ESTRO PT 2018

Refresher session Basic physics and radiobiology Oliver Jäkel, Vienna 2018

Oliver Jäkel

Medical Physics

Page 1

Depth dose characteristics

12MV X-rays

220 MeV/u C-12

Absorbed dose in %

Depth in water in cm

X-rays: Steep built-up; exponential attenuation of fluence

Particles: Bragg maximum; gradual slowing down to stop

Oliver Jäkel

Medical Physics

Page 2

Clinical depth dose Depth dose distributions of particle beams

Spared dose

Biol. eff. dose in %

Depth in water in cm

Significant reduction of integral dose in normal tissue

Oliver Jäkel

Medical Physics

Page 3

Proton RT for Medulloblastoma treatments

Stokkevåg et al. Acta Oncol 2014

Finite range of protons reduces dose to dose reduction in heart, lung, intestine, mediastinum

Oliver Jäkel

Medical Physics

Page 4

Beam Target Interactions

• Elastic and inelastic collisions • Interactions with electrons and nuclei • Coulomb and Nuclear interactions

Incident Proton or Ion (+)

Which are the Main Interactions of Interest in our field?

Oliver Jäkel

Medical Physics

Page 5

3 important interactions of particles with matter

Inelastic collision with nuclei:

production of neutrons and fragments

Inelastic collision with electrons: Dose

Elastic collision with nuclei:

multiple Coulomb scattering lateral penumbra

Oliver Jäkel

Medical Physics

Page 6

Energy loss & Stopping Power of charged particles

 E = E in -E out

E out

N in ≈ N out

12

N out

C ,N in

, E in

dE dx

 E  x

 x

The particles slowly loose their energy until they come to rest.

Linear stopping power is the mean energy loss dE of a charged particle per pathlength dx in a material: S = dE/dx

Mass stopping power is defined as S divided by the density r of the traversed material: S/ r

Oliver Jäkel

Medical Physics

Page 7

Energy loss of charged particles

Bethe formula: The average energy loss increases quadratically with the inverse velocity (1/v 2 ) and the charge of the particle (Z 2 )!

R=16cm H2O

Protons Carbon

Energy (MeV/u)

150

300

Velocity (v/c)

0,26

0,43

Charge (Z)

1

6

Energy loss (Mev/cm)

5,5

128,1

Hans Bethe 1930

The energy loss of a carbon ion is much higher than for protons. Where does this energy go? Very many low energy electrons are produced!

Oliver Jäkel

Medical Physics

Page 8

The meaning of high LET

Energy (or dose) can be transferred in different ways:

Low LET

High LET

High LET means, that more of the transferred energy is deposited into a smaller volume along the track!

Oliver Jäkel

Medical Physics

Page 9

Lateral scattering of carbon ions vs. protons

Proton penumbra in depth is not as good as for X-rays

Oliver Jäkel

Medical Physics

Page 10

Relevance of lateral penumbra Treatment plan for identical parameters (scanned beams)

Carbon (GSI)

Protons (MGH)

H. Suit et al, Radiat. Oncol. 2010

Oliver Jäkel

Medical Physics

Page 11

Cell survival curves for high LET radiation

High LET is more effective in cell killing Increasing effect with decreasing velocity Survival curves for high LET are linear

Oliver Jäkel

Medical Physics

Page 12

Definition of RBE

The relative biological effectiveness is defined as the ratio of doses of two rad. qualities to achieve the same effect.

Due to the shouldered photon response curve, RBE is dose dependent!

Oliver Jäkel

Medical Physics

Page 13

Dependence of RBE on cell type

D



RBE



Isoeffekt

D

Ion

RBE is higher for resistant cell types Ions are better suited for radio-resistant tumors and maybe also for hypoxic tumors

Oliver Jäkel

Medical Physics

Page 14

Direct and Indirect Radiation Damage

Indirect radiation damage • produces mainly single strand breaks ( SSBs ) • Needs oxygen • Dominates for low LET Direct radiation damage • More likely to produces DSBs • No oxygen needed • More important for high LET

High LET may be more efficient for hypoxic tumors

Oliver Jäkel

Medical Physics

Page 15

The principle of a particle accelerator

M. Schippers, PSI

Not that simple unfortunately…

Oliver Jäkel

Medical Physics

Page 16

Available accelerator types

M. Schippers, PSI

Oliver Jäkel

Medical Physics

Page 17

Classical beam delivery: Passive beam shaping

No optimal dose conformation Material in beam leads to neutron production Workshop needed to for patient specific devices Alignment very critical

Oliver Jäkel

Medical Physics

Page 18

Passive depth dose modulation

Superposition of Bragg peaks with various energies and different weights:

n

i i zDw zD )(

 )(

 

i

1

100

80

60

40

relative Dosis (%) 0 20

0

5

10

15

20

Tiefe (cm)

range

modulation width

Oliver Jäkel

Medical Physics

Page 19

Adaption to distal edge: Range compensation

Adaptation of the beam range to the distal edge

Accounts for inhomogeneities

Image: Chu (1999)

Image: Minohara (2010)

Oliver Jäkel

Medical Physics

Page 20

Passive vs. active delivery

Example: Liver treatment with scanning beam (right)

Image: Gillmann 2014

• Variable depth modulation possible • No patient specific hardware • Intensity modulation possible

Oliver Jäkel

Medical Physics

Page 21

• Poin by point irradiation with a pencil beam of few mm width • Variation of beam energy : mm resolution in depth Active beam delivery: Scanning

