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MRI-guided Radiotherapy
Seeing what to treat!
Cornelis (Nico) van den Berg
MR physicist, Associate Professor
Department of Radiotherapy, Centre of Image Sciences
UMC Utrecht, The Netherlands.
• Brief intro in radiotherapy
• State-of-the art radiotherapy and its shortcomings
• Why MRI in radiotherapy?
• Combining an MRI and a linear accelerator
• New therapeutic possibilities with MRI-guided RT
Contents
External beam radiotherapy
First treatment with cobalt unit, 1953Borgo Val Sugana, Source: ESTRO 30th anniversary book
After WWII: Cobalt Sources From 1970s, linear accelerators
From mid 1980, computer controlled LinacsSource: Elekta website
• Dose deposition by secondary electron cascade
Radiaton physics behind dose deposition
Source: slideshare: Amus Sygenus, Aarhus hospital
• Radiation causes damage in the
DNA
– Direct damage by double strand
breakage
– Through creation of oxygen
radicals.
• The damage cannot repaired ->
cells die at cell division
• Tumor cell divide faster than normal
cells
• The body naturally eliminates the
damaged cells -> tumor shrinks
Effect of ionizing radiation on cells
The balance between therapeutic effect and
toxicity
• The higher the dose to the tumour -> the higher the
therapeutic effect
• However, normal healthy cells are also affected ->
toxicity
• Two important factors than can increase therapeutic
effect and lower toxicity
1. Focusing the radiation to the target and minimize dose
to healthy tissue
2. Apply radiation in multiple fractions of limited dose (~ 2
Gray) -> exploit higher ability of healthy tissue to repair.
• A x-ray machine mimicking the MeV radiation machine was used to
localize the target with respect to bony anatomy
• Radiation field was defined and through light transferred to patient
• This process is called the simulation process in radiotherapy
2D Simulation in the old days..
Target Localization and set up of the radiation field
• Minimum info
– Patient outline
– Target location
• Dose was modulated by entry angles and lead wedges.
• Dose calculated by integrating along beam path
Dose planning in the old days..
Starting in later nineties: A revolution due to CT
imaging, inverse planning, beam shaping.
MLC
Portal
Imaging
Device
Linac
CT
Computerized Inverse planning
CT imaging Delineation Dose definition
Image guided
30x radiation
Dosis
evaluationComputerized dose
planning
Beam
shaping
State of the art simulation workflow
Courtesy: Bram van Asselen, UMCUtrecht
Image guided dose deliveryCone beam CT
Patient anatomy aligned to radiation beam by registration of daily CBCT to planning CT
Provides translation and rotation of patient table
Technology advancement -> better quality treatment?
• We can design based on 3D CT image very conformal 3D
dose coverage to tumor for a given patient
• Radiotherapy: 50% of the patients now receive radiotherapy
– As adjuvant therapy combined with chemo or surgery
– As primary treatment
However, we should not be satisfied!!
• There is still considerable uncertainty in the process
• Consequence: we irradiate a lot of healthy tissue
• We have to limit the dose to tumor to mitigate toxicity
TumorClinical target volumeMotion target volume
CT of pancreas with delineated tumor
Where are the uncertainties?
Treatment = 'mimicking of simulation' (1-40 times)
Del
iver
y
CT imaging Treatment planning
Sim
ula
tio
n (
“on
ce”) Manual delineation
“Tumor delineation, the weakest link in search
for accuracy”Njeh et al, Med Phys 2008
“Much to be gained by addressing position/motion
uncertainties during dose delivery”
Baumann et al, Nature. Rev. 2016
• Exploiting the superior soft tissue contrast of MRI to
perform better target definition ->Seeing more
1. Addressing delineation uncertainty by
adopting MRI in the simulation workflow.
CT
MRI
2. Address delivery uncertainties: MRI-
Linac
• Integrating MRI and a Linac provides soft tissue contrast
during treatment delivery -> see tumor during therapy
Lagendijk and Bakker, MRI guided radiotherapy - A MRI based linear acceleratorRadiotherapy and Oncology Volume 56, Supplement 1, September 2000, 220
+
MRI for improved target
definition (and OARs)1
Oesphageal cancer CT vs MR
CT
1.3 x 1.3 x 3 mm3 0.7 x 0.7 x 3 mm3
MR (T2W)
MRI has superior soft tissue contrast
CE-CT T1w MRI Gd
Verd
uijn
et
al,
IJR
OB
P, 2
009
T2N2b hypopharynx tumor,
Registration CT-MRI facilitates overlay of
MRI delineation to CT.
