The Radiobiology Behind Alternate
Physical Forms of Radiation Delivery
Bill McBride
Dept. Radiation Oncology
David Geffen School Medicine
UCLA, Los Angeles, Ca.
wmcbride@mednet.ucla.edu
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Alternatives Forms of Radiation
Delivery
Sometimes called
plesiocurie therapy
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The Alternatives are Growing!
Category
Particle
Implementation
Brachytherapy
Isotope Based
Ultra low dose rate, LDR, HDR
Proton
Synchrotron
Heavy Ion
Heavy Ion Centers
Photon
SRS - GammaKnife®
Photon
Tomotherapy®
CyberKnife®
X-Knife®
SRT, 3D-CRT, IMRT, IGRT
Particle
Cobalt60 Based
Linear
Accelerator
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Brachytherapy
Therapeutically
relevant range 3-20mm
Potential radiobiological
advantage in reduced
exposed normal tissue
volume and dose
distribution fall-off.
Relative dose
Seed
100
10
1
0.1
Normal
tissue
125I
r1
r2
Dose falls off with one upon the square of distance
0
1
2
3
4
5
6
Distance (cm)
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Brachytherapy
• Potential radiobiological advantages of brachytherapy
include varying treatment times
– Short treatment time could prevent tumor
repopulation,
– Longer could redistribute cells into sensitive cell
cycle phases,
– Longer could allow re-oxygenation with time after
implantation.
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• ULDR
– 0.01 - 0.3 Gy/hr
– permanent implants
– 125I, 103 Pd
• LDR
– 0.4 - 2 Gy/hr
– treatment times of 24 - 144 hrs
– 226 Ra, 137 Cs
• HDR
– 12 - 430 Gy/hr at 1 cm
– treatment time in mins to hrs
–
60Co, 192Ir
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LDR and HDR Brachytherapy
• LDR differentially spares late-responding tissues
compared to early-responding normal tissue and
tumors
• HDR is assumed to compromise the radiobiological
advantage of LDR in favor of patient convenience,
minimizing risk to staff, and better dosimetry
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Dose Rate Effects
• In general decreasing dose rate decreases
killing, however in some cases there is an
inverse dose rate effect, which is thought to
be due to redistribution and cells piling up in
the radiosensitive G2 cell cycle check point.
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Inverse Dose Rate Effect
HeLa cells log
phase
V79 cells log
phase
0.55 Gy/hr
1.54 Gy/hr
1.43 Gy/hr
1.54 Gy/hr
1.43 Gy/hr
Dose (cGy)
Dose (cGy)
Mitchell J.B. et al., Rad. Res. 79:552, 1979
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0.55 Gy/hr
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Inverse Dose Rate Effect
a/b = 10
1/2 s2 = 0.02
T1/2 repair = 0.7 hr
T1/2 resens. = 4 hr
1
T1/2 pot = 33 hr
0.1
0.1Gy/hr
S.F.
0.01
0.15 Gy/hr
1 Gy/hr
0.75 Gy/hr
0.25 Gy/hr
0.001
0
10
20
30
Dose (Gy)
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40
R. Suwinski
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Determinants of Radiation Response
• Repair
• Repopulation
• Redistribution
Resensitization
• Reoxygenation
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LQR Model
• A LQR model that takes into account repair, repopulation, and
resensitization
• Assumes decrease in radiosensitivity immediately after
irradiation followed by a resensitization phase
• Assumes intratumoral heterogeneity that averages out
oscillations in the process of resensitization
• Assumes resensitization can be described by a single amplitude
and a single characteristic time
Brenner et al. Int. J. Rad. Oncol. Biol. Phys. 32:379, 1995
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A Mathematical Model
S = exp [ - a.D
one-track killing
- b.G(tr).D2
two-track killing
+ (1/2s2).G(ts).D2
resensitization
+ T/tp]
repopulation
where:
a is average of a Gaussian distribution with variance s2,
G is the generalized Lea-Catcheside function, and represents reduction in damage due to repair or
resensitization
tr is repair time in min.- hrs.,
ts is resensitization time in hrs.- dys.,
tp is the repopulation time,
and a total dose D is delivered in time T.
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Suggested Parameters
a
b
a/b
T pot
T 1/2
repair
T 1/2
1/2 s 2
sens
Early
0.3
0.03
10
2 dy s
1 hr
4 hr
0.01
Late
0.15
0.075
2
60 dy s
4 hr
4 hr
0.01
Prostate
0.225 0.053
Ca
4.3
30 dy s
3 hr
4 hr
0.01
Fast
Growing
Tumor
10
10 dy s
2 hr
4 hr
0.02
0.3
0.03
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A Mathematical Model
3.5
Therapeutic
Benefit
TUMOR
(a/b=10, Td=30 days)
vs.
