Physics - based techniques for the treatment of cancer translational research from the physics laboratory to the clinic

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Physics - based techniques for the treatment of
cancertranslational research from the physics
laboratory to the clinic

• Stuart Green
• University Hospital Birmingham and British
  Institute of Radiology
• Rutherford Appleton Lab
• March 2009

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Collaborations and Acknowledgements

• UHB Trust
• Profs Alun Beddoe and Bleddyn Jones (now Oxford),
  Drs Cecile Wojnecki and Richard Hugtenburg (now
  Swansea Uni)
• University of Birmingham
• Profs David Parker and Garth Cruickshank, Drs
  Monty Charles, Andy Mill and Chris Mayhew
• Rutherford Laboratory
• Dr Spyros Manolopoulos (now UHB Trust)
• PhD students
• Dan Kirby, Zamir Ghani, Ben Phoenix, Shane
  OHehir, Adam Baker and Mohammed Sidek

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Cancer

• Genetic abnormalities found in cancer typically
  affect two general classes of genes.
  Cancer-promoting oncogenes are often activated
  while tumour suppressor genes are often
  inactivated in cancer cells
• Active oncogenes can lead to cells exhibiting
  hyperactive growth and division, protection
  against programmed cell death (apoptosis) loss of
  respect for normal tissue boundaries, and the
  ability to become established in diverse tissue
  environments.
• Inactive tumour suppressor genes cause loss of
  many properties such as accurate DNA replication,
  control over the cell cycle, orientation and
  adhesion within tissues, and interaction with
  protective cells of the immune system.

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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
• Improving the dosage of chemotherapy drugs

locally spread disease
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X-ray radiotherapy

• Basics

• Usage

• Effect is related to the physical radiation dose,
  and the increased sensitivity (inability to
  repair damage) of tumour cells
• X-ray radiotherapy delivers many lethal events
  per cell

• Approx 40 of cancer patients receive
  radiotherapy
• This consumes approx 5 of the cancer budget
• Of the patients who are cured, approx
• 50 is by surgery
• 40 by radiotherapy
• 10 by drugs
• BUT most cured patients need ALL of these
  treatments

Probability
Dose / Gy
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Standard radiotherapy technology
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IMRT
Evolving radiotherapy techniques
standard radiotherapy
3D-conformal radiotherapy
Intensity Modulated Radiation Therapy
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Conventional RT dose distributions
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Conformal RT dose distributions
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Conformal radiotherapy- the limitations
Conformal RT cannot produce concave dose
distributions...
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Intensity Modulated Radiation Therapy
.IMRT can!
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Intensity modulation
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Treatment issues and capabilities

• Multimodal imaging
• Respiratory motion
• Imaging during treatment
• Improved dose delivery (IMRT etc)

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New dosimetry techniques - DOSI

• Specifications
• Si (single crystal) detectors
• 128 channels
• 0.25 mm pitch
• tINT gt 10 ?sec
• Qmax 15 pC

Approx 5 cm
From Dr Spyros Manolopoulos, STFC (now
Bham) Recent Publications in Medical Physics and
PMB
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Overview of techniques

• External beam treatments
• X-ray therapy
• Proton and ion beam therapy
• Binary therapies
• Boron Neutron Capture Therapy
• High Z enhanced radiotherapy
• Improving the dosage of chemotherapy drugs

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Approaches to cancer treatment
ANTIPROTONS
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Protons and x-rays compared
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Unavoidable dose
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Proton therapy in UK we already have it!