Typically 30-50 Energies, 20000 - 50000 beam spots

Oliver Jäkel

Medical Physics

Page 22

Additional problem: Range uncertainty

Small uncertainties in density may result in larger dose uncertainties as compared to MV photons

Oliver Jäkel

Medical Physics

Page 23

Initial Planning CT GTV 115 cc 5 weeks later GTV 39 cc Lung Tumor shrinkage during p-therapy

Beam overshoot

Beam stops at distal edge

Courtesy of S. Mori, G. Chen, MGH, Boston

Need for replanning and adaption during course of RT

Oliver Jäkel

Medical Physics

Page 24

Image guidance in PT

• Particle therapy is lacking proper IGRT (mostly orth. X-rays)

• Only some recent facilities have X-ray CBCT

• Proton RT is clearly indicated for pediatric patients – can we justify the additional imaging dose ?

CT on rails at PSI, Dresden, Trento; Novel DECT system at MedAustron; Robotic C-arm at HIT

Oliver Jäkel

Medical Physics

Page 25

Conclusion

• Particle therapy is an extremely precise method

• Biggest challenges are costs and organ motion

• Image guidance / motion mitigation are lacking behind X-ray technology

Particle RT has still has a great potential for development

Literature:

Proton and Charged Particle, T.F. Delaney and H.M. Kooy (eds.), Lippincott Raven (2007)

Principles and Practice of Proton Beam Therapy, I.J. Das and H. Paganetti (eds.), AAPM (2015)

Carbon-Ion Radiotherapy: Principles, Practices and Treatment Planning, H. Tsujii et al (eds.) Springer 2015

Oliver Jäkel

Medical Physics

Page 26

Thank you for your attention

Oliver Jäkel

Medical Physics

Page 27

Introduction to clinical particle therapy

W. De Neve

March, 2018

Contents

• Proton therapy – History

• Role of physics research centers • Historical ‘niche’ of clinical indications – Fast progress of photon therapy – Securing advantages for proton therapy • Light ion therapy – The neutron therapy saga – The choice of carbon as light ion • Indications other than the historical niche

1903 Sir William Henry Bragg (2 July 1862 – 12 March1942)

• Experiments done for a speech • α-particle radiation from radium • Unexpected ionization pattern in-air

W.H. Bragg, R. Kleeman. On the ionization curves of radium. Philos Mag, S.6 (1904), pp. 726-738

Not the least remarkable fact about the 1904 paper was that it represented Bragg's first original experimental research after nearly two decades occupying the chair in Adelaide. The immediate stimulus for the experiment was the need to generate original material for his presidential address to the Australasian Association for the advancement of science. Brown A, Suit H. The centenary of the discovery of the Bragg peak. Radiother Oncol. 2004 Dec;73(3):265-8.

1929 Ernest Orlando Lawrence (8 Aug 1901 –27 Aug 1958)

• 1931 functioning cyclotron 4.5 inch (11.4 cm) 80 keV protons – 6 months later 11 inch (27.8 cm) cyclotron 1 MeV. • 1946 Berkeley synchrocyclotron 184 inch (467 cm) >100 MeV

Drawing of the cyclotron according to Lawrence’s 1934 patent. Lawrence never asked royalties

1944 Vladimir Iosifovich Veksler (Ukrainian) ( March 4, 1907– September 22, 1966)

Invented the synchrotron

Veksler, V. I. (1944). "A new method of accelerating relativistic particles" (PDF). Comptes Rendus (Doklady) de l'Académie des Sciences de l'URSS. 43 (8): 346–348

1946 Robert Wilson (1914-2000) physicist at Harvard

• Protons can be used clinically • Accelerators are available • Maximum radiation dose can be placed into the tumor • Proton therapy provides sparing of normal tissues • Modulator wheels can spread Bragg peak

*Wilson, R.R. (1946), “Radiological use of fast protons,” Radiology 47, 487.

History of proton therapy

• 1954 First treatment of pituitary gland (Berkeley) • 1956 First treatment of pituitary tumors (Berkeley) • 1958 Neurosurgical tool in Sweden • 1967 First large-field proton treatments in Sweden • 1974 Large-field fractionated proton program at Harvard Cyclotron Laboratory, Cambridge, MA • 1990 First hospital-based proton treatment center opens at Loma Linda University Medical Center, CA

Physics research laboratories: sites of clinical proton therapy

• Patient treatment was a side activity • Beam shared between physics experiments and clinical treatment • Medical treatments were grouped in periods of a few weeks 2-3 times per year • Highly selective medical activity – Uncommon cancers – Challenging tumour locations nearby normal tissue – Paediatric cancer avoiding • Growth and development disturbances • Secondary cancer

Proton therapy in physics research laboratories

• Unique selectivity offered by proton therapy – Attracted specialists in paediatric oncology, neurosurgery and surgeons specialized in treating bone and soft-tissue tumours – These specialists joined the physicists, engineers and radiation oncologists who were treating patients in physics research centres – Together, they formed specialized teams who further improved the therapeutic results thereby consolidating their top-reference position and centralizing treatment of these rare tumours. • This sequence of events resulted in the ‘historical niche of proton indications’

Historical niche of proton therapy indications

Pediatric

Type • Imaging 1950-1970s – Indirect target imaging of hadron therapy

No. Pathology

1 2 3 4 5 6 7 8 9

Skull base & spinal chordoma Skull base chondrosarcoma

Protons Protons Protons Protons Protons Protons Protons Protons Protons Protons Protons Protons Protons

