1. Toward a multi-modality approach to radiotherapy for cancer treatment in UK (Unity is strength) Barbara Camanzi STFC – RAL & University of Oxford

2. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/102/30 Outline  Why cancer  Radiotherapy  Toward multi-modality  The technological challenges: dosimetry and imaging  Conclusions

3. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/103/30 The challenge of cancer in UK  Cancer is the leading cause of mortality in people under the age of 75. 1 in 4 people die of cancer overall  293k people/year diagnosed with cancer, 155k people/year die from cancer  Incidence of cancer is rising due to: 1. Population ageing 2. Rise in obesity levels 3. Change in lifestyle  Cancer 3 rd largest NHS disease programme

4. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/104/30 Radiotherapy

5. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/105/30 Radiotherapy and cancer in UK  Radiotherapy given to 1/3 of cancer patients (10-15% of all population)  Overall cure rate = 40%. In some instances 90-95% (for ex. breast and stage 1 larynx cancers)  Radiotherapy often combined with other cancer treatments: 1. Surgery 2. Chemotherapy 3. Hormone treatments

6. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/106/30 Radiotherapy treatments  External beam radiotherapy: 1. X-ray beam 2. Electron beam 3. Proton/light ion beam  Internal radiotherapy: 1. Sealed sources (brachytherapy) 2. Radiopharmaceuticals  Binary radiotherapy: 1. B oron Neutron Capture Therapy (BNCT) 2. Photon Capture Therapy (PCT)

7. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/107/30 A new approach to radiotherapy  Cure cancer & protect healthy tissues Dose escalation in tumour Dose escalation in tumour Minimise dose to normal tissues Minimise dose to normal tissues  Different treatment strategies are required depending on cancer type, stage and degree of spread  Radiotherapy treatments not linked = impact lowered = missed opportunity → New approach needed

8. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/108/30 My vision: multi-modality  Unified approach to radiotherapy needed to maximise efficacy and improve care  Multi-modality = bringing together the different forms of radiotherapy treatments: 1. Select best treatment depending on tumour type 2. Combine different treatments when appropriate  Highly beneficial to patient: better local control and lower toxicity

9. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/109/30 Multi-modality: selection  External beam and internal radiotherapy best for localised diseases  Binary therapy best for locally spread diseases with high degree of infiltration  Proton/light ion therapy very promising for paediatric tumours  Some other considerations: 1. Proximity of organs at risk 2. Tumour dimension and location 3. Previous irradiation (recurrences)

10. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1010/30 Multi-modality: combination  Combination of different sources → dose escalation  Different organs at risk for various treatments → toxicity not increased  Some examples: 1. External beam therapy + brachytherapy 2. External beam therapy + radiopharmaceuticals

11. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1011/30 The challenge

12. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1012/30 The technological challenges  The challenge of radiotherapy from the patient end Make sure that the right dose is delivered at the right place = improved dosimetry + improved imaging  The challenge of early diagnosis “See” smaller tumours = improved imaging  New advanced technologies desperately needed for dosimetry and imaging

13. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1013/30 How particle physics can help "The significant advances achieved during the last decades in material properties, detector characteristics and high-quality electronic system played an ever-expanding role in different areas of science, such as high energy, nuclear physics and astrophysics. And had a reflective impact on the development and rapid progress of radiation detector technologies used in medical imaging." "The significant advances achieved during the last decades in material properties, detector characteristics and high-quality electronic system played an ever-expanding role in different areas of science, such as high energy, nuclear physics and astrophysics. And had a reflective impact on the development and rapid progress of radiation detector technologies used in medical imaging." “The requirements imposed by basic research in particle physics are pushing the limits of detector performance in many regards, the new challenging concepts born out in detector physics are outstanding and the technological advances driven by microelectronics and Moore's law promise an even more complex and sophisticated future.” D. G. Darambara "State-of-the-art radiation detectors for medical imaging: demands and trends" Nucl. Inst. And Meth. A 569 (2006) 153-158

14. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1014/30 State-of-the-Art

15. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1015/30  All external dosimeters placed on patient skin: TLDs TLDs Diodes Diodes MOSFETs MOSFETs  Disadvantages: No reading at tumour site No reading at tumour site No real-time information for some (TLDs) No real-time information for some (TLDs) Difficult to use (wires: diodes, MOSFETs) Difficult to use (wires: diodes, MOSFETs) Dosimetry

16. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1016/30 Imaging  Most medical imaging systems, CT, gamma cameras, SPECT, PET, use particle physics technologies: scintillating materials, photon detectors, CCDs, etc. Courtesy Mike Partridge (RMH/ICR) Collimator Scintillator Diode CT scanner Gamma camera (SPECT)

17. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1017/30 Positron Emission Tomography  18 F labelled glucose given to patients: e + annihilates in two back-to-back 511 keV   A ring of scintillating crystals and PMTs detects the  511 keV  Courtesy Mike Partridge (RMH/ICR)

18. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1018/30 Conventional PET Conventional PET scanner: 1. Coincidences formed within a very short time window 2. Straight line-of-response reconstructed 3. Position of annihilation calculated probabilistically Courtesy Mike Partridge (RMH/ICR) PETCTPET + CT

19. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1019/30 The future

20. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1020/30 The dosimetry challenge  The requirements for new dosimeters: 1. Measure dose at tumour site and not at skin 2. Measure total dose (including during imaging procedures) 3. Measure in real-time and not long time after each treatment fraction 4. System easy to use  The answer: in-vivo dosimetry

21. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1021/30 In-vivo dosimetry  Radiation sensitive MOSFET transistors (RadFETs) used in particle physics experiments (BaBar, LHC, etc.) for real-time, online radiation monitoring  Development of RadFET based miniaturised wireless dosimetry systems to be implanted in patient body at tumour site for real-time, online, in-vivo dosimetry → Seek funding

22. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1022/30 The imaging challenge  The requirements for new imaging systems: 1. More accurate, more quantitative and highly repeatable imaging 2. Imaging during treatment: organ movement (breathing), patient set-up, tumour shrinkage 3. Image smaller lesions (early diagnosis) 4. Treatment specific requirements (for ex. Bragg position in proton/light ion therapy)  The answer: higher spatial resolution, higher linearity, lower noise, less drift, faster imaging

23. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1023/30 Time-Of-Flight PET (TOF-PET)  TOF-PET scanner: 1. Time difference between signals from two crystals measured 2. Annihilation point along line-of-response directly calculated  Goal: 100 ps timing resolution (ideally 30 ps and below) = 3 cm spatial resolution (ideally sub-cm)  Advantages: higher sensitivity and specificity, improved S/N  Technology needed: fast scintillating materials and fast photon detectors

24. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1024/30 Fast scintillating materials Decay time (ns) Light Yield (  /keV) Density (g/cm 3 ) att at 511keV (cm) LaBr 3 (Ce) BrilLanCe TM 380 16635.32.23 LYSO PreLude TM 420 41327.11.20 LSO40277.41.14 BGO30097.11.04 GSO6086.71.61 BaF 2 0.81.84.92.27 NaI(Tl)250383.72.91 BrilLanCe TM 380 and PreLude TM 420 produced by Saint-Gobain Cristaux et Detecteurs

25. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1025/30 Photon detectors: SiPMs Hamamatsu Inc. 1x1 mm 2 3x3 mm 2  Array of Silicon Photodiodes on common substrate each operating in Geiger mode  SiPMs have high speed (sub ns) and gain (10 6 ) and work in high magnetic fields (7T)

26. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1026/30 Tests on TOF-PET prototypes  LaBr 3 (Ce) and LYSO scintillating crystals from Saint-Gobain  SiPMs from Hamamatsu, SensL and Photonique  Various two-channel demonstrator systems tested at RAL and RMH  Timing resolution analysis still ongoing

27. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1027/30 Preliminary results  Prototypes with Hamamatsu 3x3mm 2 best of all. SensL blind to LaBr 3  Best timing resolutions measured: 1. 430 ps with 3x3x10 mm 3 LYSO 2. 790 ps with 3x3x30 mm 3 LaBr 3  Performance of prototypes with LaBr 3 highly dependent from SiPM- crystal coupling  Best SiPMs: Hamamatsu (electrical problem with 11-25) and SensL  Best timing resolutions measured: 1. 20 ps for single SiPM 2. 40 ps for pairs of SiPMs  Hamamatsu performance as function of pitch still under investigation

28. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1028/30 Where next with TOF-PET  Preliminary results very encouraging. Next step: dual-head demonstrator system. Two planar heads with identical number of channels → Funded by FP7 as part of ENVISION (European NoVel Imaging Systems for ION therapy)  Use of fast scintillators can be expanded to other imaging systems (CT, SPECT, etc.)  Use of SiPMs opens up the possibility of designing a compact PET/MRI scanner

29. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1029/30 Conclusions  Cancer is a leading cause of mortality in UK. Its incidence is rising.  Radiotherapy is and will be given to a large number of patients.  Patients will benefit from a multi-modality approach to radiotherapy. This requires the development of new, advanced technologies.  Particle physics holds the key to the development of these technologies.

30. Barbara Camanzi RAL & Oxford University NPAE-Kyiv2010, Kiev, 7-12/06/1030/30 Acknowledgements  Dr Phil Evans and Dr Mike Partridge (Royal Marsden Hospital / Institute of Cancer Research - UK)  Prof Ken Peach (John Adams Institute - UK)  Prof Bleddyn Jones (Radiation Oncology and Biology Institute - UK)  The STFC Futures Programme team (UK)  Dr John Matheson and Mr Matt Wilson (STFC-RAL - UK)