• World First hospital based proton therapy at
  Clatterbridge, Liverpool, converted fast neutron
  therapy facility.
• gt1400 patients with ocular melanoma local
  control gt98.
• First example of 3D treatment planning in UK
• Unsung success story of British Oncology.
• 62 MeV protons so eye tumours only

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To be able to treat deep seated tumours
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Paul Scherrer Institute

• Swiss National Research Lab
• Long-standing investment in proton therapy
• Major expansion in progress, with new cyclotron
  (250 MeV) and new treatment room

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The Siemens synchrotron system
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Medulloblastoma in a child (MD Anderson)
100 60 10
Patients treated prone with 3 field technique
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Medulloblastoma in a 5 year old boy (PSI)
No complex overlaps as with x-rays all treated in
one field 15 mins instead of 30 mins. under
general anaesthetic each day Roughly 100 cases
per yr in UK, mostly ages 3-8
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Advanced Radiotherapy Recent UK History

• 1990 the end of neutron therapy trials
• 1991 - Proton 3-D radiotherapy in UK
• 1990 -2002 four UK bids for higher energy proton
  therapy
• 1990s - Conformal Radiotherapy UK slow to uptake
  but trials performed
• 2000 on - X-ray IMRT uptake at several UK centres
  but not yet widespread
• UK radiation research output reduced in 1990s
• Noticed by National Cancer Research Institute and
  efforts have started to redress this
• International proton and ion expansion (soon USA
  8, Germany 6-8, Japan 8, France 1-2, Italy 1,
  Austria 1?, Switzerland 1, Sweden 1)

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Proton therapy - where are we now?

• Department of Health has produced the Cancer
  Reform Strategy states we are aiming for World
  Class Cancer services
• For proton therapy we will
• Coordinate referrals abroad in an organised
  manner
• Consider the options for a UK facility or
  facilities, and develop a business case
• 2006-7 EPSRC funded 2 large Basic Technology
  Consortia developing technology for advanced
  proton and ion radiotherapy (BASROC Ken Peach et
  al and LIBRA Dave Neely et al)
• Signed contract to end of commissioning takes
  approx 3 years.
• UK will be fortunate if it has one functional
  high energy centre by 2012
• International proton and ion expansion (soon USA
  8, Germany 6-8, Japan 8, France 1-2, Italy 1,
  Austria 1?, Switzerland 1, Sweden 1)

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LIBRA Project (www.libra-bt.co.uk)

• Project Overview

• EPSRC Basic technology grant (approx 5m)
• Intended to develop target technology for
  laser-induced beams of protons, ions, x-rays and
  neutrons
• Birmingham role in beam dosimetry working with
  NPL

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Proton dosimetry jig
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Experimental setup
optional collimator
proton jig
primary collimator
MD55
?? MeV protons
compression plunger
Markus chamber
transmission chamber
absorbers
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Experiments using the Birmingham cyclotron
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FLUKA, Gaf Chromic film (MD-55) and ionisation
chamber measurements
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Overview of techniques

• External beam treatments
• X-ray therapy
• Proton and ion beam therapy
• Binary therapies
• Boron Neutron Capture Therapy
• High Z enhanced radiotherapy
• Improving the dosage of chemotherapy drugs

