1. Accelerator based technology for cancer treatment with intense micro-beams of synchrotron radiation Daniel Häusermann Imaging and Medical Beamline

2. PRESENTATION CONTENT  The Australian Synchrotron Imaging and Medical Beamline (IMBL)  Micro-beam Radiation Therapy (MRT)  Principle  In-vivo results  Radiobiology / radio-chemisrty  MRT (and imaging with a very wide beam) on a medium energy storage ring: Technical challenges  Dose rate and dosimetry (not micro-beams –Michael Lerch this afternoon)  Clinical research programs and planning for patient trials  The Patient Safety System (PaSS)

3. To Monash Biomedical Imaging 138m - Mode 3: High resolution imaging (inc PC) and (slower) computed tomography 34m – Mode 2: Fast imaging and computed tomography (CT) 22m - Mode 1: High dose irradiation, MRT The IMBL

4. Maximum beam size (mm) and beam quality for phase contrast imaging 2B at 34m 10 x 170 3B at 138m 40 x 500 1B at 22m 6 x 105 2.5 times narrower at 7 x E(keV) So for MRT 2mm x 10mm (2x50 later)

5. Radiotherapy   Approximately 50% of all cancer patients receive radiation therapy, with typical doses of up to 70Gy (J/Kg), split into daily doses of 2Gy to spare normal tissue.  10Gy in 1 dose to the whole body causes death within 12 months.  The radiobiology of the interaction of radiation with living cells (of different types) is poorly researched and understood.  How does it work?  Ionising Radiation causes DNA damage  Damage to blood vessels  Need to kill tumour but minimise damage to normal tissue

6. Zeman et al, 1961 Deuteron Beam: Mouse Brain, Visual Cortex Why microbeams?

7. Zeman et al, 1961 Deuteron Beam: Mouse Brain, Visual Cortex Why microbeams?

8. Microbeam Radiation Therapy Very high x-ray dose Very short exposure Parallel beams Relatively low dose Long exposures Divergent beams Conventional (broad beam) MRT versus ‘broad beam’

9. Pig cerebellum, 15 months post 300Gy MRT Laissue et al., 2001 Peter Rogers Monash Medical Centre (now RWH), 2007 MRT demonstration (D) Central portion of a mouse hair follicle bulb, positive for g-H2AX, indicates the path of an X- ray microbeam.

10. MRT setup on the IMBL 25 and 50μm beams every 200μm 30mm 23 motors, micron resolution 3 high resolution cameras Peak-to-Valley dose Ratio (PVR) Michael Lerch this afternoon

11. Micro-beam radiotherapy (MRT) 14 days post 2 × 560Gy Normal mouse leg irradiated with 2 x 560Gy (orthogonal) synchrotron MRT Hair loss, scaly skin, but no blistering, oedema or loss of mobility MRT in-vivo

12. In-vivo quantitative results Despite showing little effect on normal tissues, synchrotron MRT causes very significant reduction in tumour growth when used to treat experimental models of cancer. [Peter Rogers et al.]

13.  We do not know for sure so research is ongoing to understand cellular and molecular response of tumour and normal tissue to MRT  In-vivo experiments on different cancer types  Radiobiology experiments on cell lines  Radiochemistry analysis  And why ‘low energy’? (compared to orthovoltage radiotherapy Why does it work? Increasing the X-ray beam energy markedly increases valley region dose. Depth profile from GEANT4 Monte Carlo simulation of a 25μm-wide beam incident on a stack of radiochromic film. The red crosses are sites of energy deposition events. 250keV100keV

14. Setup for cell cultures irradiation

15. Radiobiology - γH2AX IHC 30 minutes post 560Gy

16. Gamma-H2AX (brown DNA damage/repair) 400Gy, 6, 12, 24, & 48 hours post-irradiation

17. Tumor cell response to synchrotron MRT differ markedly from cells in normal tissues Cell migration and complete intermixing were observed in tumor tissue 24hr after MRT. In contrast the response of normal skin tissue to MRT appears to be ordered with minimal cell migration. Representative images of g-H2AX/BrdU–stained sections of EMT-6.5 tumors (Left column) and skin (right column) from mice culled at: 4hr (A, B) 12hr (C, D) 24hr (E, F) post-irradiation, with a peak entrance dose of 560Gy. Cells undergoing phosphorylation at DNA double strand breaks (g-H2AX) are stained brown and proliferating cells (BrdU) are shown in blue. Unirradiated tumor (G) and skin section (H). Scale bar, 100µm Jeffrey C. Crosbie et al., Int. J. Radiation Oncology Biol. Phys., Vol. 77, No. 3, pp. 886–894, 2010

18. Producing high energy X-rays on a medium energy machine... E c (keV) = 0.665 E 2 (GeV) B o (T) K = (eB o λ o) /(2πmc) = 0.0934 B o [T] λ o [mm]

