14 months)

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 Nodes relapsed from sarcoma: march 2004 sept. 2004

liver and nodes metastases from paraganglioma: vg. PR lasting 28 wks liver and nodes metastases from paraganglioma: vg. PR lasting 28 wks

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

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