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Glioblastoma - clinical course
Courtesy of Tetsuya Yamamoto, Tsukuba, Japan
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Glioblastoma
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On the LEFT is a histology slide (x400) of glioma
cells infiltrating the  neuropil, whilst the
RIGHT is a fully-fledged GBM showing necrotic
areas and microvascular proliferation (arrowhead).
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Standard XRT for GM
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Courtesy of Tetsuya Yamamoto, Tsukuba, Japan
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Performance status, age and survival
Survival (months)
Age
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Boron Neutron Capture Therapy
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Dose escalation studies for GBM
Edema
Main Tm
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Courtesy of Tetsuya Yamamoto, Tsukuba, Japan
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Medical Physics Building (The Radiation Centre)
Dynamitron
Protons
Cyclotron vault
Maze
Neutrons
Li target, Beam moderator / shield
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Li target during fabrication
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Neutron generation and moderation
scanned proton beam shield graphite
reflector FLUENTAL moderator / shifter Li
target lead filter heavy water cooling circuit
Neutron source is gt 1 x 1012 s-1
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Thermal neutron intensity map
Thermal neutrons per source neutron
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FLUKA Radioactive inventory calculations
Isotope Peak Activity (Bq/cm³) Uncert () Half life
3H 5100 13 12.32 y
7Be 2.44x1012 0.5 53.22 d
20F 6.22x105 11 11.163 s
28Al 3.15x105 8 2.2414 min
64Cu 3.28x107 10 12.70 h
66Cu 6.32x106 17 5.12 min
205Pb 1.14x10-3 17 15.3x106 y
209Pb 4.38x104 18 3.253 h
Rob Chuter and Nigel Watson, 2007
Max value in system for a 1mA proton beam
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In-phantom dosimetry
Leads to beam monitor chambers Ionisation
chamber water phantom (40 x 40 x 20 cm) 12 cm
beam aperture
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Doses to Tumour and normal cells
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Measurements and MCNP, Weighted Doses to normal
brain
Assuming 10B at 15 mg/g, N at 2.2 and usual
RBE/CBE factors
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The Tsukuba approach
Courtesy of Tetsuya Yamamoto, Tsukuba, Japan
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Clinical Results from Tsukuba
A comparison of Progression Free Survival Time
for GBM tumours between BNCT and other
radiotherapies from the University of Tsukuba in
Japan
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A Cancer Research UK pharmacokinetic study of
BPA-Mannitol in patients with high grade glioma
to optimise uptake parameters for clinical trials
of BNCT
G. S Cruickshank1, D. Ngoga1, A. Detta1, S
Green1, N.D James1, C Wojnecki1, J Doran1, J
Hardie1, M Chester1, N Graham1, Z. Ghani1, G
Halbert2, M Elliot2 , S Ford2, R Braithwaite3,
TMT Sheehan3, J Vickerman4, N Lockyer4, H.
Steinfeldt5, G. Croswell5, R Sugar5 and A
Boddy6 1University of Birmingham and University
Hospital Birmingham, Birmingham 2CR-UK
Formulation Unit, University of Strathclyde,
Glasgow 3Regional Laboratory for Toxicology,
Sandwell West Birmingham Hospitals Trust,
Birmingham 4Surface Analysis Research Centre, The
University of Manchester, Manchester 5CR-UK Drug
Development Office, London 6Northern Institute
for Cancer Research, University of Newcastle,
Newcastle-Upon-Tyne,
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Overview of techniques

• External beam treatments
• X-ray therapy
• Proton and ion beam therapy
• Binary therapies
• Boron Neutron Capture Therapy
• High Z enhanced radiotherapy
• Improving the dosing of chemotherapy drugs

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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 Z4, and
  decreases as 1/E3
• Introduction of a high Z material preferentially
  into a tumour can significantly increase the
  local dose for the same irradiating x-ray fluence

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• 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

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Final thoughts

• Different treatment strategies are required
  depending on the type, stage and degree of spread
  of the cancer to be treated
• Physics-based techniques are not static but are
  developing rapidly to better treat this disease
• Curing cancer while protecting tissue function
  will need a combination of the best of all
  treatment options

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Gantries provided by mirror reflection of laser
Acceleration modes Target Normal Sheath
Acceleration Ion energy a I0.5 Radiation
Pressure Acceleration Ion energy a I
laser power gt 1020 W/cm2
Target
E gt 1012 Vm-1
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The Costs

• Turn-key centres with up to three treatment rooms
  that can operate virtually simultaneously cost
  c. 70 Million
• Proton only cyclotron plus single gantry
  treatment room, 25M
• Treatment costs 8000 - 25,000 depending on
  complexity and numbers of treatments required
  (Complex conventional radiotherapy costs 4000 -
  5000, prostate seed brachy around 9000)
• German insurance-based health system now funding
  proton / ion therapy at around Euro 20k per
  course
• Saving of long term costs of side effects in many
  cases and costs of long-term care of patients
  with recurrent cancer

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Proton Therapy beam-lines

• Passive Scattering beam-lines
• The focussed beam from the accelerator is
  scattered, (by a metal foil) to form a broad beam
• Spot-scanning beam-lines
• The focussed beam from the accelerator is used
  directly to irradiate the patient, and is
  raster-scanned to cover the target volume as
  required