Spinal & paraspinal “adult” soft tissue sarcomas

• Bone, air • Contrast – Radio-opaque markers-spacers – Target edges • Calculation • Informed guess

Pelvic sarcoma

Rhabdomyosarcoma Ewing’s sarcoma

Retinoblastoma

Optic pathway & other selected low-grade gliomas

Ependymoma

10 11 12 13

Craniopharyngeoma

Pineal parenchymal tumors Esthesioneuroblastoma

Medulloblastoma/primitive neuroectodermal tumors (PNET) Central nervous system (CNS) germ-cell tumors

14

Protons

• Immobile targets – Nearby bone – Superficial

Adult • Skull base, paraspinal and sacral chordoma and (chondro)sarcoma • Glioma

– No moving organs in path

Photon radiation therapy of 1950s – 1970s

• Plane radiography • Patient surface contouring devices • Educated guess of edges of tumor and organs-at-risk • Roughly shaped fields related to • Bony anatomy • Radiographical projection of contrast, fiducials or tumor • Dose calculation using transparant overlays • 2D dose-depth curves • Wide penumbra of kilovoltage, telecobalt, betatrons Techniques for accurate target volume definition could be applied for the historical niche of proton therapy indicatio s when m st of the patien s in photon therapy were treated by fields widely (wishfully) encompassing the tumours.

Technological progress since 1970s

Image Fusion

Cerrobend blocks

Multileaf collimator

IMXT dose-painting

First Linac

2000

2010

1980

1990

1960

1970

Robotic XT/tracking

High resolution IGXT/gating

Standard collimator

Shaped electron fields

Computerized 3D CT treatment planning

Progress in photon technology

IMRT: arbitrary sharp dose gradients concave dose distributions

IGRT/gating/tracking: reducing PTV-margins reducing surrounding dose

Adaptive/painting: reducing CTV (sub)volumes reducing surrounding dose

Reduce the advantages of proton therapy Unless using the same techniques

IMPT IGPT/gating/tracking APT/dose-painting/LET-painting

Challenges in particle therapy

• Physical/physiological uncertainties • Biological uncertainties • Dose computation • Planning, plan robustness, robust optimization • Technological limitations • Clinical limitations

Physical/physiological uncertainties

R. Mohan, D. Grosshans, Proton therapy – Present and future, Adv. Drug Deliv. Rev. (2016)

Physical physiological uncertainties

• Generous overshoot may result in loosing the advantage of proton therapy • Imaging • Motion, gating, tracking • Planning, plan robustness, adaptive replanning

Relative biological effectiveness (RBE)

• RBE is the inverse ratio of the doses required for equal biological response • The standard of comparison is cobalt gamma-rays or megavoltage x-rays RBE(exp) = D(cobalt)/D(exp)

Proton RBE = 1.1

Biological uncertainties

• A two-beam IMPT plan for brain tumor optimized based on criteria defined in terms of constant RBE of 1.1 (squares) and in terms of variable RBE computed using a model published byWilkens, et al. (triangles). After optimization, both dose distributions were converted to variable RBE- weighted dose for comparison. R. Mohan, D. Grosshans, Proton therapy – Present and future, Adv. Drug Deliv. Rev. (2016) Over the last years 3 publications of unexpected brain image alterations or brain necrosis at presumably safe Gy(RBE) levels in children undergoing proton therapy for CNS tumors

Dose computation uncertainties

Plan robustness, robust optimization

Tony Lomax

Technological limitations

• Spot size • Energy switching • In-room volumetric imaging • Gating/tracking • Proton installation – Limited RBE-range of protons

– No solution for delivering other particles – Investment, operational and upgrade cost

Clinical limitations

• Proton therapy is behind – Hypofractionation – Combination therapy – Exploiting immunogenic/vascular mechanisms • Integration in photon departments a necessity?

High LET: neutron beams

p(66) / Be NEUTRONS SSD = 150 cm

Photon beam

d(50) / Be NEUTRONS SSD = 157 cm

Neutron beam

The RBE of neutrons is energy dependent. Neutron beams produced with different energy spectra at different facilities have different RBE values.

Batterman et al. Eur. J. Cancer 17: 539-548; 1981

Equal growth delay

D(neutron) D(photon)

RBE =

Photon RT

Variety of tumors

Variety of RBE-values

Tumor RBE-values generally higher than the 3.0-3.5 value, measured for normal tissues

Neutron RT

ACC RBE-values ≈ 8

The 1970s rise and fall of neutron beam therapy

The rise: tumor control

• Relatively small installations - spread of neutron therapy facilities • Demonstration of tumor control in radio-resistant tumors • Salivary gland • Prostate • Pancreas •

Neutron beams produced by protons or deuterons with energies greater than about 50 MeV could produce tumor control with side effects no worse than low LET radiation. For this reason facilities which had performed clinical trials using relatively low energy beams either stopped treating patients or upgraded their accelerators to a higher energy.

The fall: toxicity

• Computations of absorbed dose did not include additional neutron capture in hydrogen-rich tissues, which results in higher energy release in hydrogen-rich tissues. Such tissues include white matter in the brain and the fat that surrounds most important organs, which is closely associated with their blood supply • Neutron therapy using the 2-D techniques of the 1970s irradiating large volumes normal tissue • The well-established finding that RBE varies in different tissues was dismissed, along with the important fact that RBE increases with falling dose/fraction, which mitigates the effect of a reduction in physical dose beyond the region of cancer • The fact that RBE also varies with cell proliferation rate, so that slow-growing cells have higher values, was not appreciated. It is the slow-growing cells that make up the majority of normal tissue and which contribute to severe tissue damage at extended time periods after irradiation

medicalphysicsweb.org/cws/article/opinion/32466 and other sources

What we learned from neutron therapy

High LET beam “ without ” high physical selectivity could never be a major player in radiation oncology.

