Technologies for Next-Generation Proton and Ion Beam Therapy

1. Technologies for Next-Generation Proton and Ion Beam Therapy: Research at Loma Linda University and in the U.S.

Reinhard W. Schulte, Professor of Radiation Medicine
Loma Linda University & Medical Center
California, USA
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18, 2013
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2. Funding Acknowledgment

• Proton CT research is funded by a 4-year grant from the National
Institute of Biomedical Imaging and Bioengineering (NIBIB) and the
National Science Foundation (NSF), award Number R01EB013118.
The content of this presentation is solely the responsibility of the
authors and does not necessarily represent the official views of
NIBIB, NIH and NSF.
• Work in pCT reconstruction has been supported by the U.S.-Israel
Binational Science Foundation (BSF)
• The Phase 1 pCT detectors were built at LLUMC, UCSC and Northern
Illinois University (NIU) with support from the U.S. Department of
Defense Prostate Cancer Research Program, award No. W81XWH12-1-0122 and the Department of Radiation Medicine at LLUMC
• The cardiac arrhtymia research is funded by translational research
grant by the LLU School of Medicine to Dr. Ying Nie and Dr. Ramdas
Pai
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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3. Outline

• The rise of particle therapy – no end in sight?
• Update on Loma Linda projects
– Nanodosimetry - RBE
– Proton CT/Radiography - Range Uncertainty
– Cardiac arrhythmia radiosurgery – New horizon
• Future of Technology Transfer- Particle
Therapy Technology Commons?
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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4. The rise of Particle therapy in the u.s. – bound to continue?

THE RISE OF PARTICLE THERAPY IN
THE U.S. – BOUND TO CONTINUE?
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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5. Ernest Lawrence and his Cyclotron

• Physicist E. Lawrence was
from the East Coast but
was lured to Berkeley in
1929
• He saw the problem of
linear particle
accelerators and invented
the RF-driven cyclotron
• The first MeV cyclotrons
(4.5” & 11 “), built by him
and student S. Livingston
accelerated protons to
about 1 MeV
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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6. Harvard Cyclotrons 1935-1956

• The usefulness of cyclotrons for physics
and (nuclear) medicine was recognized
soon after its invention by Ernest
Lawrence and Stanley Livingston
• In 1937, Harvard physicists Kenneth
Bainbridge & Jabez Street and
electrical engineer Harry Mimno
constructed the 1st Harvard Cyclotron
• The 2nd cyclotron was completed after
WWII and accelerated protons to 90
MeV, it was used for physics
experiments until 1955
• 1956, an improved 2nd cyclotron
accelerating protons to 160 MeV was
installed at the HCL
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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7. An idea is born …

• During his short stay at
the Harvard Cyclotron,
Robert R. Wilson, Ph.D.
(1914-200) published
his seminal paper on
the use of protons for
therapy (Radiology
1946:47:487-91)
• It took 45 years before
protons finally entered
a hospital
Robert R. Wilson, Ph.D., 19142000
R Schulte, Status and Future of Hadron
December 17, 2013
Therapy, CNAO Workshop, Dec 17-18,
2013
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8. The Beginnings of Proton & Heavy Ion Radiosurgery at Lawrence Berkeley National Laboratory (1948-1955)

The Beginnings of Proton & Heavy Ion Radiosurgery at
Lawrence Berkeley National Laboratory (1948-1955)
• Starting in 1948, John Lawrence
(physician, brother of Ernest) and
Cornelius Tobias (biophysicist)
developed biomedical program of
heavy ions at the LBNL cyclotrons
• In 1954, the LBNL group began to
direct the high doses of heavy ion
beams (protons & helium) at human
pituitary glands (about 50 patients)
• The program later continued with
helium and neon ions to treat base of
skull tumors, gliomas, ocular
melanomas & arteriovenous
malformations under Drs. J. Castro &
J. Fabrikant
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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9. Proton Therapy at Harvard 1961-2001

