Part I

Physicists do it in Hospital

Tong Xu

Dept. of PhysicsCarleton University

Why there are physicists in the hospital?

Medical Physicists

Where in the hospital can you find them? Diagnosis imaging departments:

• Radiology and Nuclear Medicine (CT, MRI, PET…) Cancer centre

• Medical Physics department (Radiotherapy)

What is their job? Make sure the equipments are working

according to their physics specifications Perform radiotherapy treatment planning

Why we need physicists to perform these tasks?

Let’s to go back to the history of some of the medical technologies.

Related Medical Technologies

X-ray CT

Magnetic Resonance Imaging

Radiation Therapy

Three examples …

Discovery of X-ray

First discovered by German Physicist Wilhelm C. Röntgen in 1895

On a New Kind of Rays Nature 53, 274-276 (23 January 1896)

Discovery of X-ray Independently

discovered by Nikola Tesla in 1896

Discovery of x-ray 1. Crookes Tube

Invented by Sir William Crookes, chemist and physicist, around 1860s.

A demonstration of the cathode ray – accelerated electron beam.

Discovery of x-ray2. Cathode ray

Cathode ray is a beam of electrons

Discovery of x-ray3. Rontgen’s experiment

A mystery radiation was coming out from the tube

Röntgen called it

X-ray

In fact, x-ray is just a ray of light photons with much higher energy than

ordinary light

Typical x-ray spectrum

Medical Application of x-ray

Röntgen received the First Physics Nobel price in 1901

X-ray radiograph

It’s a shadow image of human

What do we need to see through a human?

X-ray

X-ray Computer tomography

X-ray projections of heart

CT Image reconstruction

Projections at different angle 3D structure

http://rpop.iaea.org/

Inventers

Theory proposed by a physicist Allan MacLeod Cormack in1956 two papers in the Journal of Applied Physics

in 1963 and 1964

First Prototype by electrical engineer Godfrey Hounsfield in 1969

The first CT prototype

First Prototype by Godfrey Hounsfield in 1969

Cormack and Hounsfield shared the Medical Nobel prize in 1979

Magnet Resonance Imaging1. Stern molecule beam (1922)

Individual gas molecules fly through a pair of magnets

developed by German Physicist Otto Stern and Walther Gerlach in 1922

Magnet Resonance Imaging2. Some nucleus are like tiny

magnets

S

N

S

N

Detector

Magnet Resonance Imaging2. Some nucleus are like tiny

magnets

N

S

S

N

Detector

S

N

S

N

Otto Stern received Physics Nobel prize in 1943

Magnet Resonance Imaging3. Precession of magnetic dipoles

Some nuclear has magnetic momentum

They are like magnetic dipoles

They precess around the external magnetic field Just like a Gyroscope

Check out this animationhttp://www.simplyphysics.com/MRI_shockwave.html

B

Magnet Resonance Imaging3. Precession of magnetic dipoles

The precession frequency

ω is in the radio frequency range is the Gyromagnetic ratio

BB

Magnet Resonance Imaging3. Precession of Magnetic dipoles

BAligned against the external

Magnetic field B

Higher energy state

Aligned with the external Magnetic field B

Lower energy state

The nucleus feel more comfortable to stay in lower energy state

N

S

Magnet Resonance Imaging4. Nuclear Magnetic Resonance

What if I send nucleurs a Radio wave that has the same frequency as the

precession?

American physicist Isador I. Rabi had an great idea!

Magnet Resonance Imaging4. Nuclear Magnetic Resonance

Detector

S

N

S

N

Radio frequency signal ~

Magnet Resonance Imaging4. Nuclear Magnetic Resonance

The nucleus will resonance with the RF wave

They absorb RF energy

And flip to higher energy state

Can measure the nuclear magnetic montemtum precisely

Isador I. Rabi received Physics Nobel prize in 1944

Magnet Resonance Imaging5. NMR with solids and liquids

In 1946, two other Americans, Edward M. Purcell and the Swiss-born Felix Bloch, separately apply this nuclear magnetic resonance (NMR) method to solids and liquids.

