IPERTERMIA RADIOTERAPIA

1.  IPERTERMIA & RADIOTERAPIA

3. Medical Enterprises Europe B.V.Hyperthermia Treatment in Conjunction With Mitomycin C Versus BCG for Superficial Bladder Cancer National Cancer Institute (NCI)Heat Activated Liposomal Doxorubicin and Radiofrequency Ablation in Treating Patients With Primary or Metastatic Liver Tumors Cancer Institute (NCI) February 2007Continuous Hyperthermic Peritoneal Perfusion With Cisplatin Plus Intraperitoneal Paclitaxel and Fluorouracil Following Surgery in Treating Patients With Peritoneal Cancer National Center for Research Resources (NCRRPhase I/II Trial of Doxil and Hyperthermia for Breast Cancer Patients With Chest Wall Recurrence or Stage IV Disease With Locally Advanced Breast Cancer Ottawa Regional Cancer Centre, Ontario, Canada.Cisplatin, hyperthermia and radiation treatment in human cisplatin-sensitive and resistant glioma cell lines. Cervix Cancer Advanced locoregional carcinoma of the cervix (IIb/III) Presurgical hyperthermic radiochemotherapy (HRCT) followed by a curative resection or, in the nonresectable carcinoma of the cervix, by an upload by brachytherapy; a phase II-study Phase II study of weekly locoregional hyperthermia combined with Cisplatin +/- radia-tion in relapsed carcinoma of the cervix An International Phase III Study of Chemoradiotherapy versus Chemoradiotherapy plus Hyperthermia for Locally Advanced Cervical Cancer Soft Tissue Sarcomas Magnetic resonance based non invasive thermometry for hyperthermia treatment of extremity soft tissue sarcomas Randomized study comparing neoadjuvant chemotherapy (Etoposide plus Ifosfamide plus Adriamycin (EIA)) combined with regional hyperthermia vs. neoadjuvant chemotherapy alone in the treatment of high risk soft tissue sarcoma in adults.

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5. Bronchial Carcinoma Randomized multicentric study of Ifosfamide, Carboplatin and Etoposide versus ICE combined with 41,8°C whole body hyperthermia in advanced non-small-cell lung cancer. Open, randomized, muticentric phase III study of Carboplatin/Etoposide versus Car-boplatin/Etoposide combined with whole body hyperthermia in patients with advanced small-cell lung cancer ("extensive disease") Colon Carcinoma Systemic multimodal cancer therapy (42°C) combined with 5-FU and Mitomycin in metastatic colorectal carcinoma Open, randomized, multicentric phase III trail of Oxaliplatin and 5-Fluorouracil/Leucovorin as second and third line therapy in locally advanced or metas-tatic, nonresectable colorectal carcinoma and documented progression within three months after high dose therapy with 5-Fluorouracil (25h)/Leucovorin (ARDALAN) or CPT-11 containing protocols. Prospective phase I/II study of regional hyperthermia and radiotherapy of hepatic metastases in colorectal carcinoma. Studies on Germ Cell Tumors Systemic multimodal cancer therapy (42°C) combined with ICE (Ifosfamide/ Car-boplatin/ Etoposide) in refractory metastatic germ cell tumors. Extracranial non-testicular malignant germ cell tumors in childhood and adolescenceCancer of the Esophagus Randomized phase III trail of presurgical radiochemotherapy combined with hyperther-mia versus radiochemotherapy alone in squamous epithelium carcinoma of the esopha-gus Head and Neck Tumors Phase II trail of interstitial radiotherapy and hyperthermia in advanced head and neck tumors. Advanced or recurrent lymph node metastases in head and neck carcinomas (combined with radiotherapy) . 

6. Hodgkin`s- and Non-Hodgkin`s-LymphomaClinical phase II study of combined thermo-chemotherapy (whole body hyperthermia plus Melphalan, Ifosfamide, Carboplatin and Etoposide) in primary refractory or recurrent Hodgkin’s and Non-Hodgkin’s-Lymphomas Pancreatic Carcinoma Neoadjuvant chemotherapy with Gemzitabine and Cisplatin combined with regional hy-perthermia in resectable pancreatic carcinoma Phase I-study of Gemzar/Carboplatin and whole body hyperthermia in pancreatic carci-noma Carcinoma of the Prostate Phase I/II study of hyperthermia combined with high-dose external radiotherapy in lo-cally advanced (T3-4pN0Mo) or relapsed (rTXcNOMO) carcinoma of the prostate Prospective randomized study of interstitial radiothermotherapy plus external radiother-apy versus interstitial radiotherapy plus external radiotherapy in local carcinoma of the prostate (T1-T3 pN0 M0)  Carcinoma of the Rectum Randomized study of presurgical hyperthermic radiochemotherapy versus radiochemo-therapy alone in locally advanced as well as relapsed carcinoma of the rectum Randomized phase II/III study of toxicity and effectivity of hyperthermic chemotherapy (Oxaliplatin/Capecitabine) vs chemotherapy alone in local recurrent carcinoma of the rectum after radiotherapy  SarcomaPhase II study of ICE polychemotherapy and whole body hyperthermia in soft tissue sar-comas

