BASIC RADIATION BIOLOGY OF PHOTONS AND PROTONS
Martin PruschyDept. Radiation Oncology University Hospital Zurich
Tumour
control
Increase the Therapeutic Window Using Proton Irradiation
Physics -
BiologyE
ffect
Tumor Dose
Normal tissue damage
TI = Therapeutic Index
TI
Effe
ct
Tumor Dose
Normal tissue damage
TI = Therapeutic Index
TI
„protons
attractive: physical
dose distibution; but
radiobiologically
unremarkable“„indistinguishable
from
250kV x-rays“
Biological
Considerations
LET: particle (proton) vs photonsparsely ionizing
DNA-damageMode of cell deathIntracellular signallingTumor microenvironmentNormal tissue toxicity
Relative Biological Effectiveness (RBE)
Definition of RBE
Ratio of D250/Dr: (as defined by National Bureau of Standards, 1954)Doses of x-rays (D250kV) and the test radiation (Dr) required for equalbiological effectCGE = RBE x (physical proton dose)(cobalt
gray
equivalent)
RBE depends on multiple parametersRadiation quality (LET); dose; numbers of dose fractions; dose rate
Which endpoint is considered?Which treatment regimen is compared?
Biological
explanation
forLET dependence
/optimum
LET: descriptor
of energy
transferred
from
the
beam
to the
irradiated
materialper units
of particle
path
length
(e.g. keV/μm)
with
increasing
LET (linear energy
transfer):
-the
slope
of the
survival
curve
gets
steeper-size
of initial
shoulder
gets
smaller
RBE: LET dependence
(2kEV/μM)
more
than
1 track
required
forx-ray/proton-induced
DSB:(sparsely
ionizing)
The
RBE has no unique
value
Dose dependence Regimen
dependence
X-ray: large shoulder; Neutrons: small
initial
shoulderRBE generally
increases
as dose decreases
The
oxygen
effect
and LET
Open circles: normoxic
conditionsClosed
circles: hypoxic
conditions
Oxygen
Enhancement
Ratio as a function
of LET
Extending the dose in depth –
the ‘Spread-out-Bragg- peak’
target
depth
dose
Proton energy
spectra
changes
over
depth
of a monoenergetic
beam
(150MeV)
Highest
LET at the
most
distal
edge, due
to the
stopping
power of the
low
energy
protons(dose deposited
increases
with
depth)
RBE in vitro/in
vivo studies
(dose; α/β
etc): upcoming
lecture
by
H. Paganetti
Photon vs
Proton Irradiation: The cellular response to radiation damage
DNA damage
Damage is excessive and/or irreparable
Activation of the survival response network
Stress Cell cycle DNA response checkpoints repair
SURVIVAL
Mutations, chromosomal
aberrationsAPOPTOSIS
MALIGNANT TRANSFORMATION
MITOTIC CATASTROPHE
SENESCENCE
Amount and type of damage can be handled
DNA damage
Damage is excessive and/or irreparable
Activation of the survival response network
Stress Cell cycle DNA response checkpoints repair
SURVIVAL
Mutations, chromosomal
aberrationsAPOPTOSIS
MALIGNANT TRANSFORMATION
MITOTIC CATASTROPHE
SENESCENCE
Amount and type of damage can be handled
RBE 1.1
? ? ?
- Repair
- Reassortment
of Cell
Cycle
(Redistribution) (redistribution
into
more
sensitive/resistant
cell
cycle
phase)
- Repopulation(rapid repopulation
of clonogenic
tumor
cells
during
treatment)
- Reoxygenation: (hypoxic
clonogenic
cells
become
better
oxygenated
after
IR-
fraction)
- (Intrinsic) Radiosensitivity
5 R‘s
of RadiotherapyFavorable alteration of tumor biology
„DNA is
not
the
only
Target Structure“
- RepairDNA-Repair Inhibitors (DNA-PK, PARP; ATM)
- Reassortment
of Cell
CycleCellCycle-Inhibitors/Abrogators
- RepopulationRTK-Inhibitors
- ReoxygenationInhibitors of AngiogenesisTumor Hypoxia Modulators
- (Intrinsic) RadiosensitivityModulators of Apoptosis
5 R‘s
of Radiotherapy
Fractionated
Irradiation
Repair: Improved
Recoveryof Normal Tissue
Reoxygenation
Repopulation
Redistribution
Favorable
alteration of tumor
biology by altered radiation scheduling
DAMAGE STRESS- RESPONSE
IONIZING RADIATION
Receptor
Tyrosine
Kinase-PI3Kinase -
PKB/Akt-pathway
- Tumor Cell
Level- Vascular
Level
0 2 4 6 8 10 120
5000
10000
15000
dsb
ssb
bd
IR Dosis (Gy)
Am
ount
of D
NA
-dam
age
per C
ell
~ 2000 per Cell per Gy
~ 1000 per Cell
per Gy
~ 30 per Cell per Gy
Amount
Repair and Recovery
Ionizing radiation
Double strandbreaks
Basedamage
NHEJHR
Single strandbreaks
SSBR
short patch
BER
long patch
damage senors damage sensors
WHAT IS THE BEST TARGET?