Key point : high LET beam with high physical selectivity

T. Kamada ESTRO Particle course, Pavia, 2013

Electrons

Protons

Anti-Protons

Iron

Helium

Carbon

Selection based on physics

Carbon ion as a compromise

• First selection based on physics – Low plateau – Distinct Bragg peak – Low fragment tail • Second selection based on biology – Low RBE in plateau – High RBE in SOBP – Part of LET range below 100 KeV/μ

Dimitri Mendeleev’s periodic table of elements

Carbon ion therapy

• Uncertainties often larger than for proton therapy – Radiobiological • Most clinical data come from 2 centers – NIRS – GSI/HIT • This course • Comparative clinical assessment • Patient selection/clinical trials

Challenges for new centers

Increase in number of centres

Historical niche will not fill to full capacity Common cancer sites will have to be treated

Superior beam but

level-I clinical evidence is lacking Non-randomized comparative evidence is scarce How choosing candidate cancers? How dealing with cost and reimbursement

Bridging the gap with photons Hypofractionation (protons) Combination therapy Exploiting immunogenic effects This course: overview of clinical data with emphasis on comparative assessments

Peter Peschke, Ph.D Medical Physics in Radiation Oncology, German Cancer Research Center, 69120 Heidelberg

ESTRO Teaching Course 2018 “Particle Therapy“

Learning Goals:

Interaction of radiation with biomolecules

Radiation damage registration & processing

Factors influencing radiation response

With a focus on:

biological processes at the subcellular and cellular level, which differ in conventional photon irradiation and particle therapy

ESTRO Teaching Course 2018 “Particle Therapy“

Cell Biology

lysosymes

membrane

intermediar filaments

endoplasmatic reticulum with ribosomes

nucleus

mitochondria

Cell Biology

to endoplasmatic reticulum

nucleus

nuclear porous

membrane

chromatin

Lamina (intermediar filaments )

DNA – a set of blueprints

• genetic instructions used in the development and functioning of all known living organisms

• information is wraped on two antiparallel DNA strands

5’Phosphate group

3’Hydroxyl group

D N A

OH

NH

H

OH

2

P

HO

O

N

N

O

N

N

CH

O

2

O

CH

2

O

HO

P

O

H

O

O

H

O

H

H

O

P

HO

O

2

N

NH

O

N

NH

N

O

CH

2

2

O

CH

2

O

HO

P

H

O

O

NH

2

H

H

O

O

P

HO

O

H

2

N

O

N

O

CH

5’Phosphate group

2

O

CH

O

2

O

3’Hydroxyl group

P

OH

H

O

HO

HO

DNA – a set of blueprints

• genetic instructions used in the development and functioning of all known living organisms

• information is wraped on two antiparallel DNA strands

• DNA occurs in linear chromosomes human genome: 2 x 23 (diploid)

double-stranded helical structure of DNA

DNA – a set of blueprints

• genetic instructions used in the development and functioning of all known living organisms

• information is wraped on two antiparallel DNA strands

• DNA occurs in linear chromosomes human genome: 2 x 23 (diploid) • a certain amount of DNA is devoted to coding biomolecules • variation is an essential factor to evolution (1000-10^6 lesions per day) • stability is important for the individual (less than 1/1000 mutations)

The Central Dogma of Molecular Biology

Cell

DNA

Transcription

mRNA

Translation

Ribosome

Polypeptide (protein)

©2000 Timothy G. Standish 1998

Effect of Ionizing radiation on biomolecules

direct effect

damage

interaction of photons or electrons with DNA

targeted effects

O + + e -

H

H

O

e -

2

2

The maximum amount of radiation-induced genetic damage is formed shortly (minutes to hours) after radiation exposure

p +

OH - + H

3 O + + e - aqu.

damage

indirect effect

Effect of Ionizing Radiation on Biomolecules

Indirect effects: Interaction of photons or electrons with water molecules Result: Formation of reactive oxygen species (ROS)

Radiolysis of water !

hν

O + + e -

H 2 O H 2

Hydroxyl radical: H 2

O + + OH -

O+ H

2 O H 3

Solvated electrons: e - + [H 2

0 + ] e -

aqu.

Hydroxyl radical: e -

2 O OH -

+ H

aqu.

Hydrogen peroxide:

OH - + OH -

H

O

2

2

Effect of Ionizing Radiation on Biomolecules

Indirect effects: R eactive O xygen S pecies (ROS)

NADPH oxidase

inducible nitric oxide synthase

Reisz et al. 2014

Effect of Ionizing Radiation on DNA

Ionizing radiation

UV

dimerisation

base modification

Basenverlust loss of base

Einzelstrang- bruch singl strand break (SSB)

double strand break (DSB)

DNA-Protein crosslinks

Effect of Ionizing Radiation on DNA

2/3 indirect effects

Estimated # of events/cell for 1 Gy

SSB

1000

DSB

30-40

DNA-Protein-crosslinks

50

complex damage (SSB + base damage)

60

1/3 direct effects

Cosmic

Rocks

Radio-active elements

DNA damage is repairable !