7. Razionale Ipertermia Effetti citotossici- Apoptosi (effetto citotossico diretto)- Sinergismo con farmaci e radiazioni- Riduzione del fenomeno di chemio-resistenza  (diffusione tissutale, permeabilità di membrana)

8. Effetti dell‘Ipertermia Molteplici effetti dipendenti da: Temperatura Tempo di esposizione al calore pH & paO2 Associazione con chemioterapici e/o radiazioni

9. Effetti dell‘ipertermia Effetti antiangiogenici nei tessuti tumorali Vasodilatazione nei tessuti normali Cambiamento nella viscosità del sangue Induzione di apoptosi Sensibilizzazione nei confronti di chemio e radioterapia Effetti Immunologici Inibizione della crescita tumorale

10. Interazione tra Ipertermia e Farmaci Citostatici Incrementa la perfusione del tessuto tumorale Incrementa la captazione intracellulare del farmaco Inibizione dei meccanismi di riparazione delle cellule tumorali Incremento sinergico di citotossicità di alcuni chemioterapici

12. Additivo: incrmento lineare della citotossicità con l’incremento della temperatura Ciclofosfmide e composti del platino (da 40° a 43°C) Effetto soglia: nessun effetto citotossico al di sotto di una determinata temperata (42°-43° C) (Antracicline) notevole potenziamento citotossico sopra la temperatura soglia è tipico della Mitomicina Indipendente: l'attività citotossica del farmaco non risulta significativamente influenzata dal variare della temperatura (5-FU, alcaloidi della vinca, Taxani) Termosensibilizzanti: Attività citotossica solo a temperatura elevata (>43° C): Lidocaina, Amfotericina B

13. Sequenza farmaco-ipertermia I dati attuali indicano che i migliori effetti di chemosensibilizzazione si ottengono quando il calore e il farmaco sono somministrati simultaneamente o con breve intervallo intercorrente. Vi sono eccezioni legate al meccanismo d'attivazione del farmaco. Ciclofosfamide/ifosfamide: 1-2 ore prima dell’ipertermia Gemcitabina: entro 24 ore prima dell’ipertermia Sono in corso vari studi per ottimizzare l’approccio farmaco-ipertermia nella pratica clinica

14. Sinergismo con Radiazioni Ionizzanti Ossigenazione:- Radiazioni più efficaci in area ossigenata- Ipertermia più efficace in area ipossica Fase cellulare:- Radiazioni più efficaci in M e G2- Ipertermia più efficace in G2 e S

16. Heat Induction

17. Range di temperatura moderata* (non letale) 39-<41oC Range intermedia (parz.-letale) 41-43oC estrema (letale/necrosi) > 43oC

18. Induction of Heat in Deep Seated Tissue

19. Ipertermia profonda Body

20. Ipertermia profonda a radiofrequenza (RF 13.56 MHz)

22. Studi randomizzati:RT vs RT+HT (I)

23. Studi randomizzati:RT vs RT+HT

24. Studi Randomizzati: RT vs RT+HT (III)

25. MALIGNANT MELANOMA Study design: 24-27 Gy vs 24-27 Gy + 3HT CR 25 vs 62 0.003 OR 72 vs 89 0.02 2yLC 28 vs 46 0.0056 Multivaried analysis: T average max: 0.009 ESHO 3/85 (Overgaard et al., The Lancet, 1996)

26. RECURRENT BREAST CANCER Italian Hyperthermia Group: Multicenter study 1980-1994 ( Genoa, Padoa, Ravenna, Rome, S. Giovanni Rotondo, Trento, Turin) 231 lesions OR -----> 92.5% CR -----> 75% LC -----> 69%

27. RECURRENT BREAST CANCER Multivaried analysis of MRC and ESHO studies: Temperature as indipendent prognostic factor Hyperthermia & radiotherapy is the treatment of choice of recurrent breast cancer in previously irradiated sites… C.C. Vernon et al, Cancer 1997 C.C. Vernon et al, Int. J. Hyp. 1998

28. INOPERABLE PELVIC TUMORS Phase II R study 147 patients 49 rectum 52 cervix 46 bladder Clinical protocol: 50-70 Gy vs 50-70 Gy + 6 HT DKK, 1998

29. INOPERABLE PELVIC TUMORS RT vs RT + HT p CR 37 vs 48 0.01 cervix + 55 78 <0.005 bladder rectum 13 19 ns DKK, 1998

30. SOFT TISSUE SARCOMAS (I) Pts with retroperitonel STS have poor prognosis 1991-1997: 58 pts with HR STS neoadjuvant 4 cycles of ETO-IFO-ADRIA + HT Surgery 4 cycles chemotherapy EBRT Issels RD 2001

31. SOFT TISSUE SARCOMAS (II) OR was 13% after neoadiuvant thermochemotherapy Pathologic response was 42%. At median observation time of 74 months, 5y probabilities were: - Local failure-free: 53% - distant mts free: 51% - overall survival: 32%. OS responding to HT+CT vs non responding were 60 vs 10 (p=0.0014) Issels RD 2001

32. ALL ESHO TRIALS endpoint: CR Radiotherapy vs RT + HT 39 vs 51 p=0.001