Transcript Physics - based techniques for the treatment of cancer

Physics - based
techniques for
the treatment of
cancer
translational research
from the physics
laboratory to the clinic
Stuart Green
University Hospital Birmingham
and British Institute of Radiology
Rutherford Appleton Lab
March 2009
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 O’Hehir, Adam Baker
and Mohammed Sidek
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.
Overview of techniques and projects
• External beam treatments
– X-ray therapy
– Proton and ion beam therapy
localised
disease
• Binary therapies
– Boron Neutron Capture Therapy locally spread
disease
– High Z enhanced radiotherapy
• Improving the dosage of chemotherapy
drugs
Systemic disease
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
Probability
– 50% is by surgery
– 40% by radiotherapy
– 10% by drugs
TCP
•
NTCP
50
60
70
80
Dose / Gy
BUT most cured patients need
ALL of these treatments
Standard radiotherapy technology
IMRT
Evolving radiotherapy
techniques
standard radiotherapy
3D-conformal radiotherapy
Intensity Modulated
Radiation Therapy
Conventional RT dose distributions
Conformal RT dose distributions
Conformal radiotherapy
- the limitations
Conformal RT cannot produce concave
dose distributions...
Intensity Modulated Radiation Therapy
….IMRT can!
Intensity modulation
Treatment issues and capabilities
• Multimodal imaging
• Respiratory motion
• Imaging during
treatment
• Improved dose
delivery (IMRT etc)
New dosimetry techniques - DOSI
Specifications:
• Si (single crystal) detectors
• 128 channels
• 0.25 mm pitch
• tINT > 10 sec
•Qmax = 15 pC
Off Axis Ratio
1.0
QE 7.5 mm
QE 10 mm
QE 12.5 mm
QE 15 mm
QE 17.5 mm
QE 20 mm
QE 22.5 mm
QE 25 mm
QE 27.5 mm
QE 30 mm
QE 32.5 mm
DOSI 7.5 mm
DOSI 10 mm
DOSI 12.5 mm
DOSI 15 mm
DOSI 17.5 mm
DOSI 20 mm
DOSI 22.5 mm
DOSI 25 mm
DOSI 27.5 mm
DOSI 30 mm
DOSI 32.5 mm
0.8
R (%)
0.6
0.4
Approx 5 cm
0.2
0.0
From Dr Spyros Manolopoulos, STFC (now Bham)
Recent Publications in Medical Physics and PMB
0
5
10
15
x (mm)
20
25
30
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
Approaches to cancer treatment
ANTIPROTONS
Protons and x-rays compared
Unavoidable
dose
Proton therapy in UK: we already have it!
• World First: hospital based proton
therapy at Clatterbridge, Liverpool,
[converted fast neutron therapy
facility].
• >1400 patients with ocular
melanoma; local control >98%.
• First example of 3D treatment
planning in UK
• Unsung success story of British
Oncology.
• 62 MeV protons so eye tumours
only
To be able to treat
deep seated
tumours
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
The Siemens synchrotron system
Medulloblastoma in a child (MD Anderson)
100%
60%
10%
Patients treated prone with 3 field technique
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
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 1990’s
• 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)
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)
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
Proton dosimetry jig
Experimental setup
primary
collimator
optional
collimator
MD55
proton jig
?? MeV protons
compression
plunger
transmission chamber
Markus chamber
absorbers
Experiments using the Birmingham cyclotron
FLUKA, Gaf Chromic film (MD-55) and
ionisation chamber measurements
200
180
Markus
160
Markus spline
FLUKA, 29.3 MeV, 0.25%
Scaled Dose /Gy
140
MD-V2-55
120
100
80
60
40
20
0
0
0.1
0.2
0.3
0.4
0.5
Depth in PMMA / g/cm^2
0.6
0.7
0.8
0.9
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
Glioblastoma - clinical course
Head trauma
9M before
Mild headache
post-surgery
9M
Post-chemoradiotherapy
Courtesy of Tetsuya Yamamoto, Tsukuba, Japan
Glioblastoma
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).
