BASIC RADIATION BIOLOGY OF PROTONS - CERN Document… · BASIC RADIATION BIOLOGY OF PHOTONS AND...

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



membrane


Ligand

Ionizing Radiation



Expressionof VEGF


Angiogenesis

Cellular Level


PP

PPPP

PP

Overexpression

DNA Repair

NHEJ



membrane


Ligand

Ionizing Radiation



Expressionof VEGF


Angiogenesis

Cellular Level


P

PP

P

Overexpression



membrane


Ligand

Ionizing Radiation



Expressionof VEGF


Angiogenesis

Cellular Level


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)

BASIC RADIATION BIOLOGY OF PROTONS - CERN Document… · BASIC RADIATION BIOLOGY OF PHOTONS AND...

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