Particle Therapy 2017

Particle Therapy 6-10 March 2017 | Essen, Germany

ESTRO SCHOOL LIVE COURSE

Lectern School course_Particle Therapy2.indd 1

27/02/17 17:02

March, 2017

therapy

W. De Neve

Introduction to clinical particle

Contents

• Role of physics research centers • Historical ‘niche’ of clinical indications

• Proton therapy – History

– 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

at Harvard

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

1946 Robert Wilson (1914-2000) physicist • 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

History of proton therapy

• 1990 First hospital-based proton treatment center opens at Loma Linda University Medical Center, CA

• 1954 First treatment of pituitary tumors • 1958 First use of protons as a neurosurgical tool • 1967 First large-field proton treatments in Sweden • 1974 Large-field fractionated proton program at Harvard Cyclotron Laboratory, Cambridge, MA

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

– 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’

Proton therapy in physics research laboratories • Unique selectivity offered by proton therapy

• Imaging 1950-1970s – Indirect target imaging • Bone, air • Contrast

– Radio-opaque markers-spacers – Target edges • Calculation • Informed guess • Immobile targets – Nearby bone – Superficial

– No moving organs in path

Adult

Pediatric

Historical niche of proton therapy indications • Skull base, paraspinal and sacral chordoma and (chondro)sarcoma • Glioma

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

Photon radiation therapy of 1950s – 1970s Plane radiography

indications when most of the patients in photon therapy were treated by fields widely (wishfully) encompassing the tumours.

Robotic XT/tracking

1960 1970 1980 1990 2000 2010

IMXT

dose-painting

High resolution IGXT/gating

Multileaf

collimator

Computerized 3D CT treatment planning

Imag e

Fusio n

Shaped

electron fields

Cerrobe nd

blocks

Technological progress since 1970s

Standar d

collimat or

First Linac

reducing surrounding dose

reducing surrounding dose

Adaptive/painting: reducing CTV (sub)volumes

Reduce the advantages of proton therapy Unless using the same techniques

IGRT/gating/tracking: reducing PTV-margins

concave dose distributions Progress in photon technology

IMRT: arbitrary sharp dose gradients

IMPT

IGPT/gating/tracking

Challenges in particle therapy

APT/dose-painting/LET-painting

• Physical/physiological uncertainties • Biological uncertainties • Dose computation

• Planning, plan robustness, robust optimization • Technological limitations

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

Physical physiological uncertainties

RBE(exp) =

D(cobalt)/D(exp) Proton RBE = 1.1

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

Biological uncertainties

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

A two-beam IMPT plan for brain tumor op6mized 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). AKer op6miza6on, both dose distribu6ons were converted to variable RBE- weighted dose for comparison. Gy(RBE) levels in children undergoing proton therapy for CNS tumors

Tony Lomax

Dose computation uncertainties

Plan robustness, robust optimization

Technological limitations

– Limited RBE-range of protons – No solution for delivering other particles – Investment, operational and upgrade cost

• Spot size • Energy switching • In-room volumetric imaging • Gating/tracking • Proton installation

p(66) / Be NEUTRONS SSD = 150 cm

d(50) / Be NEUTRONS SSD = 157 cm

High LET: neutron beams

Photon beam

Neutron beam

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

D(photon)

D(neutron)

Equal growth delay RBE =

Variety of tumors

ACC RBE-values ≈ 8

generally higher than the 3.0-3.5 value,

Tumor RBE-values

measured for normal tissues

Variety of RBE-values

Photon RT

Neutron RT

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

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

The fall: toxicity

The rise: tumor control

• Rela)vely small installa)ons - spread of neutron therapy facili)es • Demonstra)on 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 radia)on. For this reason facili)es which had performed clinical trials using rela)vely low energy beams either stopped trea)ng pa)ents or upgraded their accelerators to a higher energy.

