Binary therapies in the treatment of cancer

Transcription

1 Binary therapies in the treatment of cancer translational research from the physics laboratory to the clinic Stuart Green University Hospital Birmingham and British Institute of Radiology STFC Innovations Birmingham, January 2010

2 Overview of techniques and projects External beam treatments X-ray therapy Proton and ion beam therapy Binary therapies Boron Neutron Capture Therapy High Z enhanced radiotherapy Systemic treatment Targeted radionuclide therapy chemotherapy localised disease locally spread disease Systemic disease

3 Boron Neutron Capture Therapy neutrons alpha 1.47 MeV Cell B 10 B 11 photon MeV Li MeV Ion combined range ~ 8-9µm. Cell diameter ~ 10 µm. => radiation damage mostly within cell

4 BPA pharmacokinetics Plot is from Kiger et al, Journal of Neuro-Oncology 62: (2003) Typical 10 B concentrations, 15 µg/g in Blood and Brain, 52.5 µg/g in Tumour BPA administered is approx 20g for an average person.

5 Photon Capture Therapy (PCT) -Physics Physics of the photo-electric effect is well known Energy not used to overcome binding is liberated as electron kinetic energy (so range is tuneable?) Cross section increases roughly as Z 4, and decreases as 1/E 3 Introduction of a high Z material preferentially into a tumour can significantly increase the local dose for the same irradiating x-ray fluence

6 Photon Capture Therapy (PCT) m ass absorption coefficient I G d P t A u H 2 0 (µ/ρ) en E (M ev) Energies released per reaction are in the kev range (for BNCT, they are in the MeV range) and both are cross-section driven For similar dose enhancements, PCT requires local contrast agent concentrations which are approx 1000 x those required for BNCT

7 Key requirements for binary therapies Efficient contrast agents with large interaction difference from normal body materials Contrast agent with very low toxicity (to allow administration at very high levels) Contrast agent must preferentially accumulate in tumour cells Tumour must be accessible to the beam (epithermal neutrons or low energy photons) But do they work?

8 Dose enhancement through high-z targeted RT EMT-6 mammary carcinomas in mice 1.9nm Au particles administered IV up to 2.7 g Au/kg in phosphate buffered saline 250 kvp RT, 30 Gy single fraction Hainfeld et al., PMB, 49: N309, 2004

9

10 PCT and BNCT Comparisons for F98 Tumour model F98 glioma model is the best we have of an infiltrating tumour BNCT and PCT are the only techniques which have achieved cures in the tumour model But it is still a very controlled system without the complexity of a real human tumour

11 Glioblastoma - clinical course Head trauma 9M before Mild headache 9M post-surgery Post-chemoradiotherapy Courtesy of Tetsuya Yamamoto, Tsukuba, Japan

12 Glioblastoma Multiforme Prognosis improvement in the last 30 years Walker et al. J Neurosurg 49 (1978) Stupp et al., N Eng J Med 352 (2005) Survival (%) A - surgery alone B - surgery + chemotherapy C - surgery + radiotherapy D - surgery + chemo + R/T Disease progression or recurrence through lack of local control

13 Dose escalation studies for GBM Conventional XRT BNCT plus XRT XRT plus boost Main Tm Edema 11 Courtesy of Tetsuya Yamamoto, Tsukuba, Japan 3-step cone-down

14 Medical Physics Building Dynamitron Cyclotron vault Protons Maze Li target, Beam moderator / shield Neutrons

15 Neutron generation and moderation scanned proton beam shield graphite reflector FLUENTAL moderator / shifter Li target lead filter heavy water cooling circuit Neutron source is > 1 x s -1

16 Cut-away of Birmingham beam shaping assembly

17 Li target during fabrication

18

19 Thermal neutron intensity map Thermal neutrons per source neutron 160 x

20 Clinical Experience (Approx data to 2008) Facility Approx. patients (compound) Tumours treated Japan (various) >300 (BSH / BPA) Mainly GBM Brookhaven, NY 54 (BPA) GBM MIT, Boston 28 (BPA) GBM, melanoma (extremity and brain) Espoo, Finland >150 (BPA) GBM, Head and Neck Studsvik, Sweden 52 (BPA) GBM Pavia, Italy 2 (BPA) Metastases in liver (ex -vivo) Petten, Netherlands 34 (BSH) GBM, melanoma mets in brain Rez, Czech Republic 5 (BSH) GBM Barriloche, Argentina 7 (BPA) Melanoma of skin

21 BPA accumulation via the Phenylalanine transport mechanism Uptake of amino-acids into cells is surprisingly poorly understood Thought to be selectively transported across the blood brain barrier, endothelial cells and astrocytic cells by a common LAT-1 transporter system. LAT-1 is up-regulated in tumour cells and might be expected to enhance the concentration of L amino acids particularly in tumour cells.