Purcell and Bloch received Physics Nobel prize in 1952

Principle of NMR

Since the gyromagnetic ratio γ is unique for nucleus of each elementsNuclear Magnetic Resonance is a powerful tool for chemical analysis

B

Resonance frequency

Until 1970s….

Magnet Resonance Imaging5. Apply NMR to imaging

Paul Lauterbur & Peter Mansfield applied NMR to image body in 1970s

Introduced gradients to the magnetic field

Thus, frequency the radio wave emitted by the nucleus tell us where they are.

Magnetic Resonance Imaging

MRI scanner

Source: sfu.ca

MRI

A technique for imaging soft tissues

source: lecture slides from Prof. I. Cameron

Lauterbur and Mansfield received Medical Nobel prize in 2003

Cancer diagnosis

http://www.dcmsonline.org/

Ch

est

X-

ray

x-ra

y C

T

Nu

cle

ar

Med

icin

e

Physics in Cancer treatment

Radiation Therapy

Uses ionizing radiation

Kills tumour by damaging tumour cells

Radiation therapy

External beam radiation therapy

Use x-ray generated from linear accelerator.

Max energy: 4~20 (MeV, 106 eV)

Mega-Electron-Volt Compare to visible light: 2-3 eV Compare to UV light: 3-5 eV 1000,000 times higher than UV light

Linear accelerator (Linac)

Source:www.cerebromente.org.br

Accelerated high energy electron beam hit aTungsten target

Produce high energy x-ray beam

Treatment planning

It’s also a job for physicists !

X-ray , electrons, photons, scatter radiation dose …

Only a medical physicist were trained to deal with them !

Summary

Many medical technologies are originated from physics discovery.

Then, developed by physicists.

Medical physicists are The “customer service” team Improve the techniques Develop new techniques

Ionizing radiation damages the cell

Ionizing radiation

DNA

x-ray photons

Electron

Ionizing radiation

DNA

X-ray photon

Excited by physics discoveries

Passionate about People’s well being

Positron Emission Tomography (PET)

http://www.mni.mcgill.ca/cog/paus/techniques.htm

PET image

How is x-ray been generated?1. Bremsstrahlung radiation

How is x-ray been generated2. Characteristic x-ray radiation

Part II

Positron Emission Tracking (PeTrack): the prototype and its evaluations

Tong Xu, Marc Chamberland, Benjamin Spencer, Simon Massad

Carleton University, Ottawa, Canada

Outline

Introduction

Concept of PeTrack

Simulation study and results

The prototype the evaluation

Conclusion

External beam Radiation therapy

http//www.stfranciscare.org

Radiation delivery requirement

Deliver high radiation dose to tumour

Minimize radiation to healthy tissue around the tumour

Accurate delivery of x-ray beam

3 Tricks...

Trick #1:Focusing multiple beams

Trick #2:Collimate the beam to the shape of tumour

This method is called3D-conformal radiation therapy (3D-CRT)

3D conformal Radiation therapy (3D-CRT)

Shape the field following the outline of tumor

Trick #3:Intensity modulation inside the field

This is one step forward of 3D-CRT, with the addition of intensity modulation inside the field.Intensity modulated radiation therapy (IMRT)

Tumour

Spinal cord3D

-CRT

Intensity is uniform inside the field

IMRT

Intensity is not uniform inside the field

Accuracy of radiation therapy Significant development has been

done in diagnose and delivery techniques (PET, SPECT, IMRT…)

The tumor motion remains a limiting factor.

The moving target

Tumour moves due to:RespirationCardiac beatingOther visceral motions

The tumor can move by more than 3 cm !

Three level of motion management

None Breath holding orRespiratory gating

Real-timetumor tracking

Radiation field

Motion management

Breath holding

Respiratory gating

Breath holding

Methods:– Self breath holding – Active breathing control device

Limitations– Reproducibility (up to 6 mm residual

motion)– Difficult for Lung cancer patient to

tolerate

Respiratory gating

Breath normally!