• Computa)ons of absorbed dose did not include addi)onal neutron capture in hydrogen-rich )ssues, which results in higher energy release in hydrogen-rich )ssues. Such )ssues include white ma=er 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 irradia)ng large volumes normal )ssue • The well-established finding that RBE varies in different )ssues was dismissed, along with the important fact that RBE increases with falling dose/frac)on, which mi)gates the effect of a reduc)on in physical dose beyond the region of cancer • The fact that RBE also varies with cell prolifera)on 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 )ssue and which contribute to severe )ssue damage at extended )me periods aRer irradia)on

The 1970s rise and fall of neutron beam therapy

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

Helium Carbon Iron

Electrons Protons An--Protons

Selec-on based on physics

Carbon ion as a compromise • First selec2on based on physics – Low plateau – Dis2nct Bragg peak – Low fragment tail

• Second selec2on 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

• Most clinical data come from 2 centers – NIRS – GSI/HIT • This course • Comparative clinical assessment • Patient selection/clinical trials

• Uncertainties often larger than for proton therapy – Radiobiological

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 comparaBve evidence is scarce – How choosing candidate cancers? – How dealing with cost and reimbursement

• This course: overview of clinical data with emphasis on comparaBve assessments

Peter Peschke, Ph.D

ESTRO Teaching Course 2017 “Particle Therapy“

Clinical Radiobiology Molecular and cellular basics

Medical Physics in Radiation Oncology, German Cancer Research Center, 69120 Heidelberg

ESTRO Teaching Course 2017 “Particle Therapy“

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

Interaction of radiation with biomolecules

Radiation damage registration & processing Factors influencing radiation response

With a focus on:

Learning Goals:

membrane

nucleus

endoplasmatic reticulum

with ribosomes

intermediar filaments

mitochondria

lysosymes

Cell Biology

nuclear

porous

chromatin Lamina

(intermediar filaments )

nucleus to endoplasmatic reticulum membrane

Cell Biology

• genetic instructions used in the development and functioning of all known living organisms • information is wraped on two antiparallel DNA strands

DNA – a set of blueprints

H2

O

HO 5’Phosphate group

H2

O

HO

P

CH

2

O

N H

HO

P HO

CH

2

O

O H

H N H O

P

O

O CH 3’Hydroxyl group 2

O

O

O

O

O

H OH

N HN N

N

CH

3

O

B

A

S

E

S

O

O

H2

N

HN N

O

H2N

NH

2

NH

N

O

N

N

NH

2

N

NH

2

N O

H OH

N

N

H

N

N

O

H

O

O

O

O

CH

2

O

P

O

O

CH

2

O

P

O

CH

2

OH

P

O

HO

HO

HO

S

U

G

A

R

-

P

H

O

S

P

H

A

T

E

B

5’Phosphate group

3’Hydroxyl group

D

N

A

• 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)

DNA – a set of blueprints

helical structure of DNA

double-stranded

• a certain amount of DNA is devoted to coding biomolecules • variation is an essential factor to evolution (1000-10^6 lesions per day)

• 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)

• stability is important for the individual (less than 1/1000 mutations)

DNA – a set of blueprints

©2000 Timothy G. Standish 1998 Timothy G. Standish

DNA

mRNA

Polypeptide (protein)

Ribosome

The Central Dogma of Molecular Biology Cell

Transcription

Translation

exposure

effects

The maximum amount of radiation-induced genetic damage is

targeted

formed shortly (minutes to hours) after radiation

p+

e-

interaction of photons

or electrons with DNA

indirect effect

direct effect

OH- + H3O++ e- aqu.

H2O++ e- H2O

damage

damage

Effect of Ionizing radiation on biomolecules

Radiolysis of water !

h

ν

Indirect effects: Interaction of photons or electrons with water molecules. Result: Formation of radicals H2O H2O+ + e- Hydroxyl radical: H2O+ H2O H3O+ + OH- Solvated electrons: e- + [H20+] e-aqu. Hydroxyl radical: e-aqu. + H2O OH- Hydrogen peroxide: OH- + OH- H2O2

Effect of Ionizing Radiation on Biomolecules

U

V

Basenverlust base modification los of base

dimerisation

radiatio n

Ionizing

double strand break (DSB)

Einzelstrang- bruch

break (SSB)

single trand

Effect of Ionizing Radiation on DNA

DNA-Protein-crosslinks 50 complex damage

(SSB + base damage) 60

SSB 1000

DSB 30-40

Estimated #

of events/cell for 1 Gy

1/3 direct effects

2/3 indirect effects

Effect of Ionizing Radiation on DNA

Cosmic Rocks

Bodies

WE LIVE IN A SEA OF RADIATION . . .