LATE EFFECT
(a/b=2, Td>300 days)
3.0
2.5
2.0
1.5
1.0
The “Golden Zone”
0.5
0.0
40.00
30.00
20.00
10.00
8.00
6.00
4.00
2.00
1.00
0.80
0.60
0.40
0.20
0.10
0.08
0.06
Dose Rate (Gy/dy)
R. Suwinski
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125I
Implants
1
Initial dose rate of
1.68 Gy/day
0.1
SF
0.01
Fast Growing
Tumor
0.001
0
10
20
30
Dose (Gy)
40
50
Normal tissue
Slow Growing
Tumor
R. Suwinski
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•
•
•
•
•
Spatial distribution of dose
– advantage can be taken of dose fall off and optimizing dose
distributions. The geometric sparing factor (f)= effective normal tissue
dose/effective tumor dose, varies with time
RBE (125I may be 1.4, but hard to estimate)
Dose inhomogeneity, including, associated dose rate effects, can
however, be particularly severe in brachytherapy
Inhomogeneity may be beneficial when implant is sub-optimal and tumor
rapidly growing
Adequate dosage to the whole tumor is paramount
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Energetic Protons (65-250 MeV)
•
Advantages
– Good dose distribution with finite range in tissue
and rapid fall off (Bragg peak), but not laterally
due to scattering
– But need to spread out the Bragg peak - SOBP
• Active scattering using deflecting magnets and
scanning (IMPT)
• Passive scattering
•
•
•
•
•
Disadvantages
Best use of fall off depends on knowing the tumor
margins
Tissue density issues
Limited clinical data, no randomized clinical trials
High energy secondary neutrons with passive
scattering from materials in the beamline may carry
increased cancer risk with high Q factor
–
From Chen Neurosurg 23: 1-5, 2007
Biological properties of
protons (RBE and
OER) similar to X-rays
RBE=1.1 but may be 2 at
distal edge of Bragg peak
Brenner and Hall Radiotherapy Oncol. 86: 165-170, 2000
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Protons
• About 25 facilities operating worldwide, and growing.
– Over 50,000 patients have
been treated
• Due to excellent dose distributions,
have shown clear efficacy for:
– Choroidal melanoma
– Some spinal cord and brain
tumors
– Sphenoid sinus tumors
• Also being used for a wide
spectrum of tumors (e.g., prostate,
pediatric, lung, breast, head and
neck, etc.)
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Heavy Charged Particles
• Helium ions in UCB-LBL since 1954 to treat AVMs but the beams
were contaminated with photons and alpha particles
• Helium ions have biophysical properties like protons
– Good dose localization (Bragg peak)
– Must use spread out Bragg peak (SOBP)
• Carbon ions have the biological advantages of high LET
– Less OER and cell cycle dependency
– RBE increases strongly with LET and therefore depth doses are
hard to calculate
• An additional advantage may be ability to use PET to image target
volume
• Currently, only Japan and Germany heavy ion clinical facilities
– Over 5,000 patients now treated with heavy carbon ions
– Very good efficacy reported, e.g., chondrosarcoma at the base of skull, spinal
tumors, adeno cystic ca, locally advanced HNSCC.
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Neutrons
H2
Be9
n
High energy
deuterons
captured by
beryllium target
Stone, at LBL between 1938 and 1943, used Cyclotron neutrons to treat 240 patients using the
wrong RBE with severe late sequelae.
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Potential Biological Advantages of High LET
Radiations
• Reduced influence of hypoxia
– OER 1.4-1.7
• Reduced influence of repair
• Reduced cell cycle differential
• Higher RBE for slowly cycling tumors
– RBE for most normal tissues 3.0-3.5
– RBE for CNS 4.0-4.5
– RBE for salivary gland tumors = 8
(Larimore, G. Adv Radiat Biol 15:153, 1992)
RBE varies with the energy
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Poor Depth Dose Distribution of Neutrons
(from Hall 2000)
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Isoeffect Curves for Neutrons
Withers et al. Int J Radiat Oncol Biol Phys. 8:2071-6, 1982
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Clinical Trials with Neutrons
• Have been tested at a number of centers world-wide
• Disappointing results
– high incidence of late complications
– relatively poor depth dose distribution; fixed
horizontal beams
– reoxygenation in conventional radiation may
reduce importance of hypoxic cells
– poor patient selection
– Currently only about 5 centers
• Current uses primarily limited to salivary gland and
prostate cancers, and (limited) soft tissue sarcomas
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The BNCT
Reaction
Boron Neutron
Capture
Therapy (BNCT)
2.33 MeV of kinetic energy is released per neutron capture:
initial LET 200-300 keV/µm; RBE v. high; OER v. low
Li-7 recoil ion
5µ
0.477 MeV Gamma (94%)
thermal neutron
B-10
(<0.1 eV)
8µ
Alpha particle
Thermal cross-section = 3837 b (that’s very big…)
LET ~ 200-300 keV/mm
RBE high
OER low
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BNCT
• Limitations
– Lack of boron compounds with specificity
for tumor rather than normal tissue
– Getting enough into tumor
– Thermal neutrons are poorly penetrating
• Tumors tested clinically
– Glioblastoma multiforme
– Cutaneous melanoma
• Currently few sites conducting studies
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SRS and SRT
• SRS - one fraction
– First proposed by Leksell
• Arch Chir Scand 102:316-319, 1951
– SRS loses the advantage of dose fractionation
and often ends up as SRT
• SRT - fractionated
• There may be no advantage to dose fractionation
based on differences between tumor and normal
tissue in terms of a/b values, but this is based on
values around 2Gy. Other differences may exist
between large fraction size and single doses.