Uses: External markers Implanted internal markers Others

– Spirometry– Temperature sensor– Strain gauge…

Respiratory gating

LinacBeam

On

Off

Gating Thresholds

Berbeco et al. 2005

External markersTang et al. 2004

Correlation between external and internal motion Koch et al 2004

Unstable breathing Ozhasoglu et al. 2002

Phase shift Ozhasoglu et al. 2002

Internal markers

Implanted in or close to tumor

Invasive

Provide exact location of tumor

Internal marker tracked by x-ray Shirato et al. 2000

X-ray tube

Image detector

Radiation dose from the x-ray fluoroscopy Shirato et al. 2004

Up to 1.2 Gy skin dose per hour of treatment time

Not feasible for intensity modulated radiation therapy – 20 – 30 minutes /fraction– large volume of normal tissue 25-30% of

tumor dose!

Calypso® 4D LocalizationSystem (EM marker)

MRI artifacts of EM transponders X Zhu et al, 2009

RealEye tracking system Shchor et al 2010

RealEye tracking system Can only track one marker

Can not be used for 10MV beam or higher due to induced radioactivity

Tracking with Positron emission marker

Miniature markers ( 0.8 mm)

Labeled with positron emission isotopes (0.1 mCi)

Track markers by detecting annihilation gamma

PeTrack

PeTrack is NOT PET

(Clinical Whole body PET)

Can PET system locates an object with <1 mm accuracy?

Over-all image resolution of PET : 4 - 8 mm

Yes, if the geometry of the source is known

Find a point in 3D with the minimum summed distance to the coincident lines

It is NOT image reconstruction !

Localize PeTrack marker

Patient

Detector Detector

PeTrack system for tumor tracking

Linac

PeTrack detectors

PositronemissionMarker

PeTrack Detector modules

Detector module

PeTrack marker and isotopes

I-124 As-74 Rb-84

T1/2

(days)

4.2 18 32

β+

Fraction23% 29% 23%

Can be implanted with biopsy needle of size 18 Gauge (1.27 mm)

The challenge

The algorithm

Classify the coincident lines using Mixture-of-Gaussians clustering technique

Determine the position of each markers from its coincident line cluster

Find the true location with iteration

Initial estimation

Computer simulation results

Based on a Monte Carlo simulation package: GEANT4.Four markers were simulated

Localization precision

0 50 100 150 200 2500.0

0.5

1.0

1.5

Loca

lizat

ion

erro

r (m

m)

Coincidient Lines per marker

Dynamic Thorax Phantom

Phantom rod

MarkerDirection of motion

RMSE (mm)

3D RMSE (mm)

R2

1

AP 0.30

0.39

0.844

LR 0.20 0.954

IS 0.14 0.997

2

AP 0.42

0.53

0.636

LR 0.26 0.812

IS 0.17 0.997

3

AP 0.29

0.40

0.969

LR 0.25 0.986

IS 0.13 0.998

Average 0.24 0.44 -

The PeTrack Prototype

BGO crystal and Position Sensitive PMT

Single Marker

Adj. R2

Measured amplitude

(mm)

Expected value(mm)

Error(mm)

x 0.99 9.63 ± 0.05 10.00 -0.37

y 0.99 5.16 ± 0.04 5.34 -0.18

z 0.81 0.65 ± 0.02 0.67 -0.02

3D track of two markers

-5

0

5

10

15

-20

-15

-10

-50

510

-15

-10

-5

0

5

10

15

Positions of one of the marker

0 10 20 30 40 50 60

-5

0

5

10

15

positio

n (

mm

)

Time(s)

X Y Z

Two markers precision

Standard deviation of the distance between the two marks during the motion tracking: 0.73 mm

Estimated precision: 0.52mm

Conclusion

PeTrack can perform tracking of multiple fiducial markers with sub-mm precision

It is a potential technique for achieve hyperfractionation treatment for moving tumors.

