HYPERTHERMIA. Inducing a controlled temperature rise in solid tumors

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2 HYPERTHERMIA Inducing a controlled temperature rise in solid tumors Goal temperature C for 1 hr Always combined with RT and/or CT 1x/2x a week

3 HYPERTHERMIA AND CHEMOTHERAPY HEAT Increase of blood flow; Increase in permeability of cells membrane; Increase of intratumoral drug uptake

4 HT + RT RATIONALE A. Oei et al., Radiation Oncology, 2015

5 HT + RT RATIONALE A. Oei et al., Radiation Oncology, 2015

6 HYPERTHERMIA - RANDOMIZED STUDIES CR Effect without HT Effect with HT 37% 70% 53% 74% 79% 59% 41% 39% 66% 68% 42% 42% 79% 48% Medline search Hyperthermia NOT fever AND cancer AND clinical trials 25% 24% 28% 38 clinical trials 6% Datta et al. 2015, Cancer Treatment Reviews

7 HYPERTHERMIA - RANDOMIZED STUDIES 2-3 yrs LC Effect without HT Effect with HT 70% 66% 33% 42% 51% 48% 55% Medline search Hyperthermia NOT fever AND cancer AND clinical trials 8% 16% 25% 38 clinical trials Bladder Cervix Rectum Various superficial High risk ST Sarcoma Datta et al. 2015, Cancer Treatment Reviews

8 HYPERTHERMIA - RANDOMIZED STUDIES 2-yrs OS Effect without HT 51% 65% Effect with HT 78% 72% Medline search Hyperthermia NOT fever AND cancer AND clinical trials 28% 22% 10% 29% 38 clinical trials Bladder Cervix Rectum High risk ST Sarcoma Datta et al. 2015, Cancer Treatment Reviews

9 STANDARD CANCER TREATMENT TUMOR SND TREATMENT PRIMARY OBJECTIVE RESULTS Stage I/II S+Adjuvant RT/CT CR Very good PRIMARY LOCO- REGIONAL RECURRENT METASTATIC Stage III/IV Oligometastatic (Neo-adjuvant CT+) S+Adjuvant RT/CT S/RT/Re-RT/CT Curative RT/CT Surgery/ Conservative Surgery CR LC OS QoF OS Qof Diffuse RT/CT Palliation May be improved May be improved May be improved May be improved Hyperthermia Radiotherapy effect Chemotherapy effect Without increasing normal tissue acute or late toxicity

10 MULTICHANNEL PHASED ARRAY SYSTEM 70 MHz Loco-regional HT Focal area ~ 12 cm Target temperature: C

11 CLINICAL INDICATIONS Cervix and uterus Rectum Bladder Prostate Esophagus Soft tissue sarcoma Deep seated melanoma Pancreas

12 FROM RESEARCH TO MARKET AMC-4 ( ) AMC-8 ( )

13 CLINICALLY PROVEN 51% 73% RT 57% RT+HT 83% 15% SUCCESFUL PHASE III TRIAL (Van der Zee, 2000) 20% 39% 56% RT RT+ HT 24% 31% Bladder Cervix Rectum COMPLETE RESPONSE 2-YR LOCAL CONTROL 3-YR OVERALL SURVIVAL 12 YEARS FOLLOW UP RT + HT 37% OVERALL SURVIVAL RT 20% FRANCKENA ET AL IJROBP 2008

14 PRODUCT DEVELOPMENT

15 PRODUCT DEVELOPMENT PHILOSOPHY

16 DESCRIPTION & COMPARISON MECHANICS THERMOMETRY RF COOLING SYSTEM

17 DESCRIPTION & COMPARISON MECHANICS THERMOMETRY RF COOLING SYSTEM

18 MECHANICS BED MOVEMENT Manual positioning of the bed easy and comfortable patient preparation fast emergency removal

19 MECHANICS GANTRY MOVEMENT ANTENNAS MOVEMENT Automatic record of gantry and antennas position

20 MECHANICS AP LAT AP : cm LAT: cm ADAPTATION TO DIFEFENT SIZE

21 MECHANICS Crs = (Peso totale x fattore di sicurezza) peso totale

22 MECHANICS Crs = (Peso totale x fattore di sicurezza) peso totale

23 MECHANICS INTEGRATED POSITIONING LASERS

24 DESCRIPTION & COMPARISON MECHANICS THERMOMETRY RF CONTROL COOLING SYSTEM

25 ANTENNAS 70 MHz Waveguide applicator

26 SIMULATED SAR DISTRIBUTION T L R 20.5 cm B Focal area ~ 12.5 cm P = intensity = position

27 FOCUS STEERING Δ =10 Δs= 1cm T L R B CERVIX RECTUM BLADDER

28 FOCUS STEERING

29 FOCUS STEERING

30 FOCUS STEERING

31 FOCUS STEERING

32 MAJOR REQUIREMENTS PHASED ARRAY SYSTEM FOR DEEP HT PHASED ARRAY INTRINSIC ISSUES SUB-OPTIMAL TARGET HEATING CRITICAL POINT SHIFT OF THE FOCUS POSITION PC GENERATOR AMP APPL. #1 DESIRED F 0 F DRIFT 0 APPL. #N Time