• In 1961, MGH neurosurgeon Raymond
Kjellberg began treating patients with
pituitary adenomas using 160 MeV
Bragg peak protons from the Harvard
Cyclotron Laboratory (HCL)
• Starting in the 1970s, Dr. Kjellberg also
treated large, inoperable
arteriovenous malformations (AVMs)
with Bragg peak protons, despite
limitations in imaging and planning
techniques at that time
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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10. The Harvard Cyclotron Goes Medical 1970-2001

• With fading use of the Harvard Cyclotron
for physics research, medical use took
over in the early 1970s, starting with
radiobiology studies (RBE)
• The invention and construction of x-ray
CT & and a grant from NCI allowed the
development of proton therapy for
ocular melanomas and large field,
fractionated proton therapy for base-ofskull and paraspinal sarcomas
• The large-field program was successful
thanks to the collaboration of physicians
(Drs N. Liebsch, J. Munzenrider, M. Austin
Seymour, E. Hug and H. Suit) and
physicists (Drs M. Goitein, L. Verhey and
A. Smith)
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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11. 1985-1990 – Proton Therapy Moves into a Hospital

• During the late 70s and early
eighties the desire for medical
proton accelerator grew
• Early plans included a compact
cyclotron (favored by Andy
Koehler) versus a variable-energy
synchrotron (favored by Bernard
Gottschalk)
• James M. Slater, MD convinced
Fermilab (director Phil Livdahl) to
construct the first 250-MeV
medical proton synchrotron
• With congressionally directed
funding, he brought proton
therapy to LLUMC; 1st treatment
of a patient with ocular
melanoma occurred in Oct 1990
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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12. Protons and Ions at Crossroads?

• The first hospital-based proton
facility showed that clinical
synchrotron & gantry operation is
feasible and leads to good clinical
outcomes
• Hospital-based charged particle
facilities continue to open
throughout the U.S. and
worldwide
• However, technology has changed
little, capital costs are high,
footprints are large
• Only one full-rotation carbon ion
gantry exists (Heidelberg)
• No large clinical trials involving
protons or ions have been
conducted
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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13. Path Forward: Accelerators for America’s Future

• In October 2009, the DOE
Office of HEP sponsored a
symposium and workshop
‘Accelerators for
America’s future’
• Medicine, and particle
therapy in particular were
recognized as one of the
key areas where
innovation is needed
www.acceleratorsamerica.or
g/files/Report
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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14. Path Forward: DOE-NCI Workshop on Ion Beam Therapy, Bethesda, MD, January 2013

• More than 60 participants
from medicine, physics,
biology & business were
charged with addressing 4
topics:
– Charge 1: Identify pertinent
clinical applications and
radiobiological requirements
– Charge 2: Assess corresponding
beam requirements for future
treatment facilities
– Charge 3: Assess the
corresponding beam delivery
system requirements
– Charge 4: Identify R&D
activities needed to bridge the
gap
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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15. From Existing to Future Proton & Ion Therapy Centers

From Existing to Future Proton & Ion Therapy
Centers
• As of now, four proton-ion beam
facilities have been established
worldwide, and two are being built
(Shanghai and MedAustron), others
are contemplated (e.g., Lyon, France)
• In February 2013, the U.S. DO NCI
invited applications for Planning a
National Center of Particle Beam
Radiation Therapy (PBRT) Research
leading to an associated clinical PBRT
center in the future (P20 grant)
• In October 2013, Walter Reed
National Military Medical Center
(WRNMMC) announced they are
planning to establish a Particle Beam
Therapy Research and Development
Center (PBTRDC),
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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16. Technological challenges & New Horizons - Update on Loma Linda projects

TECHNOLOGICAL CHALLENGES & NEW
HORIZONS - UPDATE ON LOMA LINDA
PROJECTS
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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17. Challenges in Particle Therapy and Related R&D Activities