Acknowledgement

Dr. Richard Wassenaar Nathan Churchill, University of

Toronto

Supported by Natural Sciences and Engineering Research Council of Canada

Thank you!

Tracking of a single Line marker

Life time dose (0.1 mCi marker)

Isotope 124I 74As 84Rb

Half life (days) 4.2 18 32

dose (Gy) @ 5 mm (volume: 0.5cc) 2.6 9.0 18.6

dose (Gy) @ 10mm (volume: 4.2cc) 0.7 2.46 4.96

dose (Gy) @ 15mm (volume: 14 cc) 0.32 1.09 2.24

As compared with x-ray fluoroscopy dose Higher maximum dose

Very small volume effected (~ 10 cc vs 1000 cc

Can be implanted inside the tumor

Precision

5.0 mm PET spatial resolution provides 0.5 mm localization precision

With only about 100 events!

lines coincident ofNumber

resolution spatial PETPrecision

Motion trace of marker #3 and

predicted motion trace

Distribution of the1D prediction error

95th percentile (100 ms) = 2.3 mm

95th percentile (200 ms) = 2.7 mm

Distribution of the3D prediction error

Latency(s)

1D pred. error(mm)

3D pred. error(mm)

0.1 0.0 ± 0.8 1.3 ± 0.6

0.2 0.0 ± 0.9 1.4 ± 0.7

Life time doseActivity = 0.1 mCi

Sensitivity within the Field of view

Frame based stereotactic neurosurgery

http://www.elekta.com/healthcare_international_stereotactic_neurosurgery.php

Fiducial-less trackingSchweikard et. al. 2004

Synthetic a serial of CT at different time points by deforming two CT scans : Inhale and exhale

Registration of real-time x-ray projections with digitally reconstructed images from Synthetic CT scans

Registration computing time: 5 -10 sec Accuracy depends on the deforming

model of lung

Physical Requirement of tumor tracked radiation therapy

Track the tumor in real-time Predict the tumor position to

account for the lag of delivery system

Fast reaction of delivery system

Current internal tracking techniques

X-ray marker EM marker

Sampling rate 30 sec-1 10 sec-1

Precision 0.5 mm 0.2 mm

Marker size Φ0.8~1.6mm

Φ1.8mm x 8. mm cylinder

Radiation dose Upto 1.2 G/h Zero

Correlation between external and internal motionOzhasoglu et al. 2002

Complex tumor trajectory Ozhasoglu et al. 2002

Correlation coefficient (R)Koch et al. 2004

SpirometryHoisak et al. 2004

Higher correlation (R= 0.51 - 0.99) than that of skin marker (R= 0.39 – 0.98)

Difficult to tolerate

Radiation dose from the x-ray fluoroscopy Shirato et al. 2004

External markers -1

Passive or active infrared skin markers

Marker position tracked by camera in real time

Linac gated by the position of external markers

Linear accelerator generate pulsed x-ray

Pulse frequency– 100 – 400 Hz

Pulse width – 1 – 10 μs

Blanking of PeTrack detector

Expected data acquisition duty cycle > 80%

PMT HV gating

Expectation-Maximization -1 Expectation step. Compute the

probabilities for all trajectories, n=1,…N, belonging to each cluster, k=1,…K

K

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ij

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parameters

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Previous worksGundogdu, 2005

Intended for industrial application Two particle was tracked Resolution 20 -30 mm

The challenge

Simultaneously tracking of three or more markers

Distance between markers: a couple centimeters

The existing algorithm for single particle tracking dose not apply

Scatter rejection

R=2σ

Patient

Expectation-Maximization iterations

1. Initial estimation

2. Expectation Clustering by the probability of each trajectory

3. Maximization Update the position of markers

4. Repeat step 2 and 3 until converge.

Speed of the algorithm

Four markers 400 coincident events 2.8GHz P4

20 ms/run Tumor position can be updated at

a rate > 10 Hz

Lift time dose for different treatment duration

Required activity at the time of implanting

Breath holding

Methods:– Self breath holding – Active breathing control device

Limitations– Reproducibility (up to 6 mm residual

motion)– Difficult for Lung cancer patient to

tolerate

Respiratory gating

Breath normally!