DNA damage

is repairable !

Radio-active elements

Plants Man-made

damage

sensors

ATM, ATR, SMG1

recognition

adapted from: Shilof Y, Nature Reviews, 2003

DNA lesions

ionizing radiation

Radiation damage registration & processing

damage

sensors

ATM, ATR, SMG1

recognition

adapted from: Shilof Y, Nature Reviews, 2003

cell survival cell death

excessive damage, irrepairable

DNA lesions

ionizing radiation

amount and type of damage that can be handled

Radiation damage registration & processing

damage

sensors

signaling pathways second messengers, tyrosin phosphorylation effectors

e.g. repairosomes

ATM, ATR, SMG1

transducer

recognition

adapted from: Shilof Y, Nature Reviews, 2003

cell survival cell death

excessive damage, irrepairable

DNA lesions

ionizing radiation

DNA repair

survival response network

activation of the amount and type of damage that can be handled

Radiation damage registration & processing

DNA repair

specialized strategies for defined problems

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

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

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

direct reversal of damage single strand breaks

20

Double Strand Break (DBS) limited degradation from 5‘ ends DNA repair: homologeous endjoining (HEJ)

DNA synthesis, joint molecule information from the homologeous chromosome

pairing of one end with maternal chromosome (template) Slow but high fidelity repair f DNA by recovering genetic

Christmann et al. Toxicology 193 (2003)

XRCC DNA- pol

PARP

Ligase

poly (ADP-ribosylation)

PARP recognizes both DNA repair: Non-homologeous endjoining (NHEJ) Double Strand Break (DBS) 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 .

Ligase

Ku70 Ku70 Ku80 Ku80

assists in repairing the break XRCC

DNA-PK

DNA repair: Non-homologeous endjoining (NHEJ) Double Strand Break (DBS) Fast repair, can be error-prone !!!

Exposed ends of the DNA strands are detected by the KU70–KU80 heterodimer DNA-dependent protein kinase ( DNA-PKcs ) stabilize broken ends The heterodimer XRCC4/Ligase IV subsequently Loss of complete possible

sequences of bases

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

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

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

H. C. Reinhardt

Maintenance of DNA is not that simple ....

Cell inactivation or cell death due to • Mitotic death • Apoptosis

• Permanent arrest

Inadequate repair:

Misrepair:

Cell survives but at the cost of

genetic changes

. . . . . . . . but things can be simplified Accurate repair: Cell survives without mutations outcomes of DNA repair:

damage

sensors

signaling pathways second messengers, tyrosin phosphorylation effectors

e.g. repairosomes

ATM, ATR, SMG1

transducer

consequences

recognition

adapted from: Shilof Y, Nature Reviews, 2003

cell death

excessive damage, irrepairable

activation of the cell death pathway

DNA lesions

ionizing radiation

amount and type of damage that can be handled

Radiation damage registration & processing

Clonogenic survival

Late cell death Apoptosis, Necrosis

Vast majority of proliferating normal cells

Most tumor cells

Mitotic

catastrophe

Cell cycles

Multiple cell cycles

Apoptosis, Necrosis

Early cell death

Mitosis

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

DNA

damage

response

Adopted from Wouters 2009 When and why cells die after irradiation ? senescence = cells cease to divide

Phagocytosis

of apoptotic cells and fragments

Nuclear chromatin

Apopto sis

condensation & fragmentation

Apoptotic body

Phagocyte

Robbins & Cotran 2006

Inflammation

Normal

Necros is

digestion and leakage of cellular

contents

Enzymatic

Sequential ultrastructural changes in cell death

damage

sensors

signaling pathways second messengers, tyrosin phosphorylation effectors

e.g. repairosomes

ATM, ATR, SMG1

transducer

consequences

recognition

adapted from: Shilof Y, Nature Reviews, 2003

cell cycle cell survival cell death regulation

excessive damage, irrepairable

activation of the

cell death pathway

DNA lesions

ionizing radiation

DNA repair

survival response network cell cycle

regulation

activation of the amount and type of damage that can be handled

stress response Radiation damage registration & processing

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.