Plants

Man-made

Bodies

Radiation damage registration & processing

adapted from: Shilof Y, Nature Reviews, 2003

ionizing radiation

damage recognition

sensors ATM, ATR, SMG1

DNA lesions

Radiation damage registration & processing

adapted from: Shilof Y, Nature Reviews, 2003

ionizing radiation

damage recognition

sensors ATM, ATR, SMG1

DNA lesions

amount and type of damage that can be handled

excessive damage, irrepairable

cell death

cell survival

Radiation damage registration & processing

adapted from: Shilof Y, Nature Reviews, 2003

ionizing radiation

damage recognition

sensors ATM, ATR, SMG1

DNA lesions

excessive damage, irrepairable

amount and type of damage that can be handled

transducer signaling pathways second messengers, tyrosin phosphorylation

activation of the survival response network

effectors e.g. repairosomes

DNA repair

cell death

cell survival

DNA repair

specialized strategies for defined problems

direct reversal of damage single strand breaks

excission of damaged regions b ase excission repair nucleotide excission repair mismatch repair

recombination repair

homologeous recombination (HR) of double strand breaks (DSBs)

emergency repair

n on-homologeous endjoining (NHEJ) of double strand breaks (DSBs)

DNA repair:

homologeous endjoining (HEJ)

Double Strand Break (DBS)

limited degradation from 5‘ ends Slow but high fidelity repair f DNA by recovering genetic information from the pairing of one end with maternal chromosome (template)

DNA synthesis, joint molecule homologeous chromosome

21

Christmann et al. Toxicology 193 (2003)

DNA repair: Non-homologeous endjoining (NHEJ)

Double Strand Break (DBS)

poly (ADP-ribosylation)

PARP recognizes both single and double strand breaks. PARP causes poly (ADP- ribosylation) to enhance access to DNA single strand repair proteins such as XRCCI, Ligase III and DNA polymerase .

PARP

Ligase

XRCC

DNA-pol

DNA repair: Non-homologeous endjoining (NHEJ)

Double Strand Break (DBS)

Exposed ends of the DNA strands are detected by the KU70–KU80 heterodimer Fast repair, can be error-prone !!! DNA-dependent protein kinase ( DNA-PKcs ) stabilize broken ends The heterodimer XRCC4/Ligase IV subsequently assists in repairing the break Loss of complete sequences of bases possible

DNA-PK

Ku70

Ku70

Ku80

Ku80

XRCC

Ligase

Why do mammalian genomes tolerate error-prone repair ?

Satellite DNA in the region of centromers and telomers

Coding genes separated by repetitive DNA elements (~ 1.5%)

(SINE and LINE): Short and long interspersed repetitive elements, consisting of introns and regulatory sequences (~ 24%) , repetitive DNA (~ 59%) and non- coding DNA (~ 15%)

because > 98% of the DNA sequence is non-coding !

Maintenance of DNA is not that simple ....

H. C. Reinhardt

. . . . . . . . but things can be simplified

outcomes of DNA repair:

Accurate repair:

Inadequate repair:

Misrepair:

Cell survives without mutations

Cell inactivation or cell death due to

Cell survives but at the cost of genetic changes

• Mitotic death • Apoptosis • Permanent arrest

Radiation damage registration & processing

adapted from: Shilof Y, Nature Reviews, 2003

ionizing radiation

damage recognition

sensors ATM, ATR, SMG1

DNA lesions

excessive damage, irrepairable

amount and type of damage that can be handled

transducer signaling pathways second messengers, tyrosin phosphorylation

activation of the cell death pathway

effectors e.g. repairosomes

consequences

cell death

When and why cells die after irradiation ?

Adopted from Wouters 2009

Multiple cell cycles

Cell cycles

DNA damage response

Clonogenic survival

Mitotic catastrophe

Mitosis

senescence = cells cease to divide

Early cell death Apoptosis, Necrosis

Late cell death Apoptosis, Necrosis

Normal cells: lymphocytes, spermatogonia, intestinal cells, embryonal cells Tumors of haematopoetic origin

Vast majority of proliferating normal cells

Most tumor cells

Sequential ultrastructural changes in cell death

Nuclear chromatin condensation & fragmentation

Normal

Apoptotic body

Enzymatic digestion and leakage of cellular contents

Inflammation

Phagocytosis of apoptotic cells and fragments

Phagocyte

Robbins & Cotran 2006

Radiation damage registration & processing

adapted from: Shilof Y, Nature Reviews, 2003

ionizing radiation

damage recognition

sensors ATM, ATR, SMG1

DNA lesions

excessive damage, irrepairable

amount and type of damage that can be handled

transducer signaling pathways second messengers, tyrosin phosphorylation

activation of the survival response network

activation of the cell death pathway

effectors e.g. repairosomes

cell cycle regulation

DNA repair

stress response

consequences

cell death

cell cycle regulation cell survival

Cell cycle

Function:

accurate transfer of genetic information

maintain normal ploidy

Two main checkpoints !

Molecular Cell Biology Lodish H, Berk A, Zipursky SL, et al. New York: ; 2000.

Radiation effects

Cell cycle

delay in the movement of cells through cell cycle phases

activation of cell cycle checkpoints !

Molecular Cell Biology Lodish H, Berk A, Zipursky SL, et al. New York: ; 2000.

