Technologies for Next-Generation Proton and Ion Beam Therapy

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. W81XWH-12-1-0122 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

R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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Loma Linda projects
Nanodosimetry - RBE
Proton CT/Radiography - Range Uncertainty
Cardiac arrhythmia radiosurgery – New horizon
Future of Technology Transfer- Particle Therapy Technology Commons?

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CONTINUE?

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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

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Robert R. Wilson, Ph.D., 1914-2000

R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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-of-skull 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)

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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.org/files/Report

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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),

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

-> 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)

Challenges in Particle Therapy and Related R&D Activities

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Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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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

R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

The biologically-weighted dose is higher in the distal regions of each beam, leading to a non-uniform biologically-weighted dose

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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 (biology-weighted treatment planning)

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

at lower doses) is observed for each particle, which is around 100 keV/μm for He ions
Minimum OER (=1) is achieved for particle LET > 100 keV/μm
Optimum RBE/OER distributions may be achieved by mixing ions and energies

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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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 high-LET radiation

R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

Courtesy D. T. Goodhead

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Principle Approaches to Single-Particle Tracking Nanodosimetry

Track Structure Imaging (TSI)

Sensitive-Volume (SV) Sampling

2 D

1 D

R Schulte et al. Australas. Phys. Eng. Sci. Med., 26(4), 149-55, 2003

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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

R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

G Garty et al., Nucl. Instr. and Meth. A 491, 212-235, 2002.

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multiplication
Sensitive volume transverse diameter matches that of DNA molecule
Penumbra simulates probability of ionization causing DNA damage via indirect effect

R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

R Schulte et al. J Instrum. 2006

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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

R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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Predicting Cell Survival RBE (V79) along a Spread-Out Proton Bragg Peak

We have further predicted the depth-dependence of RBE for the repair-efficient 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

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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, 2009, Verona, Italy

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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

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CNAO Workshop, Dec 17-18, 2013

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pCT Concept

An energetic low intensity cone beam of protons traverses the patient
The position and direction (entry & exit) and energy loss of each proton is measured
Proton histories from multiple projection angles
Minimal proton loss and high detection efficiency make this a low-dose imaging modality

Design of a Proton CT Scanner rotating with the proton gantry (R Schulte et al. IEEE Trans. Nucl. Sci., 51(3), 866-872, 2004)

Low intensity proton beam

Tracking of individual protons

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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

R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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object solution can be found by solving a very large, sparse linear system
Iterative reconstruction algorithms exploit massive parallelism

R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

 

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path performs best

R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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Li T, et al
Med Phys. 2006 33:699-706. PMID: 16878573;

phantom QA phantom (made from polystyrene) with different cylindrical inserts
Quantitative RSP comparisons gave agreement with expected values to better than 1%

R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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H. F.-W. Sadrozinski, et al, Nucl.Instrum.Meth. A 699, 205-210, 2013.

loss of a realistic hand phantom were obtained with 200 MeV protons
More faithful representation of relative bone and soft tissue electron densities compared to x-ray radiographs
pRadiographs can be used for QA and fast verification purposes (before treatment)

R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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Plautz T, et al. 200 MeV Proton radiography studies with a hand phantom Using a prototype proton CT scanner. Submitted to IEEE Trans. Nucl sci, Oct 2013

cm long x 36 cm wide)
New sensors with slim edges
Simplified energy detector (5-stage plastic scintillators with PMT readout)
Dedicated ASIC for high data rates (2 MHz nominal rate) – acquisition times < 5 min
Reconstruction in under 10 minutes on GPU cluster

R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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energy corrections

For Tiling with no Overlap: “Slim Edges”

Si SSD with
900μm dead edge

S-C-P process:
Scribing (XeF2)
+ Cleaving
+ Passivating
(N2 PECVD)

Cut within 50 μm
of Guard Ring

M. Christophersen et al.,
SSE 81, (2013) 8–12

SCP: low leakage current

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Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

Noise occupancy measurements.
The expected signal from a 250 MeV proton is about 10 fC.

New ASIC optimized for pCT.