Cell cycle Radiation effects

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.

cell cycle supports DNA repair:

Cell cycle Radiation effects

Slow down of

stimulate DNA repair

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

allow time for repair

co-operative efforts

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

Base Repair Cell cycle Radiation effects G 1 S G 2 M Single strand Repair Excision

end-joining

end-joining Homologous

Non-

homologous

Sensitive: Cell cycle Radiation effects

G0-phase

late S-phase

G2/M-phase

Resistant:

Highly resistant:

Synchronized Chinese Hamster Cells (CHO)

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

damage

sensors

signaling pathways second messengers, tyrosin phosphorylation effectors

e.g. repairosomes

ATM, ATR, SMG1

transducer

consequences

recognition

adapted from: Shilof Y, Nature Reviews, 2003

cell survival cell death

excessive damage, irrepairable

activation of the

cell death pathway

DNA lesions

ionizing radiation

DNA repair

stress response cell cycle regulation

survival response network

activation of the

amount and type of damage that can be handled

Radiation damage registration & processing

cell survival adhesion

migration NFkB

damage-inducible and

stress-related proteins reactive oxygen species (ROS)

cytokines for intercellular signaling

(TNF α, interleukin 1, 8, TGF ß)

Radiation-induced signals transmitted through existing pathways: No radiation-specific pathways ! Signaling in both directions ! death receptor Fas-R TRAIL-R apoptosis repair proliferation growth factors e.g. EGF inflammation immunity, survival cytokines e.g.TNF- alpha

Radiation-induced cell communication

damage

sensors

signaling pathways second messengers, tyrosin phosphorylation effectors

e.g. repairosomes

ATM, ATR, SMG1

transducer

consequences

recognition

adapted from: Shilof Y, Nature Reviews, 2003

cell survival cell death

excessive damage, irrepairable

activation of the

cell death pathway

DNA lesions

ionizing radiation

cell cycle regulation stress response DNA repair

survival response network

activation of the

amount and type of damage that can be handled

Radiation damage registration & processing

damage

sensors

signaling pathways second messengers, tyrosin phosphorylation effectors

e.g. repairosomes

ATM, ATR, SMG1

transducer

consequences

recognition

adapted from: Shilof Y, Nature Reviews, 2003

cell survival cell death

excessive damage, irrepairable

activation of the

cell death pathway

genetic

instability

low fidelity repair

DNA lesions

ionizing radiation

cell cycle regulation stress response DNA repair

survival response network

activation of the

amount and type of damage that can be handled

Radiation damage registration & processing

Cells proliferate with:

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

checkpoint control

cell cycle

DNA-repair

Radiation-induced genomic instability

Cells proliferate:

undisturbed without damage !

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

damage

sensors

signaling pathways second messengers, tyrosin phosphorylation effectors

e.g. repairosomes

ATM, ATR, SMG1

transducer

consequences

recognition

adapted from: Shilof Y, Nature Reviews, 2003

cell survival cell death

excessive damage, irrepairable

activation of the

cell death pathway

genetic

instability

malignant

transformation

low fidelity repair

DNA lesions

ionizing radiation

DNA repair

stress response cell cycle regulation

survival response network

activation of the

amount and type of damage that can be handled

Radiation damage registration & processing

Summary

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

gene

activation

DNA

damage

modified from Coleman CN, Radiotherapy and Oncology 46: (1998) DNA repair cell death

stress

growth

factors

response

Summary

gene

activation

DNA

damage

cell cycle effects

modified from Coleman CN, Radiotherapy and Oncology 46: (1998) DNA repair cell death

stress

growth

factors

response

Summary

gene

activation

DNA

damage

.

O

2

O

2

signal

transduction

lipid

peroxidation

receptor

cell cycle effects

modified from Coleman CN, Radiotherapy and Oncology 46: (1998) DNA repair cell death

stress

growth

factors

response

Summary

gene

activation

DNA

damage

.

O

2

O

2

signal

transduction

lipid

peroxidation

receptor

cell cycle effects

modified from Coleman CN, Radiotherapy and Oncology 46: (1998) DNA repair cell death

stress

growth

factors

response

Summary

gene

activation

DNA

damage

.