Challenges in Particle Therapy and Related R&D
Activities
• Radiobiological (RBE) uncertainty -> Biologically based
treatment planning
• Range uncertainty better conformality -> proton
CT/radiography
• Interfraction variation/adaptive therapy -> low-dose
proton CT
• Range uncertainty due to motion/better conformality ->
4D motion management: gating vs. tracking, predictive
motion models, high-frequency jet ventilation
• Better conformality-> new algorithms in IMPRT
• New horizons: Cardiac arrhythmia particle radiosurgery
(CAPRS)
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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18. Particle-tracking nanodosimetry & Track structure imaging

PARTICLE-TRACKING NANODOSIMETRY
& TRACK STRUCTURE IMAGING
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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19. The Importance of Biological Weighting

• Protons and ions have a depthdependent biological effect profile
• Current concept of DRBE = RBE× D, has
limitations
• RBE is depth-, dose-, and tissue- (or
endpoint) -dependent
• In proton therapy, RBE = 1.1 = const is
assumed, which was recently
endorsed by ICRU report 78
• However, the higher biologically
effective dose in the distal third of the
SOBP is missed
• Micro/nanodosimetry-based
treatment planning can address this
issue
December 17, 2013
The biologically-weighted dose is
higher
in the distal regions of each
R Schulte, Status and Future
of Hadron
Therapy, CNAO Workshop,beam,
Dec 17-18,
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leading
to
a
non-uniform
2013

20. Radiobiological Rationale of Proton-Ion Beam Therapy

Radiobiological Rationale of ProtonIon Beam Therapy
• Protons and ions have
excellent dose-localization
properties
• Ions, in addition, produce a
higher ratio of clustered
DNA damages (complex
DSB) compared to low LET
protons and x-rays
• Protons may thus be used
for volume-sparing, while
ions have advantages for
resistant +/- hypoxic tumor
regions and may be used as
integrated dose boost to
those regions (biologyweighted treatment R Schulte, Status and Future of Hadron
December 17, 2013
Therapy, CNAO Workshop, Dec 17-18,
planning)
2013
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21. Biological Optimization: Mixing Ions?

• A maximum RBE (higher
for resistant tumors & at
lower doses) is observed
for each particle, which is
around 100 keV/mm for
He ions
• Minimum OER (=1) is
achieved for particle LET
> 100 keV/mm
• Optimum RBE/OER
distributions may be
achieved by mixing ions
and energies
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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22. Radiation Quality – Microscopic Radiation Quantities

December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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23. Monte Carlo Track Structure Simulations: Lessons Learned

• All particle tracks are
highly structured on the
nanoscopic scale
• Low-energy electrons can
produce ionization
clusters on the DNA scale
• Mean free path length
comparable to diameter
of DNA molecule (~2 nm)
for most effective highLET radiation
Courtesy D. T. Goodhead
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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24. Principle Approaches to Single-Particle Tracking Nanodosimetry

Principle Approaches to SingleParticle Tracking Nanodosimetry
2D
1D
Track Structure Imaging (TSI)
Sensitive-Volume (SV)
Sampling
R Schulte et al. Australas. Phys. Eng. Sci.
R Schulte, Status and Future of Hadron
149-55,
December 17, 2013 Med., 26(4),Therapy,
CNAO2003
Workshop, Dec 17-18,
2013
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25. Ion Counting Nanodosimeter with Particle Tracking Weizmann Institute, LLUMC, UCSC, PTB

• Propane based (1.3
mbar)
• Operating in DC or pulsed
mode
• Electron multiplier (EM)
for ion counting
• Particle tracking system
(4 silicon strip detectors)
developed by SCIPP @
UCSC
G Garty et al., Nucl. Instr. and
R Schulte, Status and Future of Hadron
Meth.
A 17,
491,
212-235, 2002.Therapy, CNAO Workshop, Dec 17-18,
December
2013
2013
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26. Sensitive Volume Maps

