Particle Therapy 2017

Introduction to clinical particle therapy

W. De Neve

March, 2017

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

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 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 • 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

•

Imaging 1950-1970s

–

Indirect target imaging

• •

Bone, air Contrast

– –

Radio-opaque markers-spacers

Target edges

• •

Calculation

Informed guess

•

Immobile targets

– – –

Nearby bone

Adult

Superficial

No moving organs in path

•

Skull base, paraspinal and sacral chordoma and (chondro)sarcoma

•

Glioma

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 t e 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

Imag e Fusio n

Cerrobe nd blocks

Multileaf collimator

IMXT dose-painting

First Linac

2000

2010

1980

1990

1960 1970

Robotic XT/tracking

High resolution IGXT/gating

Standar d collimat or

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

• Physical/physiological uncertainties • Biological uncertainties • Dose computation • Planning, plan robustness, robust optimization • Technological limitations Challenges in particle therapy

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 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. 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

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

• • • • •

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.

The fall: toxicity

• 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

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

An--Protons

Iron

Helium

Carbon

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 • 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 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

Clinical Radiobiology Molecular and cellular basics

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

ESTRO Teaching Course 2017 “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 2017 “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

CH 3

P O OH CH 2

O

S U G A R - P H O S P H A T E B

NH 2

H OH

HO

O

HN N

N N

N

D N A

B A S E S O

O

N

O

O

CH 2

O P O

H2N

HO

O

H

P O O

O

H

H

H2 O

HO

O

N

N

N N

NH

NH 2

N

O

CH 2

O

CH 2 O

O

O H H P HO

H

O

O

NH 2

N HN N N

H2 O

HO

P O

O

N

N O

5’Phosphate group

H2 N

CH 2

O

O

CH 2

P O

3’Hydroxyl group

O

HO

H OH

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 mRNA

Transcription

Translation

Ribosome

Polypeptide (protein)

©2000 Timothy G. Standish 1998 Timothy G. Standish

Effect of Ionizing radiation on biomolecules

direct effect

damage

interaction of photons or electrons with DNA

targeted effects

H2O++ e- H2O

e-

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

p+

OH- + H3O++ e- aqu.

damage

indirect effect

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 Radiolysis of water ! h ν Effect of Ionizing Radiation on Biomolecules

Effect of Ionizing Radiation on DNA

Ionizing radiatio n

U V

dimerisation

base modification

Basenverlust los of base

Einzelstrang- bruch singl trand break (SSB)

double strand break (DSB)

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

WE LIVE IN A SEA OF RADIATION . . .

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

amount and type of damage that can be handled

excessive damage, irrepairable

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

excission of damaged regions b ase excission repair nucleotide excission repair mismatch repair direct reversal of damage single strand breaks

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

20

Christmann et al. Toxicology 193 (2003)

DNA repair: Non-homologeous endjoining (NHEJ) Double Strand Break (DBS)

PARP 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 .

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 DNA-dependent protein kinase ( DNA-PKcs ) stabilize broken ends The heterodimer XRCC4/Ligase IV subsequently assists in repairing the break Fast repair, can be error-prone !!! 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: Cell survives without mutations

Inadequate repair: Cell inactivation or cell death due to • Mitotic death • Apoptosis • Permanent arrest

Misrepair: Cell survives but at the cost of genetic changes

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

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

Cell cycles Multiple 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

Necros is

Apopto sis

Robbins & Cotran 2006

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

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

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

Radiation effects

Cell cycle

Base Excision Repair

Single strand Repair

G 1

S

G 2

M

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

amount and 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

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 ! death receptor Fas-R TRAIL-R growth factors e.g. EGF cytokines e.g.TNF- alpha

damage-inducible and stress-related proteins reactive oxygen species (ROS) cytokines for intercellular signaling (TNF α, interleukin 1, 8, TGF ß)

cell survival adhesion migration

repair proliferation

NFkB

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

amount and 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

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

amount and 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

DNA repair

stress response

genetic instability

consequences

cell death

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

Cells proliferate:

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 and 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

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

DNA damage

gene activation

Summary

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

DNA repair

cell death

DNA damage

gene activation

stress response

cell cycle effects

growth factors

Summary

lipid peroxidation

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

.

O 2

DNA repair

O 2

cell death

DNA damage

receptor

signal transduction

gene activation

stress response

cell cycle effects

growth factors

Summary

lipid peroxidation

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

.