Radiation effects

Cell cycle

Slow down of cell cycle supports DNA repair:

stimulate DNA repair

allow time for repair

co-operative efforts

Molecular Cell Biology Lodish H, Berk A, Zipursky SL, et al. New York: ; 2000.

e.g. NHEJ + homology-directed repair at G2

Radiation effects

Cell cycle

Base Excision Repair

Single strand Repair

G

S

G

M

1

2

Non- homologous end-joining

Homologous end-joining

Radiation effects

Cell cycle

Synchronized Chinese Hamster Cells (CHO)

Sensitive:

G2/M-phase

Resistant:

late S-phase

Highly resistant:

G0-phase

Sinclair & Morton, Biophys J. 5: (1965)

Radiation damage registration & processing

adapted from: Shilof Y, Nature Reviews, 2003

ionizing radiation

damage recognition

sensors ATM, ATR, SMG1

DNA lesions

excessive damage, irrepairable

amount and type of damage that can be handled

transducer signaling pathways second messengers, tyrosin phosphorylation

activation of the survival response network

activation of the cell death pathway

effectors e.g. repairosomes

cell cycle regulation

DNA repair

stress response

consequences

cell death

cell survival

Radiation-induced cell communication

Radiation-induced signals transmitted through existing pathways: No radiation-specific pathways ! Signaling in both directions !

growth factors e.g. EGF

death receptor

cytokines e.g.TNF- alpha

Fas-R TRAIL-R

damage-inducible and stress-related proteins

reactive oxygen species (ROS)

cell survival adhesion migration

repair proliferation

NFkB

cytokines for intercellular signaling (TNF α, interleukin 1, 8, TGF ß)

apoptosis

inflammation immunity, survival

Radiation damage registration & processing

adapted from: Shilof Y, Nature Reviews, 2003

ionizing radiation

damage recognition

sensors ATM, ATR, SMG1

DNA lesions

excessive damage, irrepairable

amount and type of damage that can be handled

transducer signaling pathways second messengers, tyrosin phosphorylation

activation of the survival response network

activation of the cell death pathway

effectors e.g. repairosomes

cell cycle regulation

DNA repair

stress response

consequences

cell death

cell survival

Radiation damage registration & processing

adapted from: Shilof Y, Nature Reviews, 2003

ionizing radiation

damage recognition

sensors ATM, ATR, SMG1

DNA lesions

excessive damage, irrepairable

amount and type of damage that can be handled

transducer signaling pathways second messengers, tyrosin phosphorylation

activation of the survival response network

activation of the cell death pathway

low fidelity repair

effectors e.g. repairosomes

cell cycle regulation

genetic instability

DNA repair

stress response

consequences

cell survival

Radiation-induced genomic instability

Increased rate of genomic instability in the progeny of an irradiated cell

DNA-repair

cell cycle checkpoint control

Cells proliferate with:

Cells proliferate:

chromosomal rearrangements, micronuclei, gene amplifications, increased rate of mutations

undisturbed without damage !

Radiation damage registration & processing

adapted from: Shilof Y, Nature Reviews, 2003

ionizing radiation

damage recognition

sensors ATM, ATR, SMG1

DNA lesions

amount + type of damage that can be handled

excessive damage, irrepairable

transducer signaling pathways second messengers, tyrosin phosphorylation

activation of the survival response network

activation of the cell death pathway

low fidelity repair

effectors e.g. repairosomes

cell cycle regulation

genetic instability

DNA repair

stress response

malignant transformation

consequences

cell death

cell survival

Summary

lipid peroxidation

modified from Coleman CN, Radiotherapy and Oncology 46: (1998)

2 .

O

DNA repair

O

2

inflammatory molecules

cell death

DNA damage

receptor

signal transduction

gene activation

stress response

cell cycle effects

external effectors

growth factors

O 2 , nutrients etc. endocrine factors

Neighbouring tumor or stroma cells

vasculogenesis

Factors influencing radiation response

Physico-chemical factors

Effect of oxygen in sensitizing cells to radiation

+ O

2 to „stabilize“ damage R º + O 2 RO 2 º

hypoxic

indirect effects

normoxic

Surviving fraction

Gray et al. 1953

Dose OER = the ratio of dose in the absence of oxygen to dose in the presence of oxygen needed to produce the same biological effect.

direct effects

mammalian cells, ratio is usually 2.5 – 3.0 .

Physico-chemical factors

Glutathione

Tripeptide containing a sulfhydryl group (-SH): gamma-Glu-Cys-Gly

Cys

Gly

  Glu

+

O

H

O

NH

O

O

3

C-C-CH-CH-C-N-C-C-N-CH-C

2

2 2

- O

O -

H

H

CH

H

2

SH

acts as an oxidative buffer : key role in detoxification by interacting with hydrogen and organic peroxides

2 GSH + R-O-OH GSSG + H O + ROH 2

Damage avoidance !

Factors influencing radiation response

Physico-chemical factors

Biological factors

Biological factors

Inherent or acquired tumor cell resistance

Human Ovarian Carcinoma

Mutated tumor suppressors (e.g. p53)

DNA repair gene amplification

Evading cell death (e.g. BCl2, Survivin)

Up-regulation of antioxidative enzymes (e.g. superoxide dismutase, catalase)

Activation of pro-survival oncogenes (e.g. EGFR)

Additional factors influencing radiation response

Physico-chemical

Biological

Physical

Physics meets biology

Local Microscopic Dose Distribution

X-rays

Carbon Ions

Density of ionization in particle tracks is described

Linear Energy Transfer (LET)

Definition: average energy deposition (keV) per traversed distance (1 µm)

Cell nucleus

low-LET

high-LET

< 20 keV/µm

> 20 keV/µm

„Randomized DNA damage“

„Clustered DNA damage“

10 m m

Krämer & Kraft 1994

Relative Biological Effectiveness (RBE)

increased effect relative to x-rays is quantified by the R elative B iological E ffectiveness ( RBE )

d

x rays 

RBE



d

same endpoin

ions

t

RBE is not a fixed parameter . . . .