• Pulsed drift voltage
operation is important
to suppress charge
multiplication
• Sensitive volume
transverse diameter
matches that of DNA
molecule
• Penumbra simulates
probability of
ionization causing DNA
damage via indirect
effect
R Schulte et al. J Instrum.
2006
R Schulte, Status and Future of Hadron
December 17, 2013
Therapy, CNAO Workshop, Dec 17-18,
2013
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27. Ionization Clustering of Protons Varies with Depth

• We have measured and
simulated the clustering
statistics of protons in
propane gas volumes of
nanometer-equivalent
size
• The rel. frequency of
large clusters increases
with decreasing energy
and thus depth
December 17, 2013
3D efficiency map of
sensitive volume
Distance from
axis
R Schulte, Status and Future of
Hadron Therapy, CNAO Workshop,
Dec 17-18, 2013
6nm
0 nm
21nm
Number of ions
per primary particle
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28. Predicting Cell Survival RBE (V79) along a Spread-Out Proton Bragg Peak

• We have further predicted
the depth-dependence of
RBE for the repairefficient Chinese Hamster
cell line V79 based on a
model that converts ion
clusters into DSBs of
different complexities
• These results confirmed
previous cell survival
measurements
December 17, 2013
R Schulte, Status and Future of
Hadron Therapy, CNAO Workshop,
Dec 17-18, 2013
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29. A Novel Detector for 2D Ion Detection in Low-Pressure Gas

• Novel 2D ion detector
developed in the LLU
Radiation Research Labs
• Principle proven and
presented in 2009
• Can be applied to proton
and ion track structure
studies
• Currently developed in
our Radiation Physics
Research lab
V. Bashkirov, 15th International Symposium on
Microdosimetry (MICROS 2009 ), October 25-30,
R Schulte, Status and2009,
FutureVerona,
of HadronItaly
December 17, 2013
Therapy, CNAO Workshop, Dec 17-18,
2013
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30. Future Goal: Optimization based on Biological Efficiency

• Particle (proton and ion) beams not only have an
increased dose (Bragg peak) near their stopping point,
but also an increase in biological effectiveness per unit
dose
• Future optimization of particle therapy should aim at
optimizing biologically-weighted dose rather than
physical dose
• The optimization goal is to maximize the number of
complex DNA breaks in tumor cells and minimize them in
surrounding normal cells
• Workshop “Nanodosimetry 2014” planned at
MedAustron from May 7-9, 2014
December 17, 2013
R Schulte, Status and Future of
Hadron Therapy, CNAO Workshop,
Dec 17-18, 2013
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31. Single-particle proton Imaging

Section III
SINGLE-PARTICLE PROTON
IMAGING
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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32. pCT Concept

• An energetic low
intensity cone beam of
protons traverses the
patient
Low intensity
• The position and
proton beam
direction (entry & exit)
and energy loss of each
proton is measured
• Proton histories from
multiple projection
Tracking of
angles
individual
• Minimal proton loss
protons
and high detection
efficiency make this a
Design of a Proton CT Scanner rotating with the
low-dose imaging
proton gantry (R Schulte et al. IEEE Trans. Nucl. Sci., 51(3), 866-872, 2004)
modality
R Schulte, Status and
Future of Hadron Therapy,
December 17, 2013
CNAO Workshop, Dec 1718, 2013
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33. First Modern Proton CT with Single Particle Detection – Phase 1 Scanner (2011)

• Employed existing tracking
sensors (silicon strip
detectors and data readout
for Fermi Space Telescope,
NASA GLAST Mission)
• Energy measurement with
multi-segmented crystal
calorimeter
• FPGA-based DAQ & GPU
based reconstruction
December 17, 2013
R Schulte, Status and Future of Hadron
Therapy, CNAO Workshop, Dec 17-18,
2013
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34. Proton CT Reconstruction: Solution Concept

• With registration of single
particle histories, the object
solution can be found by
solving a very large, sparse
linear system
• Iterative reconstruction
algorithms exploit massive
parallelism