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
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