3. GIAMMARIA FIORENTINI, DIPARTIMENTO ONCOLOGICO OSPEDALE S.GIUSEPPE – ANTICA SEDE EMPOLI (ITALY) CAGLIARI – 23/24 giugno 2005 CHEMIO-IPERTERMIA: primi risultati clinici su 100 casi con lesioni epatiche avanzate

4. 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 summary Micro-embolization, angiogenetic block HSP membrane expression, gain of the apoptotic signal

5. pH RELATIVE SURVIVAL Developing lactic acid (acidosis)

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

7. Temperature (°C) Relative change in blood flow Temp. Change (°C) Decreasing blood perfusion

8. University Witter-Herdecker, Dr. Sahimbas May 22, 2000May 24, 2000May 25, 2000 Angio-block by electro hyperthermia

9. E + [ 500 V/m = 5 V/cm  5 mV/cell ] cell (2- 10  m) 4-5 nm, 50-90 mV [ 1*10 7 - 9*10 7 V/m ] + Cell-membrane Cell membrane “encapsulation” Membrane shielding for electric field

10. Extracellular heating Tumor heating Healthy tissue Tumor tissue Current lines Conductivity of tumor-tissue is considerable higher Selective conduction behavior

11. Polarizing energy absorption disorderedordered Good absorptionNo absorption External field  tttt Condenser arrangement Patient-like dielectrics Tumor-like dielectrics Active electrode Passive electrode Healthy tissue Tumor tissue Current lines Conductivity of tumor-tissue is considerable higher Complex impedance selectsSelf-focusing

12. 0.00 20.00 40.00 60.00 80.00 100.00 120.00 0.002.004.006.008.0010.0012.0014.0016.00 18.00 time [h] no electrohyperthermia no chemo CDDP alone electrohyperthemia alone no chemo CDDP with electrohyperthermia Tumor-cell activity [%] Electro-hyperthermia effects

13. 1.0 10 -1 10 -2 10 -3 10 -4 0 4812 radiation only Rad.+ heat Heat + rad. Survival Dose (Gy) EHY action Increasing radio-sensitivity

14. Indice Terapeutico dei tumori CHEMIO RADIO HT Cell. ossigenate +++ +++ + Cell. ipossiche + - +++ Endotelio vasi + ++ ++ Stroma + + + Microcircolo - + ++ SCORE 6+ 7+ 9+

15. 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

16. 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 2

17. 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 3

18. 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 SECONDO LE VEEN 4

19. 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 HYPERTHERMIA IN PELVIC TUMORS: A PROSPECTIVE, RANDOMIZED, MULTICENTRE TRIAL

20. 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

21. 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.

22. 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)

23. 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.

24. 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

25. EHY NON-INVASIVE Treating area: REGIONAL (Deep seated tumors) Invasivity: Electro-Hyperthermia Therapy

28. 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

29. PATIENTS SELECTION 112 112 pts proposed with liver metastases from colo-rectal cancer and hepatoca. 12 12 excluded for: 4 far advanced disease 4 body conformation and obesity 3 cardiac pace makers 1 implanted electronic pump

30. PATIENTS SELECTION 2 78 78 pts with liver metastases from colo-rectal cancer: stage II/III (30/48) Pettavel classification. All All pts treated with at least 3 lines of chemo 66 66 received also RFA 52 52 underwent surgical excision 2222 22 pts with hepatoca: 22 Child C., Okuda stage II/III (15/7)

31. PATIENTS SELECTION 3 22 pts with hepatoca: 22 Child C., Okuda stage II/III (15/7) All All pts treated with different chemotherapy 18 received RFA 8 underwent surgical excision

32. 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%)

33. 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% 10 PD = 45.4% ST = 16 (5 – 21) wks Better QoL = 16 (68.2%)

34. RESULTS AND TOXICITY 3 SKIN BURNS: 2 CASESSKIN BURNS: 2 CASES LOCAL PAIN/RUSH/OEDEMA: 4/3/1 CASESLOCAL PAIN/RUSH/OEDEMA: 4/3/1 CASES NEUROPATHY G 2-3: 6 CASESNEUROPATHY G 2-3: 6 CASES MYELOSOPPRESSION G 2: 8 CASESMYELOSOPPRESSION 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

35. 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

36. No pain Before treatment (%) 0 10 20 30 40 50 60 70 % Moderate painSevere pain 3 month after treatment (%) Pain-reduction, higher life quality

37. HCC vg PR lasting 24 weeks

38. Metastases from CRC: CR lasting 20 weeks

39. Metastases from CRC: CR lasting 24 weeks

40. DEEP ELECTRO- HYPERTHERMIA WITH RADIOFREQUENCIES COMBINED WITH THERMO-ACTIVE DRUGS IN PATIENTS WITH LIVER METASTASES FROM COLORECTAL CANCER: VERY GOOD PR (lasted 11 months)

41. 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: 12.5% MINOR RESPONSE: 12.5% STABLE DISEASE: 8.3% STABLE DISEASE: 8.3% OVERAL RESPONSE: 36.1% OVERAL RESPONSE: 36.1% 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

42. 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) after treatment Glioblastoma

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

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

45. Nodes relapsed from sarcoma: march 2004 sept. 2004

46. liver and nodes metastases from paraganglioma: vgPR lasting 28 wks

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

48. 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 1 Pain reduction, improving life quality Warrant further well planned studies.

49. Hyperthermia conclusions 2 ESHO European Society Hyperthermia OncologySITILO Società Italiana Terapie Integrate Locoregionali in OncologiaAIRO Associazione Italiana Radioterapia OncologicaICHS International Clinical Hyperthermia Society

50. XXVII ICHS XXVII ICHSCONFERENCE FLORENCE 27/28 Oct. 2005 Mark on your calendar!!!