CE-CT T1w MRI Gd
Verd
uijn
et
al,
IJR
OB
P, 2
009
T2N2b hypopharynx tumor,
MRI's superior soft tissue contrast: cervix
GTV pathological lymph nodes (right)
GTV pathological lymph nodes (left)
T2-weighted
CTVnodes (path.lymph nodes)
GTV primary tumor
rectum
bladder
CTVprimary (cervix, corpus uteri)
CT MRI –T2w
MRI – T1wMRI – Diffusion Weighted
Tumor-background contrast: versatile MR contrast
Pancreas
Functional imaging for prostate cancer
Diffusion weighted imaging
• Diffusion MRI provides information about water mobility
– In tumor mobility restricted
• By making scans with strong diffusion encoding gradients -> we
can make MRI sensitive to microscopic motion of free water
molecules in tissue.
b=0 s/mm2 b=1000 s/mm2 ADC
2. Planning 3. Treatment1. Imaging
MR-CT Radiotherapy simulation workflow…
Electron density
for dose planning
Delineation of
tumor and organs
at risk
Image
fusion
Matteo Maspero, UMCUtrecht
2. Planning 3. Treatment1. Imaging
State-of-the-art simulation workflow…
Image
fusion
Reference
Images
Plan &
DoseDelineation
Linac
Position
Verification
Prostate =
x 35 times
IT news
Linac
Setup adaptation MRI: scan in treatment position
MR-RT simulator:
Flat table top instead of Concave MR diagnostic table top
At Treatment (Linac)
- Wide bore to allow scan in treatment position- Positioning lasers to record patient position
MRI guided RT2
Current RT workflow: where to improve?
Treatment = 'mimicking of simulation' (1-40 times)
CT imaging Treatment planning
Sim
ula
tio
n (
“on
ce”) Manual delineation
Del
iver
y
“Tumor delineation, the weakest link in search
for accuracy”Njeh et al, Med Phys 2008
“Much to be gained by addressing position/motion
uncertainties during dose delivery”
Baumann et al, Nature. Rev. 2016
Different anatomical conditions between
radiation fractions for cervix cancer patients..
Ellen Kerckhof, Bas Raaymakers, UMCU, NL
Day to Day motion
Patient 1 Patient 2
Tumor
Clinical Target volume
Total target volume due to motion uncertainties
2. Address delivery uncertainties: MRI-
Linac
• Integrating MRI and a Linac provides soft tissue contrast
during treatment delivery -> see tumor during therapy
Lagendijk and Bakker, MRI guided radiotherapy - A MRI based linear acceleratorRadiotherapy and Oncology Volume 56, Supplement 1, September 2000, 220