O

2

O

2

signal

transduction

lipid

peroxidation

receptor

cell cycle effects

external

effectors

O2, nutrients etc.

endocrine factors

modified from Coleman CN, Radiotherapy and Oncology 46: (1998) DNA repair cell death

stress

growth

factors

response

vasculogenesis

Summary

gene

activation

DNA

damage

.

O

2

O

2

signal

Neighbouring tumor or stroma cells

transduction

lipid

peroxidation

receptor

cell cycle effects

external

effectors

O2, nutrients etc.

endocrine factors

inflammatory molecules

Factors influencing radiation response Physico-chemical factors

produce the same biological effect. mammalian cells, ratio is usually 2.5 – 3.0 .

ti OER = the ratio of dose in the o n

absence of oxygen to dose in the presence of oxygen needed to

Dose

hypoxic

Gray et al. 1953

normoxic

S

u

r

vi

vi

n

g

fr

a

c

indirect + O2 to „stabilize“ damage R º + O2 RO2 º effects

direct

effects

Effect of oxygen in sensitizing cells to radiation

Tripeptide containing a sulfhydryl group (-SH): gamma-Glu-Cys-Gly acts as an oxidative buffer : key role in detoxification by interacting with hydrogen and organic peroxides

Glutathione

Damage avoidance !

Physico-chemical factors

Biological factors

Factors influencing radiation response Physico-chemical factors

Activation of pro-survival oncogenes (e.g. EGFR) Up-regulation of antioxidative enzymes (e.g. superoxide dismutase, catalase)

Human Ovarian Carcinoma

Mutated tumor suppressors (e.g. p53) Evading cell death (e.g. BCl2, Survivin)

DNA repair gene amplification

Inherent or acquired tumor cell resistance

Biological factors

Physical

Biological

Additional factors influencing radiation response Physico-chemical

> 20 keV/µm

high-LET

Krämer & Kraft 1994

(LET)

average energy deposition (keV) per traversed distance (1 µm) low-LET < 20 keV/µm

Linear Energy Transfer

Density of ionization in particle tracks is described Definition:

m m

10

Carbon Ions

„Clustered DNA damage“

Cell nucleus

X-rays

Physics meets biology

Local Microscopic Dose Distribution

„Randomized DNA damage“

to x-rays is quan-fied by the R ela-ve B iological E ffec-veness ( RBE )

RBE is not a fixed parameter . . . .

increased effect rela-ve

Relative Biological Effectiveness (RBE)

linear energy transfer [LET]

biological system intrinsic radiosensitivity,

micromilieu, structural organization

RBE

depends on:

endpoint

biological

dose/fraction

Relative Biological Effectiveness (RBE)

LET [keV/µm] LET [keV/µm]

Belli et al. 1997; Weyrather et al.1999 Kilagua et al. 1978

1 10 100 1000

4

1

3

2

R

B

E

Entrance

SOBP front

SOBP center

SOBP distal

10-2 10-1 1 10 100 Protons : For a small volume within the distal part of a radiation field RBE increases throughout the SOBP I n t e g r a l d o s e d is tr i b u ti o 160 MeV protons, 10 cm SOBP

Particles: LET dependencies

Thank you very much for your attention !

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

Literature

Beam production techniques for hadron therapy Marco Schippers

See also: J.M. Schippers, Rev. Acc. Science and Techn. 2 (2009) 179-200 H. Paganetti (ed.), Proton Therapy Physics, Chapter 3.