Relative Biological Effectiveness (RBE)

linear energy transfer [LET]

dose/fraction

RBE depends on:

biological endpoint

biological system intrinsic radiosensitivity, micromilieu, structural organization

Literature

Hall Eric J.: Radiobiology for the Radiologist . Philadelphia: Lippincott, Williams & Wilkins, 2000 (5th. ed.), ISBN 0-7817-2649-2 Joiner M, van der Kogel A.: Basic Clinical Radiobiology. Hodder Education Group, 2009, ISBN 0-340-929-667 Steel, Gordon G.: Basic Clinical Radiobiology . London: Arnold, 1997 (2nd ed.), ISBN 0-340-70020-3 Das IJ, Paganetti H.: Principles and Practice of Proton Beam Therapy . AAPM Monograph, ISBN 9781936366446

03/01/13

Physical aspects of particle therapy with protons and ions

Alejandro Mazal Institut Curie, Paris, France

In cooperation with F.Goudjil, L.DeMarzi, ,S.Delacroix, C.Nauraye, I.Pasquié, J. Brenot,

M.Robilliard, S.Meyroneinc, A.Patriarca, C.Devalckenaer, R.Dendale, S.Helfre, C.Alapetite, V.Calugaru, S.Bolle, L.Fevret, L.Desjardins, J-L.Habrand, A.Fourquet, P.Poortmans… and staff

Institut Curie Centre de Protonthérapie d ’ Orsay France Estro Particles Vienna 2018 Acknowl : France Hadron, FEDER, Physicancer, Inspire

Menu :

I. Types of particles II. Interactions with electric (E ) and magnetic fields (B) » Beam production and transport III. Interaction with matter (eg: beam line, patient) » Microscopic concepts: Stopping power (S), multiple scattering » Macroscopic concepts: Bragg peak, penumbra IV. Moving from protons to ions » … from physics (density of ionisation) to biology

Protons/Ions

Electrons

Photons

“no max in path”

“any depth”

“nothing”

20 cm

Indeed : Much more than just “filling the gap”… ! :

Court J-C.Rosenwald. I. Curie

I. « Hadrons » in therapy Physical selectivity and/or Radiobiological effects

* pions

IMXT

* fast & slow neutrons

* protons

* light and heavy ions

Biology

Linear Energy Transfer

Raju & Koehler, 1980

Pi meson (pions)

• « Ideal particles »? High expectations in 60 ’ s

• « Star » near end of range

(protons, a , heavy ions, neutrons, gammas,… )

Raju, 1980

NEUTRONS : * Depth dose similar to photons (Co - 8 MV vs neutrons)

* High Linear Energy Transfert  High Biological effect

Menzel,1990

D.Jones

From neutrons to ions

* Oxygen Effect : lower radioresistance of hypoxic cells

n ° of fractions

* No repairing of cells:

* differences in radiosensitivity : treat radioresistant tumors

« Hadrons » in therapy Physical selectivity and/or Radiobiological effects

* pions

IMXT

* fast & slow neutrons

* protons

* light and heavy ions

Raju & Koehler, 1980

Menu :

I. Types of particles II. Interactions with electric (E ) and magnetic fields (B) » Beam production and transport III. Interaction with matter (eg: beam line, patient) » Microscopic concepts: Stopping power (S), multiple scattering » Macroscopic concepts: Bragg peak, penumbra IV. Moving from protons to ions » … from physics (density of ionisation) to biology

II. Beam production, transport & delivery

Acceleration :

1

m

+

-

q +

0

+

-

Electric Field

-1

‘Dee’ voltage

Time

Acceleration of a Charged Particle :

Magnetic Field « B » Bended Trajectory:

‘Dee’ Electrodes in Magnet

N

N

r

v

B

S

Particle Motion in Magnetic Field S

a) Linac : Light (Advanced Oncotherapy

Linear

Synchrocyclotron

Diam 4m 235 MeV

Harvard Orsay…

talk Marco Schippers

b) Synchrocyclotron (Mevion, IBA, …) c) Cyclotron (IBA, Varian, Sumitomo, Pronova)

Diam 12m 250 MeV

cyclotron

synchrotron

d) Synchrotron (Mitsubishi, Hitachi, Toshiba, Optivus, Siemens, Protom, …)

Magnetic fields and beam : exs. Dipoles (deviate and select E) and Quadrupoles (focalize and defocalize)

Beam transport in vacuum tubes with « magnetic lenses »

And delivery with a gantry

http://eucard-old.web.cern.ch/eucard-old ; petra3-project.desy.de; en.wikipedia.org/wiki/Quadrupole

Image Guided Radiation Therapy : on line MRI => Beam interaction with magnetic field… in the patient !

Protons + IRM Patent Overweg Philips

Raaymakers et al, AAPM, 2014

Menu :

I. Types of particles II. Interactions with electric (E ) and magnetic fields (B) » Beam production and transport III. Interaction with matter (eg: beam line, patient) » Microscopic concepts: Stopping power (S), multiple scattering » Macroscopic concepts: Bragg peak, penumbra IV. Moving from protons to ions » … from physics (density of ionisation) to biology

III. BEAM-TARGET INTERACTIONS :

- Elastic & inelastic collisions - Coulomb Forces : (+) & ( - ) charges

Incident Proton or Ion (+)

Which are the Main Interactions of Interest in our field?