+
brachy2
Conventional RT
move patient to suit a fixedtreatment plan
brachy2
MRI-guided RT with a MRI-Linac
adjust treatment plan to suit the “daily” patient
situation
2:) MR guided RT addresses delivery uncertainties
Courtesy: R Tijssen, UMCU
MRI-guided radiotherapy: seeing what to treat
Image acquisition and VOI
delineation
Online
treatment
planning
Delivery
1. Make MRI and delineate relevant structures
2. Make a conformal new plan based on anatomy at time of treatment
3. Allows smaller margins -> less toxicity.
1999 2009 2014
invention 1st prototype 3rd prototype
2004
Design/principles
2012
2nd prototype
in collaboration Elekta and Philips
2015
(pre)Clinical
Radiotherapy Department UMCUDevelopment MR linac
MRI system
Technical feasibility of a hybrid MRI-accelerator
1. Effect static magnetic field of MRI on accelerator
2. Beam transmission through MRI system
3. Dose deposition in 1.5 T magnetic field
4. RF interference
Schematic design
RFwaves
dB/dt B0
Bo static magnetic field MRI
• Static magnetic field affects Linac
– Behaviour of magnetron that accelerates electrons altered
Exploit principle of active B0 field shielding to minimize stray field
B0=Bpin-Bcin
B0out=Bpout-Bcout=0
0 T area
0 T area
Bpou
t
Bcout
+ =
cross section through magnet
Currentdirection
Inner Windings Outer shielding Windings
Courtesy Bas Raaymakers, UMCUtrecht
Magnetic field MRI
Magnetic coupling solved by modified active shielding
Zero-field zone on outside of magnet (position of Linac gun)
Achieved by shift and change in #turns of shielding coils
Johan Overweg et al. Proc. Int. Soc, Mag. Res. 2009
Design requires transmission through the
cryostat
Gap between central coils increased to ~ 150 mm
Possible without compromising homogeneity
Cryostat with reduced and uniform gamma attenuation
“Standard” MR/RT design
150 mm
Split gradient coil
• Actively shielded coil system
• Central gap width 200 mmCourtesy Johan OverwegPrototype gradient coil(Futura, Heerhugowaard, NL)
Dose deposition in magnetic field
Electron trajectory is changed by the
Lorentz force
Therefore the local dose deposit will
change
Lorentz Force:
hνhν’
eB0
Pacific Northwest national laboratory
http://physics503.one-school.net/
ԦF = qԦv × B
Dose deposition in a magnetic fieldThe Electron Return Effect (ERE)
γ
γ
e-
e-
γ
e-
B = 0
γ
γ
e-
e-
γ
e-
B = 1.5 T
ERE at tissue-lung transitionssimulation geometry
water
water
lung ρ = 0.25
ρ = 1
ρ = 1
-ray, 6 MV4 x 4 cm2
ERE at tissue-lung transitionsDose distribution and in-depth dose profiles
20 12080 1006040
Dose (%)
0 140
0 2 4 6 8 10 12 14 160
20
40
60
80
100
120
140
0 T
1.5 T
Depth (cm )
Re
lati
ve
Do
se
(%
)
0 2 4 6 8 10 12 14 160
20
40
60
80
100
120
140
0 T
1.5 T
Depth (cm )
Re
lati
ve
Do
se
(%
)
ERE at tissue-lung transitionsDose distribution and in-depth dose profiles
20 12080 1006040
Dose (%)
0 140
larynx IMRT treatment plan at 1.5 Teslatreatment 6 beams setup
larynx IMRT treatment plan at 1.5 Teslasingle beam dose distribution showing ERE
90˚
B
0 1 2 3 4 5 6 7
0
1
Distance (cm)
Arb
. U
nits
air gap
0
1
0 68 Gy3417 51
larynx IMRT treatment plan at 1.5 Teslaoptimized dose distribution
0 10 20 30 40 50 60 700
20
40
60
80
100
Dose (Gy)
Vo
lum
e %
myelum
PTV
Dashed lines: B = 0 T
Solid lines: B = 1.5 T
larynx IMRT treatment plan at 1.5 TeslaDVH for optimized dose distribution and comparison to B = 0 T
Courtesy: Alexander Raaijmakers, UMCutrecht
0 10 20 30 40 50 60 700
20
40
60
80
100
Dose (Gy)
Vo
lum
e %
PTV
myelum
Dashed lines: B = 0 T
Solid lines: B = 1.5 T
larynx IMRT treatment plan at 1.5 T with 5 beamsDVH for optimized dose distribution and comparison to B = 0 T
Courtesy: Alexander Raaijmakers, UMCutrecht
1999 2009 2014
invention 1st prototype 3rd prototype
2004
design
2012
2nd prototype
in collaboration Elekta and Philips
2015
(pre)Clinical
Radiotherapy Department UMCUDevelopment MR linac
1.5 T MRI accelerator: prototype 1Simultaneous beam on and MRI
Artist impression
1.5 T diagnostic MRI quality No impact of beam on MRI (image quality)
First prototype MRI accelerator
Second prototype MRI linac: rotating gantry
with linac integrated with MR system.