33 MAJOR REQUIREMENTS PHASED ARRAY SYSTEM FOR DEEP HT FEEDBACK SYSTEM OPTIMAL TARGET HEATING PC GEN./ VVM AMP APPL. #1 DRIFT CORRECTION Phase /Power Control Loop APPL. #N Time

34 IMPEDANCE MISMATCHING a i = forward power of i-esimo ch b i = reflected power of i-esimo ch S ii :the lower the better

35 IMPEDANCE MISMATCHING a i a i LOAD 50 Ohm LOAD 50 Ohm a i = forward power of i-esimo ch b i = reflected power of i-esimo ch b i THE MORE THE LOAD 50 OHM THE MORE REFLECTED POWER (b i ) IS HIGH INSTABILITIES IN THE LINE NOT RELIABLE MEASUREMENTS FROM BI- DIRECTIONAL COUPLERS

36 MECHANICS THERMOMETRY RF CONTROL COOLING SYSTEM

37 WATER BOLUS C shaped top water bolus Rectangular bottom bolus OPTIMAL ADAPTATION INDEPENDENTLY THERMO-REGULATED AUTOMATIC RECORD OF WATER VOLUME

38 WATER BOLUS DIFFERENT TOP BOLUS ACCORDING TO PATIENT SIZE

39 WATER BOLUS

40 WATER BOLUS

41 WATER BOLUS

42 DESCRIPTION & COMPARISON MECHANICS THERMOMETRY RF CONTROL COOLING SYSTEM

43 REAL TIME DOSIMETRY Invasive thermometry is the the ONLY ESHO approved measuring system Bladder Vagina rectum Axilla applicator water bolus 64 SENSORS POSITIONED IN NATURAL CAVITIES

44 REAL TIME DOSIMETRY Invasive thermometry is the the ONLY ESHO approved measuring system Rectum Spinal cord Oesophagus water bolus applicator 64 SENSORS POSITIONED IN NATURAL CAVITIES

45 MULTI-TIPS TEMPERATURE PROBES

46 SPECIAL SUPPORT DEVICES

47 PATIENT COMFORT IPAD 4 FANS WITH ADJUSTABLE INTENSITY

48 Q.A RADIOTHERAPY HYPERTHERMIA

49 Requisiti Essenziali Gestione del rischio Descrizione del prodotto Ciclo di sviluppo, disegno ed implementazione Valutazione clinica (pubblicazioni) Documenti di progettazione (disegni meccanici, schemi elettrici, data sheet componenti critici) Prove di compatibilità elettromagnetica Schede materiali a contatto con il paziente e prove biocompatibilità Progetto di etichettatura Depliant e Manuali Dichiarazione di conformità

50 HYPERTHERMIA TREATMENT PLANNING SYSTEM

51 PATIENT SPECIFIC IMAGING (CT SCAN) IN TREATMENT POSITION 60 cm WATERBOLUS Rectum catheter Pelotte in situ Bladder catheter CT SCAN / X RAY WITH THERMOMETRIC PROBES INSERTED

52 TARGET DELINEATION (BLADDER) transversal sagittal coronal

53 PATIENT POSITIONING TISSUE SEGMENTATION muscle fat bone air target Transversal Sagittal Coronal

54 SEGMENTATION BASED ON CT HOUNSFIELD UNITS

55 SAR SIMULATION( W/Kg) 100 W kg -1 0 W kg -1 Transversal Sagittal Coronal

56 Penne s Bioheat equation TEMPERATURE SIMULATION( C ) 45 C 37 C Transversal Sagittal Coronal

57 Graphical user interface provides visualization and assistance during treatment alternative settings Improved T 90

58 SAR/temperature visualization Graphical user interface provides visualization and assistance during treatment

59 MODELING BIOHEAT TRANSFER Different methods available 1. Continuum Pennes bio heat equation 2. Discrete vessels e.g. DIVA (Discrete vasculature) Kok et al, 2013

60 LA PROSTATE CANCER 15 prostate cancer patients treated with RT without HT. The effect of adding HT to RT was evaluated using the AMC-4 regional HT device and assuming a 1-h time interval between RT and HT. Conclusion: adding HT is equivalent to a radiotherapy dose escalation of about 10 Gy, 76 Gy RT ALONE 86 Gy RT+ HT

61 TREATMENT DATA All data are recorded in a standardized way according to the guidelines READY FOR MULTICENTRIC STUDY

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64 MRI + HT Thank you for your attention

65 HT INHIBITS DNA REPAIR BRCA 2 A. Oei et al., Radiation Oncology, 2015

66 HT INHIBITS DNA REPAIR HT 41 C BRCA 2 A. Oei et al., Radiation Oncology, 2015