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IMRT etc.
• Since mid 1990s IMRT and related procedures have
been use to conform high dose areas to target
volumes with sharp dose fall-off to organs at risk
(OARs), potentially reducing morbidity
• This raises questions
– How do you best define GTV? CT, PET, MRI…
• Geometric miss a problem as margins decrease?
– Higher volume receiving lower dose
– Higher ‘integral’ dose
• Increased risk of cancer induction
• Should IMRT be used for pediatric patients?
– Increased time for delivery may decrease efficacy
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Xu et al. Phys. Med. Biol. 53 (2008) R193–R241
Radiation Type
Energy
Approx. dose to
primary
target
Approx. dose to tissue
outside the treatment
volume
1. Radiotherapy
a. External Beam
X-ray photons, electrons, protons and
neutrons
6-250 MeV
Up to 100 Gy
(or Gy x RBE)
Low dose region:
D< 5 Gy
Intermediate dose region
5 Gy < D < 45 Gy
High dose region
D > 45 Gy
b. Brachytherapy
Gamma-ray photons, electrons, and
neutrons (Ra-226, Cs-137, Ir-192, I125, etc)
< 2 MeV
~60 Gy
~ 1 Gy
c. Radioimmunotherapy (RIT)
Photons, electrons, alphas (Y-90, Bi-214,
etc)
< 5 MeV
~100 Gy
~ 10 Gy
2. Diagnostic Imaging
a.Radiography
X-ray photons
<150 kVp
~ 0.01 Sv
a.Multi-slice CT (4D)
X-ray photons
<140 kVp
~ 0.05 – 0.1 Sv
c. Interventional
Fluoroscopy
X-rays photons
<140 kVp
~ 0.5 Sv
d. Hybrid PET/CT
Photons/positrons
0.511 keV
~ 0.02 Sv
e. Cone beam CT
IGTR
X-ray photons
KV or MV
0.02 – 0.1 Sv per scan
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Non-Homogeneous Dose Distributions
• Historically, in RT homogeneous dose
distributions have been used. With IMRT,
more opportunities exist to use nonhomogeneous dose distributions
– Dose painting eg hypoxic regions, PET
positive regions, etc.
– Simultaneous boost technique
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Simultaneous Integrated Boost (SIB) Technique
• Dose > 2 Gy/fraction to the tumor and < 2 Gy/fraction on
the normal tissues
• Small volume with dose/fraction > 2 Gy
• Benefit of a reduced overall treatment time
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SIB IMRT
(49.9 Gy + 19.7 Gy)
Two-phase IMRT
(50 Gy + 20 Gy)
Courtesy of Ph. Maingon
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Final Thoughts
• How much are we going to gain by pushing
the limits of conformal types of therapy?
• Will the gains ever be properly evaluated?
• What about the economics?
• The greatest gain may come from being sure
we hit the tumor…….
• The radiobiology of low dose and high dose
delivery, and low dose rate and high dose
rate, are very likely different
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Questions:
The Radiobiology of Alternate Physical Forms of Radiation Delivery
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139. Low dose rate implants deliver
– <0.01 Gy/hr
– 0.1-0.4 Gy/hr
– 0.4-2.0Gy/hr
– 2.0-4.0 Gy/hr
#3 – A generally accepted figure…
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140. What is least likely to give a radiobiological
advantage for low dose rate implants
– Increased reoxygenation during treatment
– Sparing of late effect tissues
– Sparing of acute effects tissues
– Cell cycle redistribution
– Decreased dose heterogeneity
#5 – Dose heterogeneity is an advantage with implants
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141. The RBE of protons compared to standard
forms of RT is
– 1.0
– 1.1-1.2
– 1.4-1.5
– 2.0-2.5
– 3.0-3.5
#2 – The advantage, if there is one, is in dose
distribution
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142. The RBE of fast neutrons compared to standard
forms of RT is
– 1.0
– 1.1-1.2
– 1.4-1.5
– 2.0-2.5
– 3.0-3.5
#5 – However, for CNS it may be over 4.0
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143. Which is an advantages of fast neutrons
• Increased influence of oxygen
• They are more potent if given as a fractionated
course
• They are more effective against rapidly cycling
tumors
• They are particularly effective against salivary tumors
#4 – The data from Seattle (G. Larimore) suggests an
RBE of 8 for salivary gland tumors
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144. The OER of fast neutrons for most normal
tissues is
– 1.0
– 1.1-1.2
– 1.4-1.7
– 2.0-2.5
– 3.0-3.5
#3 – This may be due in part to beam contamination
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