Slipring
Cooling equipment
Power supplies
& electronics
MLC & accelerator
waveguide
RF waveguides
Modulator
Magnet prototype at Philips Helsinki
Key specifications Atlantic:
• 1.5 T MRI
• 7 MV linac
• Cylindrical geometry– 70 cm Bore diameter
– Radiation perpendicular to B-field
• JJW Lagendijk et al. Semin Radiat Oncol 24:207-209 2014• JJW Lagendijk and Bakker, MRI guided radiotherapy - An MRI based linear accelerator Radiother Oncol. 56, S1, 2000, 220
Third pre-clinical prototype MRI accelerator
Raaymakers et al. PMB. 2017;62(23):41-50
Online workflow
MRI
“deformedCT”
Independent CalcDelineations
Pre-Treatment CT
Defo
rmab
le registratio
nAutoPlanning
PV
OK
• Patient population
– Patients with bone metastases treated
with palliative intention
First clinic treatment on 1.5 T MR-Linac: First in Man
• Treatment8 Gy in a single fraction3 or 5 field IMRT
• Goal:Demonstrate technical accuracy and safety in the clinical setting
Courtesy Bas Raaymakers, UMCUtrecht
Clinical MRI-guided RT has become reality at UMC Utrecht
stereotactic treatment of positive lymph nodes
• May 2017: First patient treatments in clinical study setting on 1.5 T MR-Linac
• June 2018: 1.5 T Elekta Unity system receives CE Mark
• August 2018: First regular clinical treatments on 1.5 T Elekta Unity in Utrecht
1.5T Unity Elekta 20.35T MRIdian Viewray 1
MRI-guided radiotherapy: seeing what to treat
1 The ViewRay system: magnetic resonance-guided and controlled radiotherapy. Mutic S, Dempsey JF. Semin Radiat Oncol. 2014
2. The magnetic resonance imaging-linac system. Lagendijk JJ, Raaymakers BW, van Vulpen M. Semin Radiat Oncol. 2014 Jul;24(3):207-9
3 Cobalt-60 sources/Linac
0.35 T superconducting MRI
Siemens MRI back-end
Treated first patient in February 2014
February 2017: FDA clearance for Linac
7 MeV Linac
1.5 T superconducting MRI
Philips MRI back-end
Treated first patient in May 2017
June 2018 CE clearance
August 2018: Start clinical treatment
1.5T Ingenia 1.5T MR-Linac
1.5 T MR-Linac has diagnostic image quality
Courtesy: M. Philippens, (UMCU), Eveline Alberts (Philips)
Use cases for MRI-
guided RT3
plan
pre-beam
MRI
beam on
MRI
contourMR-sim plan
1 week per treatment session
contour
MRI integration in MRgRT workflow
Courtesy: R Tijssen, UMCU
Hypo fractionated Radiotherapy of prostate with MRI-Linac
• With MRI-guided RT allows designing a radiation
plan based on the actual anatomy
– Reduce uncertainties
– Exploit this to lower the amount of fractions
• Soft tissue and functional contrast allows
localization of tumor in prostate
– Dose boost to tumor
anatomical
ADC
Diffusion
Dose
• Presence of positive lymph node is a
strong negative prognostic factor in
many cancers
• Lymph nodes are located (on CT) based
on anatomical boundaries
– Large target volumes
– Dose to OAR
– Toxicity (e.g edema)
• We can treat lymph nodes with MRI-
guided RT much better than currently
occurs in radiotherapy.
Lymp nodes: Room for improvement.
PTV
Courtesy Van Heijst et al., UMCUtrecht
2D T2 TSE
Mar
ielle
Ph
illip
en
sTr
ista
n v
an H
eijs
t
• With MR-Linac we can re-localize the positive nodes and
stereotactically sterilize it.
Stereotactic treatment of lymph nodes on MRL
T. Van Heijst, UMCU
axillary Lymph nodes on T2-FFE sequence
Ongoing technological
developments for MRI-
guided RT4
Real time dose adaption
The goal we are working towards..
Patient-ID: 00900 name: F. Ictitious real-time MR-Linac tracking tumor-site: kidney
offsets
FH:
RL:
AP:
resp:
1.0mm
0.5mm
0.2mm
3.2mm
Tracking is
ON
Beam’s eye view
Beam is
ON
Accumulated Dose
Real-time imaging
Motion history
Courtesy Rob Tijssen, UMCUtrecht
Real time dose adaption: Latency and imaging speed
• Latency: difference between time stamp of imaging and beam
adaptation
• For a 2D imaging case with standard Fourier reconstruction:
– MRI acquisition + reconstruction adds about 300-500 ms latency.
– motion analysis + multi-leaf collimator control about 100-150 ms
• What happens if we go for the 3D imaging case?