Two readout boards back-to-back, with Spartan-6 FPGAs to manage the data flow from the ASICs

Ultra-low-noise readout ensures that there will be zero background, zero added data volume, and no confusion from electronics noise hits.
High-speed, compact FPGA-based, triggered readout will move > 106 events/s to the computer.

R. Johnson et al., IEEE TNS, Vol. 60, No. 5, October 2013

Only two of eight SSD sensors shown installed.

Therapy, CNAO Workshop, Dec 17-18, 2013

Custom board with three 65-MHz, 14-bit digitizers and FPGA-based readout.

Four of the five plastic scintillators, with PMTs.

Above: signals from one scintillator in which the beam was stopping, for nine different absorber thicknesses in front of the detector. Below: reconstruction of the water equivalent thickness of one of the absorbers.

Data from a beam test at LLUMC

Therapy, CNAO Workshop, Dec 17-18, 2013

Custom FPGA-based “Event Builder”

Gigabit Ethernet

Xilinx ML605 Virtex-6 Board

Custom high-density interconnect “mezzanine board”

Tracker module

5-stage energy detector

Digitizer boards

Above: reconstructed beam spot from about 1 million protons at the LLUMC accelerator.

Left: one of two tracker modules (with beam window uncovered), and the 5-stage energy detector.

problem in charged particle therapy, the uncertainty of placing the Bragg peak,
It requires a multi-disciplinary team with input from high-energy & solid-state physics, computer science and applied mathematics and radiation oncology

R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

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of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

mortality in the US
Societal burden is increasing with the aging population
Atrial fibrillation (AF), the most common form of arrhythmias, affects 2.5 million Americans (25% life time risk)
Estimated number of adults with AF in 2050 will exceed 16 million

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

which target the PVs and/or PV antrum are the cornerstone for most AF ablation procedures.”

Cappato et al., Circ Arrhythm Electrophysiol 2010;3;32-38 http://www.HRSonline.org/Policy/ClinicalGuidelines

Isolate each PV independently

2007 HRS Consensus Statement

Complete electrical isolation should be the goal for targeted PVs and entrance and/or exit block should be demonstrated

Left Superior Pulmonary Vein

Left Inferior Pulmonary Vein

Right Inferior Pulmonary Vein

Right Superior Pulmonary Vein

Superior Vena Cava

Inferior Vena Cava

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

collimation with radiosurgery cone (2-5 mm)
Robotic positioner calibrated to CT coordinates
Dedicated rat holder with rat in prone position
Clinical dosimetry

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

well for 4D CT of the rat heart (respiratory-cycle sorted CT scan)
Cardiac target (AV-node) is defined in end-in- and expiration by LLUMC cardiologist
The study is imported into the clinical planning system (Odyssey™) and an updated plan is developed for each rat and exported to the treatment room

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

for dose finding study
AVN can be stained with IHC and beam signal can be shown with H2AX for verification of correct targeting

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

attractive non-invasive treatment modality
Next R&D steps:
Rat study technology (complete)
Dose finding study (with respiratory 4D contrast CT, no beam gating)
Large animal model: sheep with AF
Proper motion management
Human trial

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

Therapy, CNAO Workshop, Dec 17-18, 2013

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to LLU and their collaborators to build and test a Phase 2 proton CT scanner.
Specific Aim 3.2 of the award stated: …develop technology transfer concepts leading to a sharing of this new technology with other proton treatment centers to maximize the benefit to patients.
We have been exploring various models of successfully implemented university-industry relationships and found that the “commons model” maybe the first likely to succeed.

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

I: first lab prototypes
Phase II: first clinical prototypes
III. Development of a Standard
IV. Product Commercialization

Limited to Commons Members

Time

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013

the attitude towards proton and ion research of the U.S. government
Protons and light-ion technology innovation may become a national goal of the U.S. over the coming years
Collaboration with existing and new hadron therapy centers in Europe and Asia has been encouraged

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R Schulte, Status and Future of Hadron Therapy, CNAO Workshop, Dec 17-18, 2013