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.

c.a.t.vandenberg@umcutrecht.nl

• 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