•
Courtesy B.Stemkens, UMCUtrecht
How fast can we image with conventional techniques?
Image acquisition speed: 1D, 2D, 3D
Pulse sequence: cartesian T1-SPGR, one readout line per RF pulse 1D navigator1RF pulse + 1 readout => 3 ms
2D imageFOV = 350 x 350 mm2
Res = 2 x 2 mm2
Matrix = 175 x 175T_acq = 3 x 175 => 525 ms
3D imageFOV = 350 x 350 x 270 mm3
Res = 2 x 2 x 2 mm3
Matrix = 175 x 175 x 135T_acq = 3 x 175 x 135 => 708 s
TR = ~3ms
Courtesy: R Tijssen, UMCU
How fast can we image with conventional techniques?
Image acquisition speed: 1D, 2D, 3D
Pulse sequence: cartesian T1-SPGR, one readout line per RF pulse 1D navigator1RF pulse + 1 readout => 3 ms
2D imageFOV = 350 x 350 mm2
Res = 2 x 2 mm2
Matrix = 175 x 175T_acq = 3 x 175 => 525 ms
3D imageFOV = 350 x 350 x 270 mm3
Res = 2 x 2 x 2 mm3
Matrix = 175 x 175 x 135T_acq = 3 x 175 x 135 => 11.8 min
TR = ~3ms
Courtesy: R Tijssen, UMCU
Accelerating 3D acquisitions
73
• We can speed up MRI acquisitions by sub Nyquist undersampling
• Results in aliasing artifacts unless we apply parallel imaging1,2 (PI)
exploiting multi-element receive arrays
• Combining PI with Compressed Sensing3 (CS) allows even higher
acceleration
2x undersampled PI reconNo undersampling
1. Pruesman et al, MRM 1999, 2. Sodickson et al, MRM 1997, 3. Lustig et al. MRM 2007
1. Development of a radiolucent, high
channel receiver array for MRI-Linac
To further advance 3D image acquisition
2. Application of advanced
reconstruction methods 1
Low latency reconstruction of undersampled
data
1. Zhu et al. “Image reconstruction by domain-transform manifold learning”,
Nature 2018
With participation of Federico d’Agata,
University of Turin
Towards fast, low latency 3D cine MRI
Zijlema et al. # 1737 ISMRM 2018
64-element coil array
Integrating MRI in RT treatment cycles
MR-Sim -> Better targetingdue to superior contrast
MRI-guidance: Designing a daily new plan based the observed patient anatomy
Evaluate therapy efficacy by systematicresponse monitoring
MRI driven by MR-Sim and
MRI-Linac
Preoperative CRT surgery
Example: Esophageal cancer:
1. Can we increase complete response rate (pCR) rate?
2. Can we identify pCR prior to surgery?
Path CR 29%
The goal we are working towards: curative
organ preserving radiotherapy treatment
Day 0 Day 10 Day 20
Characterizing and adapting to the daily
tumor status with MRI-guided RT
Geometrical
response
b
e
h
ΔADC = 48%
ΔADC = 44%
Functional (Diffusion)
response
DWI (b=800) ADC map
Courtesy: Gert Meijer
Peter van Rossum
Before RT
During RT
After RT
Online MR guidance facilitates tumour and OAR visualization
With online MR guidance we see tumor and risk organs
Courtesy Gert Meijer
Cone beamCT
T2WMRI-Linac
MRI guided RT: Better sight on what to treat!
• MRI simulation:
– Better target definition and characterization
• MRI guided Radiotherapy
– Brings MRI to treatment table -> seeing what to treat.
– Design radiation plan on actual anatomy
– Real time beam adaptation.
• MR based response assessment
– Evaluating and optimizing treatment efficacy
– Incorporate in therapy management.
• MRI in RT reduces uncertainties
– increase of therapeutic effect with equal/ lower toxicity!!
• Interventional radiotherapy/surgery without a knife
Center of Image Sciences. UMC Utrecht
Developing new MRI_guided therapies
• MRI linac (3x)
• MRI brachytherapy (1x)
• MRI HIFU (1x)
• MRI Holmium Radioembolisation (1x)
• MRI guided protons (in silico)
Acknowledgements
UMCUtrecht
Federico d’Agata , Caterina Guiot, University of Turin