Research(atthe( Interface(of(Physics(and(Medicine:( An...

Research at the Interface of Physics and Medicine:

An Update on the Development of Proton Computed Tomography

Reinhard Schulte Department of Radia@on Medicine

Loma Linda University Medical Center Loma Linda, California, USA

R Schulte, Proton Computed Tomography, UCSC Physics Colloquium, Nov 3, 2011

Outline

•  The Clinical Perspec@ve: Proton Therapy and Proton Imaging

•  Concepts of Proton CT •  Technical Realiza@ons of Proton CT – Phase I preclinical head scanner – Phase II clinical head scanner

•  Next steps & future applica@ons/Plans


THE CLINICAL PERSPECTIVE: PROTON THERAPY AND PROTON IMAGING

SECTION I


Depth-‐Dose Characteris@cs of Mono-‐Energe@c Protons

•  Compared to x-‐rays and electrons (which are also used therapeu@cally) protons have a unique inverted depth dose profile

•  The dose peak at the end of the proton range is called “Bragg peak” aXer the physicist William Henry Bragg, who discovered it in 1903


Protons in Comparison •  Proton energy deposi@on per

track length (propor@onal to dose) increases as they slow down

•  Bragg peak dose at the end of the proton range

•  Depth of peak (proton range) adjustable by choosing right energy

•  Ac@ve or passive modula@on generates spread-‐out Bragg peak (SOPBP)

•  Dose sparing up-‐ and down-‐stream from tumor


Protons for Precision Radia@on Therapy / Radiosurgery

•  Addi@onal features that make protons an a^rac@ve modality for proton radia@on therapy/radiosurgery: –  Pencil beam forma@on with

magne@c lenses –  Magne@c tracking of proton

pencil beams –  Edge tracking (not possible with

photon beams)


Proton Therapy: A man – A Vision •  Robert Wilson, Ph.D.

(1914-‐200) was the first to publish a paper on the medical uses of protons (Radiology 1946:47:487-‐91)

•  It took 45 years before his dream became reality when the first hospital-‐based proton treatment center opened at LLUMC


Robert R. Wilson, Ph.D., 1914-‐2000

The Early Years of Proton & Heavy Ion Radiosurgery at the

Lawrence Berkeley Laboratory (1948-‐1955) •  Star@ng in 1948, John Lawrence

(physician) and Cornelius Tobias (biophysicist) developed biomedical program of heavy ions at the LBL cyclotrons

•  In 1954, the LBL group began to direct the high doses of heavy ion beams (protons & helium) at human pituitary glands (about 50 pa@ents)

•  Reported successful hormonal abla@on & regression of disease in advanced breast cancer pa@ents


Large-‐Scale Proton Radiosurgery: The Harvard Experience

1961-‐2001 •  In 1961, MGH neurosurgeon Raymond

Kjellberg began trea@ng pa@ents with pituitary adenomas using 160 MeV Bragg peak protons from the Harvard Cyclotron Laboratory (HCL)

•  Star@ng in the 1970s, Dr. Kjellberg also treated large, inoperable arteriovenous malforma@ons (AVMs) with Bragg peak protons, despite limita@ons in imaging and planning techniques at that @me


Proton Therapy at LLUMC

•  Proton therapy was used in a hospital sekng first at LLUMC in 1990

•  More than 14,000 pa@ents have been treated at LLUMC

•  Due to the Bragg peak feature, protons deliver less dose to normal @ssue than IMRT


LLUMC Facility Design •  Built around a proton accelerator (weak-‐focusing synchrotron) used to deliver

protons of 10-‐300 MeV (Gantry accepts up to 250 MeV).

•  4 Clinical rooms (1 fixed beam room w 2 beam lines, 3 Gantries)

•  Research rooms with 3 horizontal beam lines


Research Room

Annual Proton Treatments at LLUMC (1990 – 2008)

010020030040050060070080090010001100

Num

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f Pat

ient

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No. 3 53 345 338 416 494 681 760 944 780 899 1033 1035 1013 984 893 894 906 847

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Worldwide Expansion of Proton Therapy (1990 – 2010)


History of Proton Radiography (pRad) •  A. Koehler was the first to point

out the poten@al value of pRad and to perform experiments with 160 MeV (Koehler, Science 160, 303–304, 1968)

•  The higher density resolu@on but poorer spa@al resolu@on was noted by Koehler and later by Kramer et al. (Radiology, 1980)

