IPERTERMIA

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IPERTERMIA RADIOTERAPIA
V. Cerreta, A. Gramaglia, M. Mapelli, GF.
Baronzio, C. Bassetti, A. Ravasio Dipartimento di
Radioterapia Ipertermia e Fisica
Sanitaria Policlinico di Monza
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• EORTC protocol 62961
• Randomized study comparing neoadjuvant
  chemotherapy EtoposideIfosfamideAdriamycin
  (EIA) combined with regional hyperthermia (RHT)
  Vs neoadjuvant chemotherapy alone in the
  treatment of high-risk soft tissue sarcomas in
  adults. An Intergroup study with the European
  Society for hyperthermic oncology.
• European Organization for Research and Treatment
  of Cancer
• Chemotherapy and Bevacizumab With or Without
  Radiofrequency Ablation in Treating Unresectable
  Liver Metastases in Patients With Colorectal
  Cancer
• Chemotherapy With or Without Hyperthermia
  Therapy in Treating Patients With Soft Tissue
  Sarcoma
• Duke University
• Cisplatin and RT With or Without Hyperthermia,
  Cervical Cancer
• Liposomal Doxorubicin and Hyperthermia in
  Treating Women With Locally Recurrent Breast
  Cancer
• Hyperthermia, RT, Surgery, and Optional
  Chemotherapy in Treating Patients With Soft
  Tissue Sarcoma
• The University of Texas Health Science Center,
  Houston
• Cisplatin, Gemcitabine, Interferon Alfa, and
  Hyperthermia in Treating Patients With Advanced
  Cancer
• Hyperthermia With Chemotherapy for Locally
  Advanced or Metastatic Pancreas Cancer
• Hyperthermia With Chemotherapy to Treat
  Inoperable or Metastatic Tumors
• Cisplatin, Metronomic Low-Dose Interferon Alfa,
  Gemcitabine, and Fever-Range Whole-Body
• Hyperthermia in Treating Patients With
  Inoperable or Metastatic Pancreatic Cancer
• Prospective phase I/II study of a combined
  therapy of hyperthermia, chemotherapy with
  Paclitaxel and radiotherapy in advanced bladder
  carcinomaBladder Carcinoma

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• 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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• Malignant MelanomaRegional recurrence of
  malignant melanomaPleural MesotheliomaMulticentri
  c, prospective randomized, clinical phase II
  study of Ifosfamide, Carboplatin, Etoposide (ICE)
  with or without whole body hyperthermia in de
  novo diagnosed pleural mesothelioma of adults
• Ovarian Carcinoma
• Clinical phase II trail of combined
  thermochemotherapy (whole body hyperthermia plus
  Carboplatin/Ifosfamide) in platin-therapy
  refractory or relapsed ovarian cancer.
• Clinical phase II trail to evaluate toxicity and
  effect of thermochemotherapy with
  Mito-mycin/Ifosfamide/Cisplatin (MIC) as a third
  line therapy of second line (MIC-alone)
  pro-gressive ovarian carcinoma
• A randomized phase II/III trial comparing
  Carboplatin-Ifosfamide (IC)-chemotherapy vs.
  IC-chemotherapy combined with extreme whole body
  hyperthermia in patients with recurrence of
  epithelial ovarian carcinoma DOLPHIN-1 Breast
  Cancer
• A Phase I, Dose Escalation and Pharmacokinetics
  Study of Temperature Sensitive Liposome
  Encapsulated- doxorubicin (ThermoDoxTM ) and
  Hyperthermia on Patients with Local Regionally
  Recurrent Breast Cancer
• Chest wall recurrence of breast carcinoma
• Prospective phase I/II study of local
  hyperthermia, Taxol-chemotherapy and
  radiother-apy in nonresectable or incomplete
  resected (R1/R2) breast carcinoma recurrence.
• Prospective phase I/II study of non-invasive
  MRI-guided high-temperature hyperthermia by
  focused ultrasound before surgery of bioptically
  proofed breast carcinoma.

