Surgery, RT, CHT have increased curability Precocious diagnosis and adequate FU have permitted early diagnoses of primary and relapses Cronicization

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2 Surgery, RT, CHT have increased curability Precocious diagnosis and adequate FU have permitted early diagnoses of primary and relapses Cronicization is the goal in a lot of patients The hope of target therapy (magic bullet) is failing

3 Cancer has a more complex origin than what we know Not only genic alteration saves cancer, but also tumor milieau, metabolic changes and weak host defence Hyperthermia might attack many known and still unknown targets

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5 The use of parachutes to prevent major trauma due to gravitational challenge after jumping out of an aircraft has not been proven in any randomised controlled trial But there are a very small number of anecdotal reports of people surviving falls from planes flying at considerable heights And the use of parachutes is not without the risk of their own inherent complications

6 !" Single Agent Combination (Chemotherapy,Radiotherapy) Hyperthermia: novel applications Limb perfusions Cavity perfusions (HIPEC) New drugs

7 # Combinations with: Liposomal drug formulations Magnetic nanoparticles Targeted drug delivery Monoclonal antibodies Tyrosine Kinases Inhibitors Proteasome inhibitors

8 ## $#%& $ #&% # Giammaria Fiorentini, Francesco Montagnani ISTITUTO TOSCANOTUMORI St Giuseppe General Hospital Oncology Unit Empoli (Florence) Italy oncologiaempoli@usl11.tos.it

9 ## $'%## %## Chen F et al, Oncology 2007, 73(1-2):98-103

10 # $ $#&&#%& Chen F et al, Oncology 2007, 73(1-2):98-103

11 ##'&# &# Inhibition of angiogenesis through binding of Zn Alteration of Redox processes Inhibition of PgP maturation and restore of chemo-sensitivity to 5-FU Increases efficacy of various chemotherapic drugs Inhibition of NF-kB basal and 5-FU induced activity Proteasome Inhibition

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14 $-#% To define the feasibility and safety of DSF as thermo-enhancer / chemoenhancer To evaluate clinical results

15 &%# Advanced pretreated solid malignancies PS 0-2 Absence of relevant comorbidities and contraindications to hyperthermia No alcohol consumption Chemotherapy allowed Patients in active progression after at least 1 cycle of praevious therapy

16 .#'/ $ n = 9 G1-2 Diarrhea 36% G 1-2 Nausea and vomiting 27% Cardiac failure NYHA class III in a patient with dilatative myocardiophaty One episode of unknown causes sudden death Complete resolution of gastrointestinal toxicity after zinc withdrawal

17 .#'/ $ Concurrent Chemotherapy Toxicity recorded Capecitabine Capecitabine Docetaxel + Gemcitabine 5-FU + Carboplatin Metronomic CTX Octreotide G3 diarrhea None NYHA class II cardiac failure (occurrence of cardiac metastases) G2 Leukopenia, G2 Neutropenia G1 Diarrea Leukopenia G1 Diarrhea G3

18 Pathology Previous lines of CHT NSCLC 1 no GBM 3 no Adrenal CA 2 no Concomitant chemotherapy Breast CA 5 capecitabine Ependimom 1 no Fibrosar. 2 no Carcinoid 1 octreotide Breast sar. 2 DOCE-GEM GIST 1 no H&H CA 2 no Colon cancer 4 Carbo FU Oligodendro glioma Endometrial cancer 3 no 2 Metronomic CTX HCC 2 no Response on target SD PR PD SD SD RP SD PD RP na RP PD SD RP Overall Response PFS SD 6+ PR 8+ PD 2 PD 2 SD 8+ SD 4 SD 4 PD 1 RP 4+ na 1 (sudden death ) PD 2 PD 2 PD 2 RP 2+

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20 ! )"" DSF can be administered in advanced solid treatment without significant toxicity Responses to DSF and hyperthermia combinations have been recorded Phase II trial on high grade glioma is ongoing