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 1

Contents

• Dose delivery techniques • Accelerators • Synchrotron • Cyclotron • Synchro-cyclotron

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 2

Proton therapy facility: modules 1 accelerator

energy selection beam transport gantry / fixed hor. Line Beam to 1 room at the time

PSI ACCEL/Varian cyclotron

Tsukuba

IBA

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 3

Proton therapy facility: modules

However, NOT independent….

accelerator

(energy selection)

beam transport

gantry

fix hor

gantry

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 4

Dose delivery techniques

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 5

Dose delivery techniques: Depth

tumour Spread-out Bragg peak

250 MeV protons

Range

Tumor distal edge  Range  Maximum Energy per field  „slow“ (sec)

tumor

Tumor thickness  spread-out Bragg peak  energy modulation During trmt  „ fast “ (<0.1 sec)

Methods: 1) at accelerator 2) just before patient (in “nozzle”)

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 6

Dose delivery techniques: Depth

Vary energy at accelerator Synchrotron: Set energy at each spill:  Sets range only  energy modulation in nozzle

Cyclotron has fixed energy => slow down (degrade) to desired energy

 Sets range And, if fast enough + fast magnets:  also energy modulation

: 5 mm ∆ Range in 100 ms

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 7

Energy setting and selection

Degrader unit Q Q Q

All following magnets: 1% field change in 50-80 ms

Carbon wedge degrader 238-70 MeV

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 8

Energy selection system

multi-wedge 235-67 MeV (PSI)

Rolled-up wedge 220-70 MeV (IBA)

Beam analysis: energy selection ∆ E/E < ± 2%

Nr of protons

∆ E/E

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 9

Dose delivery techniques: Depth Vary energy in nozzle (cyclotron and synchrotron)

Energy modulation : rotating wheel or insertable plates

But: material in front of patient - increases scatter  unsharp edges

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 10

Location of energy definition

Energy modulation in nozzle : no beam analysis

or

Energy modulation upstream : includes beam analysis

86 MeV

214 MeV

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 11

Dose delivery techniques: Depth

Degrader purpose: decrease energy

however: - energy spread (%) increases with amount of degradation

degrader system

- beam size increases due to multiple scattering - beam loss due to nuclear reactions in degrader

Collimators define transmitted beam size

 Beam intensity from cyclotron must be high enough

Van Goethem et al., Phys. Med. Biol. 54 (2009)5831

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 12

Dose delivery techniques: Width

transversal spread:

scattering

scanning

Scatter system

Fast magnet

Collimator

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 13

Pencil beam scanning

Requirements for accelerator: - stable beam position

Spot scanning: step & shoot

Continuous scanning

allows fast target repainting : 15-30 scans / 2 min. Requirements for accelerator: - stable beam position - continuous and stable beam - fast adjustable beam intensity - fast adjustable beam energy

kHz-Intensity modulation

0 time (ms) 10 intensity

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 14

Accelerators

High potential energy

Source + + + +

250 MeV

+ _ 250 000 000 Volt

Potential energy  Kinetic energy

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 15

Present accelerator choice

3.5 m

cyclotron

synchrotron

Protons

in use, ∅ 3.5-5 m

in use, ∅ 8-10 m in use, ∅ 25 m

Carbon ions test phase, ∅ 7 m

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 16

Synchrotron (1945)

Hitachi Ltd

Extracted beam

Protons only: ( ∅ ~8 m)

synchrotron

Proton source + injector

synchrotron

Ions (p-C): ( ∅ ~25 m)

Injector

Ion sources

Heidelberg

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 17

Synchrotron

Extraction into beam line

Ring:

• collect 10 11 particles • acceleration to desired E • storing of the beam

+

Magnet to select ion source Injection in ring at 7 MeV/nucl 2 linear accelerators in series Ion sources for different particles

~50 m

+

(DKFZ, GSI, Siemens)

+

+

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 18

Acceleration in synchrotron

magnets

Acceleration Voltage at RF frequency f

V

At electrode slit crossing: Energy gain ΔE= V.q

Energy increases:

 speed ↑  RF frequency ↑  field in magnets ↑

p =

= constant ! r

Bq

Magnets and RF frequency change Synchronous to particle revolution frequency

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 19

Beam extraction from synchrotron

RF-Knock Out

Unstable orbits  extracted

With RF-knock Out: Beam position and size remain constant

RF kicker: increases emittance (beam size)

Beam shape:

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 20

Synchrotron beam: noisy & spills

σ =15%

Beam intensity

Time 

1-10 sec

0.5-1 sec

“spill” time • fill ring with ~10 11 particles • accelerate to desired energy • extract slowly during 1-10 sec • decelerate and dump unused particles

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 21

Cyclotron (1930)