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Passive Scattering Beam-lines

• The beam can be shaped by a collimator to conform
  to the x-y dimensions of the tumour
• The beam can be shaped in depth (z) by use of
• A fixed range-shifter to reduce the overall
  proton beam range
• A patient specific compensator to match the
  distal edge of the PTV
• A patient specific modulator to spread the
  Bragg peak over a range of depths to cover the
  PTV

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The Benefits improved dose distributions

• Children and young adults with cancer reduced
  collateral organ doses risk of second cancers,
  organ dysfunction, growth retardation, skeletal
  deformity, sterility etc
• Safer dose escalation for improved cure and / or
  reduced side effects
• Reduced bone marrow doses tolerance of
  chemotherapy and radiotherapy will improve

• Curable cancers close to spine and brain,
  applications in head and neck, base of skull,
  orbit, meningiomas, sarcomas, primary
  intra-thoracic cancers
• Difficult locations, e.g. porta
  hepatis/liver/para-aortic nodes
• Pelvis esp. patients with metallic hip
  replacements
• Breast enlarged heart/ significant pulmonary
  disease

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Passive Scattering Simple Schematic
Source Degraders
Fixed Collimator
Patient compensator
Range Modulator
Patient collimator
Dose
Range Shifter
Depth
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Spot Scanning beam-lines

• The beam direction is altered in a raster-scan
  across the target volume
• The beam energy is varied (either by the
  accelerator or with a moving range-shifter) to
  provide the range required for the present z
  position
• The dwell-time of the spot beam in each position
  is varied according to the requirements of the
  treatment plan

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Spot-scanning beam-line schematic
Scanning magnets
Moving wedge Range-shifter
Dosimetry system Position and dose sensitive
Dose
Depth
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Comparative aspects of different therapeutic
beams in medicine
x-rays neutrons protons helium ion carbon ion
Attenuation with depth Pseudo- exponential Pseudo- exponential Bragg Peak Bragg Peak Bragg Peak
Integral biological dose high highest low lower lowest
Average RBE 1 3 1.1 1.4 3
Oxygen modification factor 2.5-3 1.5-1.8 2.4 2.3 1.7-1.8
refer to relative peak dimensions
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Radiobiological complexity of ions SOBP

• T. Kanai et al, Rad Res, 14778-85, 1997 (HIMAC,
  NIRS, Chiba, Japan)

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Recovery ratios i.e. -Log ratios of surviving
fractions At low dose (?H - ? L) d At high
dose (?H - ? L) d (?H - ?L) d2 The least
recovery is at low dose. RBE is higher at low
dose
RBE2
Low LET
RBE1.9
High LET
RBE1.8
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Survival curves, high and low LET
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High LET radiobiology
OER
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The BNCT Reaction
Tissue Cell
Alpha 1.47 MeV
Gamma 0.478 MeV
B 10
B 11
Neutrons
Li 7 0.84 MeV
The range of the ions is about 9mm cell
diameter. Thus the radiation damage is localised
to the cell in which the boron containing
compound is located.
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The actual treatment facility
Proton beam-tube Heavy water reservoir FLUENTALT
M moderator Li-polythene delimiter /
shield Heavy water inlet To pumps /
chiller Neutron source is gt 1 x 1012 s-1
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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.

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LAT-1 expression in GBMs
Photomicrograph of tumour cells in GBM showing
the LAT-1 cells as red, PCNA (proliferating)
cells as blue and the LAT-1PCNA cells as
red-blue (arrows) Slide courtesy of A Detta
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Results for counted stained cell populations in
GBMs
60-90 of tumour cells express LAT-1 A much
lower proportion are proliferating
Slide courtesy of A Detta
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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, 209-1218)
• CANCER RESEARCH 64, 23172323, 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
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Synchrotron Stereotactic Radiotherapy (SSR)
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)
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