19. ... requires a superconducting multi-pole wiggler (SCMPW), but at the a cost... Very high X-ray power onto components

20. Component design is a challenge due to the 1-D cooling geometry allowed by the beam aspect ratio* * wide beam for imaging Filter paddle (3 foils and straight through)

21. Front-end diamond window 2.16kW absorbed with the APSw at 15mm gap and failed first month of operation with SCMPW at 3.0T

22. Filter failure (?) leading to crystal damage

23. Calculated dose (‘pink beam’, enclosure 2B) Comparison of spectra and dose for various wiggler fields in station 2B, 35m from the source Calculations include “ roll-off ” effects: Flux does not scale linearly with beam size and dose-rate value is not constant beam size (H  V) (mm 2 ) max. flux (ph/sec/0.1%BW) integ. flux (photons/sec) surf. dose rate to air (Gy/sec) Field & Roll-off 10  25.19  10 9 {1.00}2.43  10 12 {1.00} 3.8 {1.00}1.4T 50  21.69  10 10 {3.26}7.84  10 12 {3.23} 2.5 {0.66}-34% 10  23.39  10 11 {1.00}2.12  10 14 {1.00} 396 {1.00}3.0T 50  21.61  10 12 {4.75}1.00  10 15 {4.72} 372 {0.94}-6% 10  29.20  10 11 {1.00}6.45  10 14 {1.00} 1338 {1.00}4.0T 50  24.49  10 12 {4.88}3.14  10 15 {4.87} 1300 {0.97}-3% Field in Teslaave. of 7 energies for max. Flux (keV) ave. of 7 weighted- average energies (keV) 1.4 (K=6.8)69.2 (0.4)72.4 (0.4) 3.0 (K=14.6)86.8 (0.4)94.3 (0.3) 4.0 (K=19.4)96.5 (0.4)105.3 (0.2) SPECTRA Ver. 9.0.2 (Tanaka & Kitamura) & Andrew Stevenson “ spec.exe ”. 3.032GeV, 200mA, calculations cover 1 to 300keV in 0.1keV steps. All filters and windows taken into account, NIST (Hubbell & Seltzer) mass-attenuation coefficients. Andrew Stevenson, 25/10/13

24. Dosimetry is another challenge, but challenge was met: Half Value Layers measurements Good agreement obtained between LEFAC- measured and Dose4IMBL-calculated dose rates in copper sheets, error bars are 2.9% for the LEFAC and ADC measurements, and 2.2% for the predicted air kerma rate. Current accuracy better than 5%. Early work Current results

25. New techniques: Absolute dosimetry with a graphite calorimeter (ARPANSA) Goals Measure the absolute dose rate of the monochromatic and ‘pink’ beams with a primary standard graphite calorimeter. Validate the calorimetry against a second measurement technique using the existing free-air chamber measurements. Investigate whether the calorimeter is an appropriate dosimeter for the IMBL beam. Early results: Achieved 3% accuracy.

26. Clinical research program and planning for patient trials  Establish strong collaboration between all MRT-related research groups*  Establish ‘routine’ cell culture irradiation  Establish ‘routine’ in-vivo irradiation ~ (2015)  Study several type of cancers in-vivo using mice ~ (began, OSA starts in 2014)  Breast  Osteocarcinoma (OSA), others  Extend the program to cats and dogs (ESRF 1 st cat Nov 2013, 1 st dog Feb 2014, will we need to repeat this work?) – (2016?)  Progress the OSA work to research trials with human patients (+3-5 years)  In parallel: Implement Patient Safety System (PaSS) and validate with rodents by June 2015 *MRT ‘coalition’ setup and still growing In-vivo, radiobiology, radiochemistry: Royal Women Hospital, Peter MacCallum, St Vincent, University of Melbourne (including veterinary school) Technical and dosimetry: IMBL team, dosimetry: ARPANSA, Alfred Hospital. Detectors: Centre for Medical Radiation Physics, University of Wollongong.  Program grants: NHMRC (MRT patient treatment planning funded), VCA

27. PaSS  Philosophy and overall concept defined (based on ESRF system, will use solid state relay based logic for fast response and standard PLC for slower requirements)  Specified in sufficient details to begin design and implementation  Fast beam kill (redundant measure for imaging), <2ms, 4 RF cavities provide redundancy  Switch to dynamic MRT (DynMRT) to reduce instantaneous dose rate and achieve the required level of patient safety  Monitor / interlock  Beam size  Filter position and integrity  Instantaneous beam dose in vacuum and before MRT collimator  Micro-beam profile  Beam mask position  Pre-patient instantaneous dose  Exposure time  Patient orientation  Patient Z-position and speed Under consideration  Imaging during treatment to check alignment if visible fiducials method not possible

28. In-vivo imaging

29. Thank you for your attention

30. And now for a rat not in space...