O 2

DNA repair

O 2

cell death

DNA damage

receptor

signal transduction

gene activation

stress response

cell cycle effects

growth factors

Summary

lipid peroxidation

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

.

O 2

DNA repair

O 2

cell death

DNA damage

receptor

signal transduction

gene activation

stress response

cell cycle effects

external effectors

growth factors

O2, nutrients etc. endocrine factors

Summary

lipid peroxidation

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

.

O 2

DNA repair

O 2

inflammatory molecules

cell death

DNA damage

receptor

signal transduction

gene activation

stress response

cell cycle effects

external effectors

growth factors

O2, 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

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

hypoxic

S u r vi vi n g fr a

indirect effects

normoxic

Gray et al. 1953

c ti o n

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

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

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

Activation of pro-survival oncogenes (e.g. EGFR) Up-regulation of antioxidative enzymes (e.g. superoxide dismutase, catalase) Evading cell death (e.g. BCl2, Survivin)

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 < 20 keV/µm

high-LET > 20 keV/µm

„Randomized DNA damage“

„Clustered DNA damage“

10 m m

Krämer & Kraft 1994

Relative Biological Effectiveness (RBE)

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

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

Particles: LET dependencies

Protons :

For a small volume within the distal part of a radiation field RBE

increases throughout the SOBP

Entrance SOBP front SOBP center SOBP distal

I n t e g r a l d o s

4

2 3

R B E

160 MeV protons, 10 cm SOBP

1

e d is tr i

1 10 100 1000

10-2 10-1 1 10 100

LET [keV/µm]

LET [keV/µm]

b u ti o

Belli et al. 1997; Weyrather et al.1999

Kilagua et al. 1978

Thank you very much for your attention !

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

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

PEDIATRIC TUMORS Still a non-scientifically explored topic !

Review literature

• Radiotherapy • English • Children • Toxicity (Acute, Late, Sequelae) • Novel technologies • 10 years (2005-2015) • Excluding: case reports, editorials, letters, unexploitable data

10 years literature: Topics Acute Late CNS Late Endo Late Cosme K2

Tech\T ox

Mixed & Others

Total

NO ® !

3D

1 4

1 7 4 4

1 1 1 1 2

1

2 2

-

6

IMRT

9 3

23 10 30 43

RXsurg 2 Proton 5 Mixed 2

1 1

6

13 10

10

18

Brachy

1

1

Total

28

35

14

27

6

3

113

Dosimetrical evidences

AUTHOR [Ref] (Year) Miralbell, R [18 ] (1997)

TOTAL DOSE (CGE) 30 Brain ± 10 ventricles

SITE / TUMOUR TYPE

RÉSULTS

Medulloblastoma (supra tentorial)

P: æ risk IQ decline

Miralbell, R [19 ] (1997)

Medulloblastoma (spine)

30

P: æ dose vertebral body, heart, liver, thyroid, gonads

Fuss, M [20 ] (1999)

Optic gliomas

50.4

P: k conformation large tumours, k protection chiasm, contralat ON, hypophysis, temporal lobes

Lin, R [21 ] (2000)

Posterior fossa

54

P k sparing cochlea, temporal lobes

Miralbell, R [22 ] (2000)

RMS orbit, NHL, meningiomas

30-54

IMPT: k sparing lens/cornea

Hug, EB [23 ] (2001)

Neuroblastoma

34.2

P: k sparing homolat/contralat kidneys, liver, spinal cord

Miralbell, R [18 ] (2002) St Clair WH [24 ] (2004)

Medulloblastoma, RMS PM

36-50

æ risk K2

Medulloblastoma

23 CS/54 PF

P: k sparing cochlea, hypophysis, heart…

Yuh, GE [25 ] (2004)

Medulloblastoma

36 CS/ 54 PF P

m dose cochlea, vertebrae, thorax, abdomen, m myelosuppression

Krengli, M [26 ] (2005)

Retinoblastoma

40 ± 6

P: k sparing orbit, Contralateral eye, brain, hypophysis

Lee, CT [ 27] (2005)

Medulloblastoma, 1, retinoblastoma, 2, pelvis3

23-54

P: k sparing1: cochlea, hypophysis; 2: orbit, lens; 3:ovaries, iliac bone

Merchant, TE [28] (2008)

Optic glioma 1,Ependymoma PF2, Medulloblastoma3, Craniopharyngioma4

Variable

P: k sparing 1,2 : temporal lobes, 3 :cochlea, 4 : æ risk IQ decline