21 Giammaria Fiorentini, Francesco Montagnani, Marco Vaira, Michele DeSimone Oncology Unit, General Hospital S. Giuseppe, Empoli, Florence, Italy Surgical Oncology Unit, National Istitute of Cancer, Candiolo, Turin, Italy

22 "$!1*) The optimal salvage therapy for Relapsed Ovarian Cancer (ROC) has not been clearly established. Response to second-line chemotherapy is low, with a short median survival ( months). We investigated the effect of a combined approach consisting of Intraperitoneal administration of Cisplatin and Paclitaxel and whole abdomen hyperthermia (EH)

23 "$!1*) Intraperitoneal administration of Cisplatin and Paclitaxel is very active against epithelial ovarian carcinoma and showed superior activity than i.v. chemotherapy Armstrong et al New Engl J Med 2006

24 "$!1*) In animal model and human pharmacokinetic studies, high intraperitoneal drug concentrations and exposure and high peritoneal tumour concentrations were achieved The combination of intraperitoneal chemotherapy with whole abdomen hyperthermia enhances the penetration and cytotoxic activity of cisplatin and induces high response rate Phase II clinical trials suggest a possible increase of i.p. chemotherapy efficacy by transient applications of hyperthermia Jones E et al,, Int J Hyperthermia. 2006

25 +2!(" Determine the safety and efficacy of hyperthermia as palliative treatment combined with intraperitoneal chemotherapy in the palliation of symptomatic peritoneal carcinomatosis from primary epithelial ovarian cancer

26 ! )"! Relapsed Epithelial Ovarian Cancer with peritoneal carcinomatosis PS < 3 Normal CBC, renal and epatic functions Absence of other major comorbidities Absence of contraindications to hyperthermia Cisplatin and paclitaxel sensitive

27 "!!"!" N = 26 Median age 57 (46-79) PS 2 16 (60%) Distant metastasis 10 (38%) Abdominal pain/ discomfort 20 (76%) Ascites 15 (57%) Stipsis 16 (60%) Nausea/Vomiting 14 (53%)

28 " 60 mg/m2 Cisplatin i.p. on day 1/ mg/m2 Paclitaxel i.p. on day 1/21 Total of 4 cycles 2x/week hyperthermic abdominal applications with EHY 2000 device. Maximum 12 applications Dexamethasone 8 mg on day 0-1-2, Ondansetron 8 mg on days 1-5 CT scans and Ca125 testing were performed every 3 months to assess for response

29 3!( Whole abdomen hyperthermia was administrated by arrangements of capacitive electrodes applied on the abdomen with a radiofrequency field of Mhz (Oncotherm). Treatment was carried out at an applied adsorbed power of Watt In all patients the number of cumulative equivalent minutes at 43 degrees C exceeded by 90% of monitored points within the abdomen (CEM 43 degrees C T(90)) as a measure of thermal dose.

30 Intratumor temperatures were measured by 4 thermocouples inserted through angiocatheters which were placed 5 cm to 12 cm deep into the tissues. If tumours were not reachable the thermocouples were applied in the 4 abdominal quadrants

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32 "")"" 1 week delay and 25% dose reduction for G 3-4 toxicity If no recovery after 2 weeks or G 3-4 toxicity after 25% dose reduction treatment was suspended If G 3-4 anemia or neutropenia growth factor support was allowed Treatment interruption was necessary in 3 patients

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35 """ Previously untreated Pretreated CR 4 (15%) 0 PR 3 (12%) 3 (12%) SD 5 (20%) 5 (20%) PD 1 (4%) 5 (20%) Previously untreated Pretreated Total Median PFS 12,3 mo 8,5 mo 11,3 mo Median OS 27 mo 14,5 mo 25,2 mo

36 ! )"" External capacitive hyperthermia and intraperitoneal cisplatin-paclitaxel is feasible and safe in relapsed epithelial ovarian cancer Symptoms amelioration occurred in the majority of patients Toxicity is manageable

37 Thank you for the attention