22 Results for counted stained cell populations in GBMs A LAT + X-Bar = 72.6 ± 16.9 PCNA + X-Bar = 22.8 ± 16.9 LAT + PCNA + X-Bar = 4.8 ± 2.2 n = % of tumour cells express LAT-1 60 A much lower proportion are proliferating Slide courtesy of A Detta, Detta and Cruickshank, Cancer Res LAT + PCNA + LAT + PCNA +

23 BNCT Clinical Results from Tsukuba 15 patients only BNCT + XRT BNCT alone Overall Survival Time Time to progression

24 Glioblastoma Multiforme Prognosis improvement in the last 30 years Walker et al. J Neurosurg 49 (1978) Stupp et al., N Eng J Med 352 (2005) Survival (%) A - surgery alone B - surgery + chemotherapy C - surgery + radiotherapy D - surgery + chemo + R/T Disease progression or recurrence through lack of local control

25 The Tsukuba approach Courtesy of Tetsuya Yamamoto, Tsukuba, Japan

26 Final thoughts Different treatment strategies are required depending on the type, stage and degree of spread of the cancer to be treated Binary therapies are aimed specifically at tumours which exhibit a high degree of infiltration into the surrounding healthy tissues Binary therapies are still at a very early stage of development (patient numbers for BNCT still < 1000) They require input from a wide range of scientific disciplines They are ripe for investment and provide a great opportunity for the UK to take a lead Can we afford to miss this opportunity? (as we did with particle therapy) What can UK Research Councils do to help?

27 Collaborations and Acknowledgements UHB Trust: Profs Alun Beddoe and Bleddyn Jones (now Oxford), Drs Cecile Wojnecki and Richard Hugtenburg (now Swansea Uni), Dr Spyros Manolopoulos (ex STFC) University of Birmingham: Profs David Parker and Garth Cruickshank, Drs Monty Charles and Andy Mill University of Oxford: Dr Mark Hill PhD students: Zamir Ghani, Ben Phoenix, Shane O Hehir, Adam Baker and Mohammed Sidek Funding bodies, EPSRC, CR-UK, UHB Charities

28 Work of Biston et al, Cures of rats bearing radioresistant F98 Glioma tumours F98 glioma model is the best we have of an infiltrating tumour Pt-based chemotherapy drug (CDDP) administered via intra-tumoral injection (3 mg in 5 ml saline) Synchrotron irradiation at various energies above / below Pt K-edge Best median survival times at 78.8 kev (above Pt K-edge) = 206 days Best previous results for this tumour model are with BNCT where median survival time = 72 days (Barth et al, IJROBP 2000, 47, ) CANCER RESEARCH 64, , April 1, 2004 This success has lead to further work to plan human clinical trials, although big questions remain on the nature of the observed effect

29 Synchrotron Stereotactic Radiotherapy (SSR) high Z 1. Administration of a high Z element therapy either via physical dose enhancement alone or from combination with chemotherapy (administration of a platinum chemotherapy drug) SR S R 2. Irradiation in tomography mode beam fitted to the tumour size tumour = center of rotation monochromatic beam From the work of Boudou et al based around ESRF, Grenoble

30 iodine 10mg/ml Tomo-irradiation beam thickness: 2 cm beam width: 2 cm 34keV 50keV Isodose lines: red = 90%, green = 50%, blue=25% 85keV 6 MV, no iodine

31 Doses to Tumour and normal cells

32 Radiobiology of BNCT For the reaction products ( 7 Li and αparticles) in BNCT, there is a further confounding factor which relates to the uniformity, at the sub-cellular level, of the alpha and 7 Li dose which follows a neutron irradiation This distribution will vary depending on the carrier compound 10 B atoms Cell nucleus Low CBE Cell wall High CBE