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• Bronchial Carcinoma
• Randomized multicentric study of Ifosfamide,
  Carboplatin and Etoposide versus ICE combined
  with 41,8C whole body hyperthermia in advanced
  non-small-cell lung cancer.
• Open, randomized, muticentric phase III study of
  Carboplatin/Etoposide versus Car-boplatin/Etoposid
  e combined with whole body hyperthermia in
  patients with advanced small-cell lung cancer
  ("extensive disease")
• Colon Carcinoma
• Systemic multimodal cancer therapy (42C)
  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 (42C)
  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)
• .

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• Hodgkins- and Non-Hodgkins-LymphomaClinical
  phase II study of combined thermo-chemotherapy
  (whole body hyperthermia plus Melphalan,
  Ifosfamide, Carboplatin and Etoposide) in primary
  refractory or recurrent Hodgkins and
  Non-Hodgkins-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

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Razionale Ipertermia

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

• Effetti immunologici - Migrazione e attivazione
  di cellule immunocompetenti- (Citochine e Heat
  Shock Protein) - Incrementa lespressione di
  antigeni sulle cellule tumorali

• Effetti Molecolari - Antiangiogenesi

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Effetti dellIpertermia

• Molteplici effetti dipendenti da
• Temperatura
• Tempo di esposizione al calore
• pH paO2
• Associazione con chemioterapici e/o radiazioni

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Effetti dellipertermia

• 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

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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

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Interazione tra Ipertermia e Farmaci Citostatici
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Interazione tra Ipertermia e Farmaci Citostatici

• Additivo incrmento lineare della citotossicità
  con lincremento della temperatura
  Ciclofosfmide
  e composti del platino (da 40 a 43C)
• 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 (gt43 C) Lidocaina,
  Amfotericina B

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Sequenza farmaco-ipertermia
Interazione tra Ipertermia e Farmaci Citostatici

• 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
  dellipertermia
• Gemcitabina entro 24 ore prima dellipertermia
• Sono in corso vari studi per ottimizzare
  lapproccio
• farmaco-ipertermia nella pratica clinica

Hildebrandt H, Oncol Hematol, 2002
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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

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Ipertermia e tumori associazione con RXT
radiosensibilizzazione
effetti di sommazione
additivi
sinergici

• RXT e HT agiscono probabilmente
• su diversi strati (la neoplasia verrebbe
  aggredita in periferia dalla RT e nel centro,
  ipossico, dall HT)
• su diverse fasi del ciclo

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Heat Induction
Biological
EMW(SW, DW, MW)
Hot Sources
US
MF
Radiation(IR-A,B,C)
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Range di temperatura

• moderata (non
  letale) 39-lt41oC
• Range intermedia (parz.-letale)
  41-43oC
• estrema
  (letale/necrosi) gt 43oC

fever, fever-like
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Induction of Heat in Deep Seated Tissue
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Ipertermia profonda Body
BSD-2000 Sigma Eye Applicator System Antennen
(Phased Array) 60-120 MHz
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Ipertermia profonda a radiofrequenza (RF 13.56
MHz)
Coppia di elettrodi capacitivi 827 MHz
Synchrotherm, due.R S.r.l.
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(No Transcript)
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Studi randomizzatiRT vs RTHT (I)
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Studi randomizzatiRT vs RTHT
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Studi Randomizzati RT
vs RTHT (III)
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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)

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RECURRENT BREAST CANCER

• Italian Hyperthermia Group Multicenter study
  1980-1994 ( Genoa, Padoa, Ravenna, Rome, S.
  Giovanni Rotondo, Trento, Turin)
• 231 lesions
• OR -----gt 92.5
• CR -----gt 75
• LC -----gt 69

Int. Hyp. Conf, Rome, 1996
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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

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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

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INOPERABLE PELVIC TUMORS

• RT vs RT HT
  p
• CR 37 vs 48
  0.01
• cervix
• 55 78
  lt0.005
• bladder
• rectum 13 19
  ns
• 
  DKK, 1998

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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

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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 HTCT vs non responding were 60
  vs 10 (p0.0014)
• 
  Issels RD 2001

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ALL ESHO TRIALS

• endpoint CR
• Radiotherapy vs RT HT
  
• 39 vs 51
• p0.001