Uses: External markers Implanted internal markers Others

– Spirometry– Temperature sensor– Strain gauge…

Respiratory gating

LinacBeam

On

Off

Gating Thresholds

Berbeco et al. 2005

External markersTang et al. 2004

Correlation between external and internal motion Koch et al 2004

Unstable breathing Ozhasoglu et al. 2002

Phase shift Ozhasoglu et al. 2002

Identify failed markers

A failed marker should be identified automatically from the output of the algorithm

ka

k

Relative activity of marker # kRoot mean square distance form marker # k to its trajectories

Identify failed markers

> 3 mm

< 0.02ka

k

Identify failed markers with criteria

The source of tumor motion Respiration

Cardiac beating

Other visceral motions

Lung tumor motions trajectoriesSeppenwoolde et al. 2002

Internal marker tracked by x-ray Shirato et al. 2000

X-ray tube

Image detector

Internal marker tracked by x-ray Shirato et al. 2000

Positron emission and annihilation

Positron Emission Tomography (PET)

http://www.mni.mcgill.ca/cog/paus/techniques.htm

PET image

Physical limits on PET resolution

Humm et al, 2003

Over-all resolution: 4 - 8 mm(Whole body PET)

http://www.raytest.de/pet/clearPET/clearPET.html

Three 22Na Markers

Activity of 22Na: ~425 kBq/marker

PET Image reconstruction

http://depts.washington.edu/nucmed/IRL/pet_intro/intro_src/section4.html

Yes! A single point source can be tracked with < 1 mm accuracy

Park et al. 1993, Park et al. 2002

The algorithm

Assuming the distance from a marker to its annihilation coincident lines follows a Gaussian distribution

k Standard deviation ~ system spatial resolution

Methods

PeTrack simulation model Based on a Monte Carlo simulation

package: GEANT4 Patient: Φ 30cm x 60 cm water

phantom Distance from isocenter to detectors:

50 cm Detector: 40x40 array of 4x4x30 mm3

BGO crystals Energy resolution: 25% Spatial resolution ~ 4 mm

PeTrack simulation model Marker: active 0.4 mm spherical

core with a 0.2 mm thick gold shell

Single marker simulation:– Sensitivity, scatter fraction, dose

Four markers with I-124 were placed around isocenter: (0,0,0), (15,0,0), (0, 20,0), (0,0,20) (in mm)– Evaluate the algorithm

Definition of a valid event (trajectory)

Detected energies fall in the energy window (420-600 keV)

Coincidence has to be between detector A1 and A2, or between B1 and B2

Simulate the initial estimation error Error on the initial estimation

– patient setup– respiration– marker migration

Initial estimation is generated randomly around the true position– ± 5, ± 10 , ± 15 mm

1000 runs of the algorithm

Definition of success marker and run Localized by the algorithm within 1.5

mm from its true position

A successful run:– All four markers was allocated successfully

Precision:– Mean error among 1000 runs from the true

positions

Run success rate

0 200 400 600 800 1000

20

30

40

50

60

70

80

90

100R

un s

ucce

ss r

ate

(%)

Coincident lines per marker

± 5 mm initial error ±10mm initial error ±15mm initial error

Total coincident lines per run

Marker success rate

0 50 100 150 200 25065

70

75

80

85

90

95

100M

arek

er s

ucce

ss r

ate

(%)

Coincident lines per marker

± 5 mm initial error ±10mm initial error ±15mm initial error

Number of runs with different number of Successful markers

Initial error range (mm)

± 5 ± 10 ± 15

All 4 markers are successful 997 985 777

3 markers are successful 3 15 144

2 markers are successful 0 0 75

1 marker is successful 0 0 4

All 4 markers failed 0 0 0

Cardiac BeatingShirato et al. 2004

Yes! A single point source can be tracked with < 1 mm accuracy

Park et al. 1993, Park et al. 2002, Sarah E. Palmer et al, 2006