•  Medical interest in pRad as a QA tool for proton therapy was revived by U. Schneider at PSA during the 1990s

•  Another strong mo@va@on of pRad development comes from nuclear weapons tes@ng programs at Los Alamos NL


Andy Koehler, former director of the Harvard Cyclotron)

Proton Computed Tomography (pCT): A man – A Vision (Harvard, 1963)

•  Alan M. Cormack, physicist (1924-‐1998) was the first to publish a paper on the reconstruc@on of tomographic images based on X-‐ray absorp@on and proton degrada@on (J. Appl. Phys. 34, 2722, 1963)

•  It took less than 10 years before his idea became reality when the first when Geoffrey Hounsfield constructed the first X-‐ray CT scanner


Alan M. Cormack, 1924-‐1998 Physics Nobel Laureate 1979

The Proton CT Collabora@on

•  Group of scien@sts first met at IEEE in Norfolk, VA in 2002 and BNL in 2003 to outline the goal of building a clinical proton CT (pCT) scanner, many have contributed since then

•  Phase 0 (2003 – 2007): Conceptual design, Geant4 simula@ons, most likely path concept, proof-‐of-‐principle experiments

•  Phase I (2008 – now): First genera@on (preclinical) pCT scanner using single par@cle tracking

•  Phase II (started in 2011): Second genera@on (clinical) pCT scanner, funded by NIH


Gensheimer F, et al., Int J Radia@on Oncol Biol Phys 2010 (50% idosdose, red = observed, blue = planned


The Mo@va@on for pCT Range Uncertain@es in Proton Therapy •  Differences in the

interac@on of x-‐rays and protons with ma^er make proton range calcula@ons uncertain

•  Range uncertain@es can range from mm to cm (see recent MGH study)

•  Materials of unknown density, streak ar@fact create addi@onal uncertainty

•  Proton CT is a poten@al solu@on to reduce this uncertainty from 3%-‐4% to ≤ 1% of range

Range Uncertainty in Proton Therapy

•  Inhomogenei@es are fundamentally more important in proton (hadron) therapy than in X-‐ray therapy

•  We have learned to deal with them by –  Op@mizing our X-‐ray CT calibra@on

methods –  Incorpora@ng addi@onal margins –  Developing robust op@miza@on

•  We have remaining issues due to –  Restric@ons in beam entry direc@ons –  CT ar@facts in the presence of metallic

hardware, dental fillings emboliza@on glue etc.

–  Intra-‐ and inter-‐treatment changes of proton range (mo@on, weight loss etc.)

–  Higher RBE of distal edge when placed into cri@cal normal @ssues


CONCEPTS OF PROTON CT SECTION II


The Principle of Tomography •  The Radon transform (Radon,

1917) relates any 2D func@on f(x,y) to an infinite number of line integrals covering an angular space of 2π

•  Radon proved mathema@cally that both of the func@on representa@ons are equivalent

•  The inversion of the Radon transform from an infinite set of line integrals forms the basis for tomographic image reconstruc@on


Computed Tomography: X-‐rays vs. Protons

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0.1

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10

100

1000

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0.001 0.01 0.1 1

X-Ray Absorption Coefficient

Muscle

Bone

Water

Air

µ

Energy [MeV]

[1/cm]

A^enua@on of Photons, Z ln(N) = No∫ µ x dx

Energy Loss of Protons, ρ ∫=Δ dx

dxdEE

NIST Data R Schulte, Proton Computed Tomography, UCSC Physics Colloquium, Nov 3, 2011 Courtesy: H. Sadrozinski,

UCSC

pCT Single Proton Concept

•  An energe@c low intensity cone beam of protons traverses the pa@ent

•  The posi@on and direc@on (entry & exit) and energy loss of each proton is measured

•  Proton histories from mul@ple projec@on angles

•  Minimal proton loss and high detec@on efficiency make this a low-‐dose imaging modality


Design of a Proton CT Scanner rota@ng 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

Principles of the pCT Imaging Process

•  The measurement is propor@onal to the outgoing energy of each proton, and thus to energy loss in the phantom

•  The energy loss can be converted to a line integral of proton stopping power rela@ve to water along the proton path, RSP is (prac@cally) independent of proton energy

•  Energy straggling → affects RSP resolu@on •  Mul@ple Coulomb sca^ering (MCS) → affects spa@al resolu@on

•  Solu@on → calculate most probable path of the proton within the object using a reconstruc@on algorithms that takes MCS into account

