Transcript Applications of the CXS to Cancer Medicine

Applications of the CXS to Cancer Medicine
E.C. Landahl, J. Boggan, W. Frederick, N.C. Luhmann, Jr.
Departments of Applied Science and Electrical and Computer Engineering, University of California, Davis
D. Matthews
Medical Technologies Program, Lawrence Livermore National Laboratory
V. Cooper, K. Iwamoto, A. Norman, T. Solberg
Departments of Radiation Oncology and Biomedical Physics, University of California Los Angeles
Dose and Contrast for Radiography
For a given target dimension x, what dose is needed
to achieve the desired contrast?
Contrast as Well as Spatial Resolution is
Important for Radiography
m1
m2
m1 T
N ( SNR) (1  R) e

A
e
Dm 2 x 4
2
x
Contrast relative to
normal breast tissue
1
T
 Dm x
1 e
C
1 R
R is the ratio of scattered to primary radiation, SNR is the
desired Signal-to-Noise ratio, e is the detector efficiency, and
N/A is the number of photons per unit area
Improvements in Image Receptors
Motivate Smaller X-Ray Source Sizes
F is the intrinsic receptor unsharpness
 1 a
UT  F
 1   2
2
m  m F
1
2
m is the magnification
.01
.001
1 mm
glandular tissue
10 20 30 40 50
Energy (keV)
Source: NIST
After S. Webb, The Physics of
Medical Imaging
• Contrast decreases rapidly with photon energy
• Low energy means a high patient dose
• Ideally, energy would be tuned to reach a desired contrast
Application of the Compton X-Ray
Source to Mammography
UT is the total unsharpness
2
0.1 mm
calcification
.1
100 mm
calcification
SNR = 5
men/r = 0.439 cm2/g
Dm = 3.6 mm-1
R = 200%
Ex = 20 keV
e = 30%
T = 20 cm
A = 100 cm2
a is the source size
Total Unsharpness / Intrinsic
Receptor Unsharpness
Total Unsharpness vs. Magnification
2.5
Conventional
2
a / F = 4 (large source)
New
1.5
a/F=2
1
a/F=1
0.5
a / F = 0 (small source)
Compton X-Ray Source
0
1
1.2
1.4
1.6
Magnification
1.8
2
CXS-1000 Flux
1.2 mGy is a
typical dose for
a cranio-caudad
projection
X-Ray Phototherapy for Integrated Targeted Cancer Diagnosis and Treatment
Data #1
1
10
0.1
Survival fraction
Dose to
Tumor is
Doubled
8
DEF
XPT Simultaneous Imaging and
Treatment of Canine Brain Tumors
20 mg I/ml
10 mg I/ml
5 mg I/ml
6
4
2
7 m g I/m l
14 m g I/m l
0.001
20
40
60
80
100 120
0.0001
0
1
2
3
4
Dose (Gy)
Energy (keV)
Dose to Bone
is Halved
Results of UIP Monoenergetic X-Ray Phototherapy Study
Before Treatment
Polyenergetic XRay Phototherapy
0.01
0
0
Conventional 10
MV Radiation
Therapy
0 m g I/m l
During Treatment
4X Increase in
Therapeutic
Ratio from
Monoenergeti
c X-Rays
•Calculated Dose Enhancement Factors (DEF) show wide
variation over the energy distributions of conventional xray devices
•Data taken at APS December 2001 shows contrast media
has anticipated PC3 cell kill in conjunction with 60 keV
monoenergetic x-rays
During Treatment
After Treatment
•Large errors due to the difficulties of using synchrotrons
for this type of research  CXS will be used for this type
of research in the future
Non-invasive Molecular Cancer Treatment Utilizing the CXS in Combination with Targeting Agents
Radiation Induced
Single Strand Break
Cisplatin-DNA adduct
Repair
Cisplatin-DNA adduct
Repair
Non-repairable damage
Non-repairable damage
Cell death
In conventional external beam
radiation therapy, sparsely
ionizing x-rays pass through a
target cell, only occasionally
depositing energy
In X-Ray Phototherapy, sparsely
ionizing x-rays are selectively
absorbed by high Z atoms which
are likely localized in extracellular
regions near target cells.
If contrast agents can be introduced
into sub-cellular regions, the x-ray
energy could be tuned closer to the
absorption edge, reducing the range
of the radiation byproducts so that
they are densely ionizing and more
likely to create DNA double strand
breaks
CXS Chemoradiotherapy. Left: Cisplatin-DNA
adducts (green) and radiation-induced singlestrand breaks (red) in close proximity result in nonrepairable damage and cell death.
Right: CXS xrays (red arrow) tuned to the Pt absorption edge
are absorbed in proximity to the adduct and
deposit radiation byproducts (orange) creating
nearby single strand breaks and increasing
likelihood of non repairable damage and cell death.
Advanced Treatment Methods
•Unique radiation responses to targeted sub-cellular X-Ray
Phototherapy may be a new parameter to adjust during
radiation therapy
•Specific x-ray energy / contrast agent combinations may
alter patient response to treatment based upon a predetermined molecular cancer profile
•X-Ray Phototherapy radiation inducible promoters for
gene therapy could have improved targeting or efficiency
over existing promoters
CXS monoenergetic x-rays
Chimeric promoter/
cytotoxic gene
Tumor cell
Heavy metal
containing targeting
agent
Cell death
Induced
Gene
Expression
•Advanced agents may incorporate a resonant x-ray
triggered conformation change to deliver chemotherapeutics
only upon external activation