Standard XRT for GM
Main tumor mass
Surrounding brain with
Surrounding brain with
Infiltrating tumor cells
Infiltrating tumor cells
Tumor
mass
Courtesy
of Tetsuya Yamamoto, Tsukuba, Japan
8
Performance status, age and survival
Survival (months)
35
70-100
40-60
20-30
30
25
20
15
10
5
0
<40y
40-60y
Age
>60y
Boron Neutron Capture Therapy
Dose escalation studies for GBM
Conventional XRT
BNCT plus XRT
XRT plus boost
Edema
Main Tm
3-step cone-down
Courtesy
of Tetsuya Yamamoto, Tsukuba, Japan
11
Medical Physics Building (The Radiation Centre)
Dynamitron
Cyclotron vault
Protons
Maze
Li target, Beam moderator / shield
Neutrons
Li target during fabrication
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 1012 s-1
Thermal neutron intensity map
Thermal neutrons per source neutron
-4
x 10
160
4
140
3.5
120
3
100
2.5
80
2
60
1.5
40
1
20
0.5
20
40
60
80
100
120
140
160
180
200
FLUKA – Radioactive inventory calculations
Isotope
Peak Activity*
(Bq/cm³)
Uncert
(%)
Half life
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
3H
Rob Chuter and Nigel Watson, 2007
*Max value in system for a 1mA proton beam
In-phantom dosimetry
Leads to beam
monitor chambers
Ionisation chamber
water phantom
(40 x 40 x 20 cm)
12 cm beam aperture
Doses to Tumour and normal cells
Measurements and MCNP, Weighted
Doses to normal brain
12.00
fast n
photon
nitrogen
boron
MCNP fast n
MCNP photon
MCNP nitrogen
MCNP Boron
total
MCNP total
Weighted Dose (Gy/MU)
10.00
8.00
6.00
4.00
2.00
0.00
0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
Depth (cm)
Assuming 10B at 15 g/g, N at 2.2% and “usual” RBE/CBE factors
The Tsukuba approach
Surgery
XRT
BNCT
Proton
Courtesy of Tetsuya Yamamoto, Tsukuba, Japan
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
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,
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
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
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
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
Gantries provided by mirror reflection of laser
Acceleration modes
laser power >
1020 W/cm2
Target Normal Sheath Acceleration
Ion energy a I0.5
Target
Radiation Pressure Acceleration
Ion energy a I
E > 1012 Vm-1
Laser
High power
pulsed Laser
Mirror
Patient on horizontal
treatment couch capable of
3600 rotation & elevation
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
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 rasterscanned to cover the target volume as required
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
The Benefits: improved dose distributions
• Children and young adults
• Curable cancers close to
with cancer: reduced
spine and brain, applications
collateral organ doses & risk
in head and neck, base of
of second cancers, organ
skull, orbit, meningiomas,
dysfunction, growth
sarcomas, primary intraretardation, skeletal
thoracic cancers
deformity, sterility etc
• Difficult locations, e.g. porta
• Safer dose escalation for
hepatis/liver/para-aortic
improved cure and / or
nodes
reduced side effects
• Pelvis [esp. patients with
• Reduced bone marrow
metallic hip replacements]
doses; tolerance of
• Breast [+enlarged heart/
chemotherapy and
significant pulmonary
radiotherapy will improve
disease]
Passive Scattering – Simple Schematic
Source
Degraders
Fixed
Collimator
Range Modulator
Range Shifter
Patient
compensator
Patient
collimator
Dose
Depth
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
Spot-scanning beam-line schematic
Scanning magnets
Dosimetry system
Position and dose sensitive
Moving wedge
Range-shifter
Dose
Depth
Comparative aspects of different therapeutic beams in medicine
x-rays
neutrons
protons
helium
ion
carbon
ion
Attenuation
with depth
PseudoPseudoBragg
exponential exponential Peak *
Bragg
Peak **
Bragg
Peak***
Integral
biological
dose
high
highest
low
lower
lowest
Average
RBE
1
3
1.1
1.4
3
1.5-1.8
2.4
2.3
1.7-1.8
Oxygen
2.5-3
modification
factor
* refer to relative peak dimensions
Radiobiological complexity of ions SOBP
T. Kanai et al, Rad Res, 147:78-85, 1997 (HIMAC, NIRS, Chiba, Japan)
‘Recovery’ ratios
i.e. -Log [ratios of
surviving fractions]
RBE=2
RBE=1.9
Low
LET
At low dose :
(aH - a L) d
At high dose :
High
LET
(aH - a L) d +
RBE=1.8
(H - L) d2
The least recovery is
at low dose. RBE is
higher at low dose
Survival curves, high and low LET
High LET radiobiology
OER
The BNCT Reaction
Tissue Cell
B 10
Alpha
1.47 MeV
B 11
Gamma
0.478 MeV
Neutrons
Li 7
0.84 MeV
The range of the ions is about 9m ~cell diameter. Thus the radiation damage
is localised to the cell in which the boron containing compound is located.
The actual treatment facility
Proton beam-tube
Heavy water reservoir
FLUENTALTM moderator
Li-polythene delimiter / shield
Heavy water inlet
To pumps / chiller
Neutron source is > 1 x 1012 s-1
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.
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-1+PCNA cells as
red-blue (arrows)
Slide courtesy of A Detta
A
Results for counted
stained cell populations
in GBMs
100
LAT+
PCNA
90
+
X-Bar = 72.6 ± 16.9
+
X-Bar = 22.8 ± 16.9
+
LAT PCNA X-Bar = 4.8 ± 2.2
n = 29
80
70
60-90 % of tumour cells express LAT-1
60
50
A much lower proportion are
proliferating
40
30
20
10
Slide courtesy of A Detta
0
LAT +
PCNA+
LAT + PCNA+
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, 2091218)
CANCER RESEARCH 64, 2317–2323, 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
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
SR
S
R
beam fitted to the tumour size
tumour = center of rotation
monochromatic beam
From the work of Boudou et al based around ESRF, Grenoble