•  Requires reconstruc@on algorithm that can handle non-‐linear paths



24

Sta@s@cal Model of a Proton Path

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Path Reconstruc@on Concepts •  Different proton paths may be

used in the reconstruc@on: MLP = Most Likely Path, SLP = straight line path, CSP = cubic spline path

•  The MLP is determined by maximizing likelihood (chi square) of output parameters, given entry parameters

•  MLP significantly improves spa@al resolu@on compared to SLP, CSP reconstruc@on is nearly as good as MLP reconstruc@on


•  A total number of m protons trace paths through the voxel space and aij is the intersec@on length of the ith proton, i=1…m with the jth voxel

•  In the fully discre@zed model, the object is treated as n-‐dimensional vector xj, j=1…n, where xj is the constant rela@ve stopping power of the jth voxel


The Discrete pCT Reconstruc@on Problem


First Itera@ve Algorithm Applied: Algebraic Reconstruc@on Technique (ART) (work done by

Tianfang Li & Jerome Liang, SUNY) •  Originally developed by

Kaczmarz, 1937 •  Sequen@al orthogonal

projec@ons onto hyperplanes

•  Works but well for proton CT but is inherently slow

•  High frequency noise is present

xk+1

Li et al Med Phys 2006


Further Development of pCT Reconstruc@on with Geant4 Simula@ons (work done by Sco^ Penfold)

•  Simulate pCT system and digital head phantom1 •  Test/compare different reconstruc@on algorithms

1G. T. Herman, Image Reconstruction From Projections: The Fundamentals of Computerized Tomography, Academic Press, New York (1980).

TECHNICAL REALIZATIONS OF PROTON CT

SECTION III


Phase I pCT Scanner Design (completed in 2010)

•  Horizontal beamline setup

•  Rota@onal stage for object rota@on

•  Upstream and downstream tracker modules

•  Downstream energy detector (calorimeter)


Phase I pCT Tracker (UCSC) •  The Phase I pCT tracker consists of

front and rear module for loca@on and direc@on measurements

•  Modules: two detector boards measuring the X-‐Y posi@on in two loca@ons => direc@on

•  Detector boards: 4 Si Strip Detectors (SSDs), 9 cm x 9 cm, 384 strips, 0.23 mm pitch

•  Strips oriented in horizontal or ver@cal direc@on (X and Y sensi@vity)

•  Total sensi@ve area 9 cm x 18 cm •  Modified GLAST/Fermi readout chip,

max rate 100 kHz


Phase I pCT scanner front module Detector board with 2 SSDs in the front (visible) and 2 SSDs in the back of the board

Phase I pCT Energy Detector (Calorimeter) (NIU-‐LLUMC, UCSC)

•  Crystal matrix with 18 thallium-‐doped cesium-‐iodide (CsI(Tl)) crystals (~3.6 cm x 3.6 cm x 12.5 cm)

•  Each crystal read out by area-‐matched Si photodiode

•  Si photodiode => preamp/shaper => ADC

•  Excellent linearity and energy resolu@on < 1% above 40 MeV

•  Integrated with rear tracker module


Phase I pCT DAQ Hardware (UCSC – LLU)

•  Design based on field-‐programmable gate arrays (FPGAs) -‐ Master & Slave

•  Reads and processes data from 16 tracker SSDs & 18 crystal frontends in parallel

•  Data rate has been op@mized


Phase I pCT DAQ SoXware/GUI (Ford Hurley, LLU)

•  User-‐friendly user interface for main pCT func@ons

•  Online display of tracker and calorimeter response

•  Root-‐based reconstruc@on of proton histories


Phase I pCT Scanner at LLUMC: Timeline

•  System component integra@on & moun@ng (April 2010)

•  Tes@ng with radioac@ve source and cosmic rays (muons)

•  Installa@on on proton research beam line & 1st test runs (May 2010)

•  Spill uniformity op@miza@on (June 2010)

•  Scanner calibra@on (July 2010) •  Phantom scans since Dec 2010


Crystal Calorimeter Calibra@on •  The rela@ve sensi@vity

(individual weigh@ng factors) for individual crystals are measured at the scan energy before each scan

•  Only central proton histories that most likely did not leave the individual crystal are used

•  Weigh@ng factors between different crystals vary within +/-‐ 15%, and between different energies <1%


Proton tracks used for to derive a rela@ve weigh@ng factor for each crystal

Phase I pCT Scanner WET Calibra@on •  The calorimeter response is

calibrated against polystyrene plates of known thickness and rela@ve stopping power, resul@ng in individual response curves, to which a Gaussian was fi^ed