Magnet

Proton source

RF electrodes “Dee”

+

RF-Voltage “Vdee” RF frequency f At electrode slit crossing: Energy gain ΔE=V dee

Septum cathode

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 22

Cyclotron

80 keV protons

1930

Dee

Ernest Lawrence

10 cm

250 MeV (ACCEL/Varian,2005)

230 MeV (IBA, SHI,1996)

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 23

250 MeV proton cyclotron (ACCEL/Varian)

ACCEL

Closed He system 4 x 1.5 W @4K

300 kW 90 tons

Proton source

superconducting coils => 2.4 - 3.8 T

1.4 m

4 RF-cavities: 72 MHz (h=2) ~80 kV

3.4 m

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 24

Internal proton source

anode cathode at -HV

pole

~5 cm

-80 kV

+

Dee 1

anode cathode at -HV

pole

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 25

intensity control

Max. intensity set by: proton source

Deflector plate: sets intensity - within 50 µs - 3% accuracy

- V

+ V

currently only possible with a cyclotron

0 2 4 6 8 10 Time (ms)

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 26

Extraction from cyclotron

r 1 ∝ δ

r

Efficiency =80%

Cathode at -50 kV

septum

δ r

Low radioactivity

← r

Last turns

δ r

Extracted beam

(ACCEL / Varian)

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 27

Small cyclotron; strong field Cyclotron works while: T circle independent from radius: (particles move in pace with Vdee)

Bq m . .2 π

T

=

Freq = 1/T circle V dee ~

circle

+

r

However (1): at very strong magnetic fields:

m = mass B = magnetic field q = charge

⇒ Magnetic field decreases with radius ⇒ T circle ↑

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 28

Cyclotron; high energy

Bq m . .2 π

T

=

circle

2 2 cv m m − 0

However (2): if v  c :

=

1

=> m ↑ => T circle

↑

m = mass B = magnetic field q = charge v = velocity c = speed of light

30 MeV p: v/c=0.24 => m= 1.03 m 0 250 MeV p: v/c=0.61 => m= 1.27 m 0

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 29

Synchro-Cyclotron

stronger magn.fields  Smaller machines ! But….

~

V dee

T circle

increases with radius.

SO: decrease f RF with radius and extract Repeat 1000 x per sec

f RF

1 ms

time

Each pulse: set intensity at source within ms (=> typ 10-30% accuracy) => Spot scanning requires >2 pulses per spot.

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 30

Synchro-Cyclotron

Proposal of H.Blosser, F.Marti, et al.,1989: -250 MeV -SC, 52 tons, on a gantry -B(0)=5.5 Tesla

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 31

Synchro-Cyclotron

S2C2

First beam extracted in May 2010

First beam at IBA in 2013

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 32

some differences…

cyclotron in development in development

synchrotron

Carbon ions

easy easy

Change particle Time structure Fast E-scanning Activation degrader

continuous (SC:pulsed)

dead time next spill

degrader

to be shielded

no

Intensity

“any ”(SC:low), adjustable limited, per spill

Intensity stability

3-5%

15-20%

Size ∅

3.5 - 5 m (SC<2)

6-8 m ( C: 25 m)

Scattering

ok

ok ok

ok (SC: >2 pulses/spot)

Spot scanning

Marco Schippers, Beam production techniques for hadron therapy Fast continuous scanning ok (SC: no)

difficult

ESTRO-course, Esen, March 6-10, 2017 33

The Holy Grail for proton therapy:

MeV

one small (cheap) accelerator per treatment room

protons

See lecture on new technologies

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 34

The End

Marco Schippers, Beam production techniques for hadron therapy

ESTRO-course, Esen, March 6-10, 2017 35

Rationale for particle therapy The paradygm of pediatric tumors

Jean-Louis Habrand, MD Pr., University of Caen Medical School , Director ARCHADE project of hadrontherapy Chief, Dept radiation Oncology François Baclesse Cancer Center, Caen, Fr