SSB DSB
(backup)
Repairing damage after X-rays
Correct
and Incorrect RepairDouble strand breaks
not repaired
1%
correct repaired96%
Incorrect repaired
3%
2 DSB on1 Chromosom
2 DSB on2 Chromosoms
DSB
Metaphase
Micronuclei
G1-Phase
Cell Proliferationwith MN
without MN
Proliferative CellInactivated Cell
azentricfragment
Chromosomal aberrations →
Loss of clonogenicity
(Inactivation)
Azentric fragments are removed via micronuclei : loss of DNA :: Loss of essential proteinsCells stop proliferation after 2-4 divisionsreproductive cell death (also (post-)mitotic cell death)
Green et al., Radiat
Res. 155,32ff 2001
Mitotic
Cell
Death
-
Micronuclei
Formation
RBE micronuclei
: 1.7Larger micronuclei: more
severe
damage(Thyroid
follicular
cells250MeV protons))
Micronuclei
as measure
of chromosomal
damage
Mode of cell
death: Apoptosis
Green et al., Radiat
Res. 155,32ff 2001
Thyroid
follicular
cells(250MeV protons)
DNA DAMAGE RESPONSE
DNA SENSORS
DNA EFFECTOR PATHWAYS
Programmed
Cell
Death(killing
damaged
cells)
DNA Repair
Pathways(physically
repair
DNA breaks)
Damage
Checkpoints(blocking
temporarly
or
transientlycell
cycle
progression)
DAMAGE SIGNALING
The cell cycle multiplies cellsThe cell cycle consists of two major phases:
Interphase,chromosomes duplicate and cell parts are made90% of the cell cycleNormal cell functions carried out
The mitotic phase cell division
There are checkpoints during which the cell “checks”
whether to
continue progressing through the cell cycle.
Checkpoints
DNA damage?Nutrients?Growth factors?
ATM –
a damage signaling molecule
Irradiation
of human lens
epithelial
cells
6hs after
4 Gy Radiation
Chang
et al., Rad Research; 164, 531-539, 2005
Qualitative and Quantitative Differences
in Expression Level of Key Proteins
p21
diff. cell cycle checkpoint activation patternmicroarray studies will follow
Withers
et al., Acta Oncol. 27: 131-146, 1988
Mainly in Head&NeckAccelerated repopulation after > 3-4 weksLoss of up to 0.6 Gy /day
Repopulation
Nu
mb
er
of
via
ble
tum
or
cells
1010
109
108
107
106
105
Treatments with radiation
Slow repopulation
rapid repopulation
accelerated repopulation
Nu
mb
er
of
via
ble
tum
or
cells
1010
109
108
107
106
105
Treatments with radiation
Slow repopulation
rapid repopulation
accelerated repopulation
Eriksen et al: IJROBP, 58, 561ff, 2004
Tumors with
high EGFR-benefit
from
reduced
overall
treatment
time (accelerated
schedule, supraglotic
larynx
SCC, DAHANCA)
Will you
use
same
stratification
parameters
for
Proton-C225 and for
Photon-C225 or
for
accelerated
treatment
regimen?