•  The Gaussian peaks are used to construct a curve that converts calorimeter response to a water-‐equivalent path length (WEPL)

•  The response vs. WEPL curve is fi^ed to a second order polynomial, providing fast conversion to WEPL

•  This inverse calibra@on was verified by comparing the measured stopping power of @ssue equivalent plates to known values


Developing Advanced Reconstruc@on Algorithms with GEANT4 Simula@ons •  Reconstruc@on of the

original object (a) with a constant intersec@on length (equal to the voxel size) leads to “noisy” images (b)

•  Using a refined intersec@on length depending on projec@on angle (c) or varying from voxel to voxel (d) leads to significantly improved images


Status of Proton CT Reconstruc@on

•  A series of pCT scans of the Lucy radiosurgery phantom was started in Oct 2010

•  Phantom images were reconstructed with our newly developed 3D reconstruc@on algorithm

•  Good image quality has been achieved

•  A sytema@c evalua@on using standard CT phantom modules and a realis@c anatomical head phantom is underway


GPU-‐Accelerated Reconstruc@on •  Reconstruc@on is

performed using an NVIDIA Tesla general purpose graphics processing unit (GP-‐GPU)

•  This state of the art inexpensive computer cluster technology speeds up reconstruc@on @me by orders of magnitude, compared to tradi@onal CPUs


NVIDIA Tesla C1060 GPU: 240 stream processors with 4 GB of device RAM

Phase I pCT Reconstruc@on of Lucy


14 cm diameter polystyrene sphere with @ssue equivalent inserts

64 slice Mul@-‐Slice X-‐ray CT, 0.53 x 0.53 x 0.625 mm3

pCT Phase I, 0.63 x 0.63 x 2.5 mm3

Phase I pCT Reconstruc@on of the Catphan® Uniformity Module


•  A series of pCT scans of standard CT performance phantom modules is underway

•  The uniformity module tests hypothesis that pCT RSP reconstruc@on is not affected by energy loss

•  The noise power analysis shows interes@ng characteris@cs of pCT reconstruc@on algorithms

NEXT STEPS & FUTURE APPLICATIONS/PLANS

SECTION IV


Phase I pCT Scanner at LLUMC: Next Steps

•  Systema@c tes@ng with contrast, spa@al resolu@on & dose phantoms (Catphan)

•  Live imaging of small animals (rats)

•  Stepwise improvement of reconstruc@on, image quality & data rates


Rat scanned on the Phase I pCT scanner at LLUMC

Development of Phase II Clinical pCT: Issues and Possible Choices

•  Size of System –  Large area tracker suitable for head & neck, thorax (36 cm x 9 cm), may move longitudinally during scan

•  Type of Tracker –  Silicon (larger, thinner, ac@ve edge = “edge less” (implemented by SCIPP)

–  Scin@lla@ng fiber with Si Photomul@plier readout (implemented by NIU)

•  Type of Energy/Range Detector –  “Modern” crystals (e.g. YAG:Ce, Menichelli et al 2010 IEEE TNS) –  Range detector: Stack of plas@c scin@llators with direct or fiber-‐mediated SIPM readout (implemented by NIU, tested at LLU)

–  Segmented scin@llators (tested at LLU)


Primary Applica@ons for pCT •  Higher planning accuracy/precision needed –  Radiosurgery for vascular

malforma@ons, pituitary adenomas, meningiomas, etc.

–  High-‐dose boosts to tumors near organs at risk for damage

–  Crea@ng lesions in defined loca@ons for pain treatment

•  Restricted beam angle choices –  Paraspinal tumors –  Craniospinal irradia@on with sparing

of vertebral bodies in children •  X-‐ray CT ar@facts


Where is the Target?

Future Physics Contribu@ons to Proton Therapy

•  Adap@ve proton treatments with fast-‐replanning

•  On-‐line verifica@on of p pencil beams using vertex tracking

•  Post-‐treatment dose verifica@on


What have we learned?

•  pCT is an interes@ng and challenging project that requires input/collabora@on from/with many scien@fic different fields

•  Interest in the physics community is quite large, but there is s@ll skep@cism in the medical community

•  Proof of principle with current Phase I prototype (beyond simula@on) will be crucial for clinical acceptance

•  Besides usefulness for proton therapy, low-‐dose aspect, faithful reproduc@on of density, and freedom from ar@facts should be inves@gated & stressed


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