Rationale: historical perspective • The « heroic » period : until late 90s – 1946:Founding concept by Wilson on the potential advantage of protons over conventional XR – 50s: pionneering work by neurosurgeons (AVMs, Pituitary) – 70s: interest from ophthalmological, and then radiotherapy communities – « niche » of rare & highly selected indications

longs-tanding reputation of specialists

Old technology conditioned indications

Basics of proton dosimetry

PROTONTHERAPY in 90s THE BOSTON « PHILOSOPHY » Protontherapy well-suited for dose- escalation studies: – Localized – well-defined, on imaging (CT) – slow-growing (waiting list) – resistant to « conventional » photon-doses – Complying with technological requirements

PROTONTHERAPY / SKULL BASE, LOW GRADE MALIGNANCIES • Comprise mainly chordomas and low grade- chondrosarcomas • Paradigms of : – Difficult surgical access – Radioresistant types – High proximity critical structures : optic pathway, brain stem, internal ears, temporal lobes, spinal cord ..

San Paolo, 2003

Why skull base ? • This highly complex technology fitted only highly selected indications, i.e. tumors : – With no internal motion (= Skull, brain) – that could be simulated with a fixed horizontal beam (seated position = Brain, cervical chord) – that could be targetted with metallic fiducials – That avoided major tissue heterogeneities (not HN)

Protontherapy : Clinical Indications in early 2000s • The oldest program: radio-surgical (Arterio-venous malformations) • the largest program: ocular melanomas • the most prestigious one: Skull base/spinal canal slow growing malignancies • the most controversial one: Prostate carcinomas

And also, behind the stage…

• Much excitement for:

• Disclosing the « secrets » of basic physics • « Saving » soon obsolete huge and expensive accelerators (…and their experienced staff)

1940 ! first cyclotron « collège de France », in Paris (Frédéric Joliot-Curie)

Orsay Synchrocyclotron 50 years operation !

Same with upgrading in 1977…

Rationale: modern perspectives • The « new » era : since the 2000s: – Need to fight back in the raising competition with IMXRT that also allows safe dose-escalation studies – Need to keep-up with modern « environment » of Rtherapy: easiness, reliability (gantries, absence fiducials), safety and reproducibility (QA, IGRT, adaptive, in vivo dosimetry…) – Need to be evaluated in the full context of multimodal armamentarium…

Protons: still technical limitations

…along with the voice of wisdom !

« there is no reason for giving any

additional dose to normal tissue s »

(HD SUIT)…

Rationale: modern perspectives – Switch in Pr philosophy = based on the concept: « Proton sparing normal tissues is unrivalled » – Flexible concept adjustable to patients’ population whether: • Need for dose-escalation (± adults) • Need for normal anatomy preservation (± children) – But still largely unproven « scientifically » : Through randomized control studies…

PEDIATRIC TUMORS A context of rare conditions, and complex presentations

Pediatric tumors :

– Rare:

• 2 % all cancers • 130 / million children

– Total / year : US : 8,000 – France : 2,000 – Management entirely multidisciplinary, and importance RT long been « eclipsed » due to « unavoidable » toxicity – Sensitivity correlated with: very young age, morbid conditions (NF1)… – Tremendous improvement outcome since the 60s

SURVIVAL NO LONGER A PRIMARY CONCERN…

Dismal survival until 70s Steady increase in 40 years Overall survival in excess of 80% since mid 90s

Ries LAG et al, NIH pub, 1999

Prevention of toxicity and quality of life have become an overriding concern

Oeffinger KC et al, NEJM, 2006

Armstrong GT et al, JCO, 2009

PEDIATRIC TUMORS

Deserve the optimal equipment

20 16

20 14

RAPID’ARC

RAPID’ARC

CT SIMULATORS 1+2

20 14

Dept Rad. Oncology F. Baclesse Comprehensive Cancer Center

TOMO. 2

DARPAC

20 13

20 11

22

CYBERKNIFE

CLINAC

TOMOTHERAPIE

ARTISTE

PEDIATRIC TUMORS A large body of evidences for IMXRT

Supine position vs prone No junction High homegeneity/conformity On board imaging Tomotherapy vs 3D CRT

The reverse side…integral dose Supine position:Tomo Prone position: 3D

Courtesy C.Dejean, Nantes

Integral dose: impact on K2

Neutron secondary emission

Children: max risk K2

Hall E et al, IJROBP, 2006