extracellular domain
intracellular domain
membrane
Tyrosine KinaseActivation
Ligand
Ionizing Radiation
ProliferativeSignaling
Anti-Apoptotic Signaling
Expressionof VEGF
Repopulation Intrinsic Radioresistance
Angiogenesis
Cellular Level
Relevant forRadiotherapy
P
PP
P
Overexpression
extracellular domain
intracellular domain
membrane
Tyrosine KinaseActivation
Ligand
Ionizing Radiation
ProliferativeSignaling
Anti-Apoptotic Signaling
Expressionof VEGF
Repopulation Intrinsic Radioresistance
Angiogenesis
Cellular Level
Relevant forRadiotherapy
PP
PPPP
PP
Overexpression
DNA Repair
NHEJ
extracellular domain
intracellular domain
membrane
Tyrosine KinaseActivation
Ligand
Ionizing Radiation
ProliferativeSignaling
Anti-Apoptotic Signaling
Expressionof VEGF
Repopulation Intrinsic Radioresistance
Angiogenesis
Cellular Level
Relevant forRadiotherapy
P
PP
P
Overexpression
extracellular domain
intracellular domain
membrane
Tyrosine KinaseActivation
Ligand
Ionizing Radiation
ProliferativeSignaling
Anti-Apoptotic Signaling
Expressionof VEGF
Repopulation Intrinsic Radioresistance
Angiogenesis
Cellular Level
Relevant forRadiotherapy
PP
PPPP
PP
Overexpression
DNA Repair
NHEJ
Reoxygenation
OER (oxygen
enhancement
ration) for
protons
is
similar
to x-rays, namely
2.5 to 3.How
will diff. fractionation
schedule
affect
OER and RBE?
Proportion of hypoxic
cells
as a function
of time
“Hypoxic Tumors are Radioresistant”
Relative Radiosensitivity
of Tumor
Cells as a Function of Tissue pO2
760 mm Hg = 100%155 mmHg
= 21%20 mm Hg = 3 %
Critical
range(0 –
20 mm Hg)
+IR
+ IoA + IoA
REDUCED HYPOXIA INCREASED HYPOXIA
Fractionated
Irradiation
Repair: Improved
Recoveryof Normal Tissue
Reoxygenation
Repopulation
Redistribution
Favorable
alteration of tumor
biology by altered radiation scheduling
α/β
Value (Ratio)
PROVIDES AN INDICATOR OF THE RELATIVE IMPACT OF FRACTION SIZE.
Small α/β → Fraction size has BIG effect
Large α/β → Fraction size has SMALL effect
S = e-(αD+βD2)
CHALLENGES (from
biological
point of view):
Generic RBE of 1.1 is currently used
RBE is variable
Where does RBE-value derive from?
How do we explain differences on molecular and cellular level?
Can we exploit these differences – are the same 4/5 R‘s relevant?
Stratification along biological parameters; genetic background?
Proton therapyProton therapy
+
Stratification
based
on biological
rationale (e.g.genetic
background)
Bon appétit
Apoptosis: quantitative and qualitative differences
Enhanced
induction
of early
apoptosis
in responseto proton
irradiation
in PC3 prostate
cancer
cells(but
with
26,7 MeV proton
beam: inceased
LET)Pietro et al., Apoptosis, 11, 57-66, 2006
10 Gy 20 Gy
Extending the dose in depth –
the ‘Spread-out-Bragg- peak’
target
depth
dose
Proton energy
spectra
changes
over
depth
of a monoenergetic
beam
(150MeV)
Highest
LET at the
most
distal
edge, due
to the
stopping
power of the
low
energy
protons(dose deposited
increases
with
depth)
RBE versus
dose: in vivo studies
- In the
center
of the
SOBP- acute
and late-reacting
tissue
systems(jejunal
crypt
cells, lung, skin, etc)Paganetti
et al., IJROBP, 2002, 53, 407ff
Gerweck
et al., Green Journ., 50, 135ff, 1999
RBE values
as a funtion
of α/β
A tendency
for
increasing
RBE for
cells/tissues
with
smaller
α/β
ratios
Summary
RBE 1.10
Data are avaliable only from cellular and animalexperimentsno human-tissue response dataClinical experience does not indicate that RBE value isdifferent from 1.10Generic value of 1.10 fits best pooled RBE values fromin vivo studies
Do we need to take microdosimetry-values intoconsideration? Fractionation? Dose Rate?Where does diff. RBE derive from?
RBE versus
dose: in vitro
studies
Paganetti
et al., IJROBP, 2002, 53, 407ff
- in the
center
of the
SOBP
- as a function
of dose- CHO, CoCa, V79 lung
fibroblast; diff. cell
lines, etc
Protons: Efficient
ROS generation
Dose response
for
ROS generation
Giedzinski
et al., Rad Res. 164, 540ff, 2005
ROS generation
Proton vs
Photon
diff. survival signal activation pattern(250 MeV protons)
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