Many interactions of particles with matter … but keep 3 :

Inelastic collision w/nuclei : neutrons

Inelastic collision with electrons: Dose

Elastic collision w/nuclei: « multiple Coulomb scattering » : all the effects you do not know why

BEAM-TARGET INTERACTIONS :

Inelastic collision w/nucleus & nuclear reactions

# Mid & High Energy : ( 10-250 MeV protons)

Incident Proton or Ion (+)

- Neutrons:

shielding patient dose

- Fragments

- Protons (large angles)

- Activation  gamma,…

Accelerator, Beam line Patient  PET, …

 Disappearance of incidental protons

Nuclear Interactions

Neutron production : 1. Shielding Concrete walls 2 - >4 m (outside doses) 2. In room : Activation and electronics !

3. Neutrons dose to patients : 1%  0.1% and lower for Pencil Beam

Neutrons

(+) Positron Emission Tomography from patient activation with the beam

W. Enghardt et al

(+) Prompt Gamma (< nsec; few MeV)

Knife-edge slit camera

Y.Jongen, F.Stickelbaut, D.Prieels, F.Roellinghoff,…..

Nuclear interactions  Disappearance of incidental protons

Nuclear interactions

Incident Proton or Ion (+)

NUMBER OF PROTONS

Faraday Cup (Q)

Number of particles

Nuclear interactions

threshold= f(E) ( 10-250 MeV protons)

NUMBER OF PROTONS

Range =f (E)

~ 1 % per cm

So, why do we have a « Bragg peak »?

Number of particles?

Dose (ionisation)

BEAM-TARGET INTERACTIONS : Why the bragg peak…?

# Intermediate Energy ( 0.1- 250 MeV)

Inelastic Collision with electrons

Incident Proton or Ion (+)

- Protons : E loss & very small angle

- Electrons: Ionization, excitation

= Dose

T

t

p+

F

F

e-

e-

Collisions with electrons

Stopping Power « S » = dE / dx

Mean Energy dE lost in electronic collisions while traversing a distance dx [ MeV / mm]

t

p+

F

e-

dx

2 e 4 (N

A Z ) { ln (2mv 2 / I (1- b 2 )) - b 2 - S (Ci/Z) } A m e v 2

(dE/dx)= 4 p z

eff

Small Energy  High Stopping Power

Stopping Power

Mass Total Stopping Power S/ro [MeV.cm 2 .g -1 ]

300

250

200

150

100

50

0

1000

100

10

1

0.1

0.01

Residual Range [mmWater] ( ~ Distance to end of range )

Dose distribution in nanometer scale

M. Kraemer, M. Scholz

Interaction proton-nucleus (Nuclear reactions ) Loss of protons

“Fluence”

(num of part)

Depth

Arbitrary Units

“Fluence”

(num of part)

Stopping Power (energy deposited per part)

Depth

Arbitrary Units

“Fluence”

(num of part)

“The Bragg Peak” (Dose in Gy)

Stopping Power (energy deposited per part)

Depth

Collisions with electrons :

Large number of events loosing small energy

Statistical  “ range straggling”

Dose (ionisation)

Electrons

Protons

Anti-Protons

Iron

Helium

Carbon

Stopping power effect on detectors: saturation…

 Test any detector in the peak area to know its response to S/ro !

Spread-out Bragg Peak (SOBP)

120

100

80

60

40

20 RELATIVE DOSE

0

0

50

100

150

200

250

DEPTH IN WATER (mm)

(Andy Kohler // graph : Niek Schreuder)

Entrance

Entrance dose

Entrance dose

Beam path

Beam path

Software: Varian ´ s Eclipse // Beam Data : IBA // Calcs : I.Curie

At target depth

Gradient in target

Homogeneous in target

Same after

Distal fall off

Small variation

Uncertainty

Software: Varian ´ s Eclipse // Beam Data : IBA // Calcs : I.Curi 36

After target

Behind and Exit dose

No Dose Behind

Software: Varian ´ s Eclipse // Beam Data : IBA // Calcs : I.Curi 37

BEAM-TARGET INTERACTIONS :

Elastic collision w/nucleus

Incident Proton or Ion (+)

Coulomb multiple small angle scattering

0 = 14.1 z { sqrt ( L / L R

) ( 1+ log(L /L R

) / 9 ) }



p v

« Get profit » of this ! : Clinical passive lines

Final Collimator

Occluding Rings and second Scatterer

First Scatterer

(from N. Schreuder,Indiana)

Lateral penumbra in depth :

(multiple) Scattering Power

Data: Curie, NAC, Darmstadt

Laterally

Lateral Penumbra

41

Spot Scanning Principle

Single Spot

Pictures With compliments from PSI

Total Picture

Few Spots

Beam Delivery : 3D Pencil Beam Scanning

Magnets

Narrow pencil beam

Target

3D Pencil Beam Scanning

Range shifted by changing beam energy (or absorbers)

Kamada, PTCOG 2014

Scattering power effect on small beams: Lack of « lateral equilibrium »

« Hadrons » in therapy Physical selectivity and/or Radiobiological effects

* pions

IMXT

* fast & slow neutrons

* protons

* light and heavy ions

Raju & Koehler, 1980