Applications of Modern Radiotherapy...

Applications of Modern Radiotherapy Systems

Thomas Rockwell Mackie

ProfessorUniversity of Wisconsin

Co-Founder and Chairman of the Board

TomoTherapy Inc.

Financial Disclosure

I am a founder and Chairman of TomoTherapy Inc. (Madison, WI) which is participating in the commercial development of helical tomotherapy.

Acknowledgements

John SchreinerJerry BattistaTim HolmesGustavo OliveraWeiguo LuKatja Langen

Paul KeallDavid ShepardCedric YuThomas BortfeldAn LiuChet Ramsey

Outline

• Setup correction for interfraction motion

• Off-line adaptive techniques

• On-line adaptive strategies

• Modern Delivery methods

• Treatment Planning Issues

• Delivery time

• Novel clinical applications

• Clinical impact

Courtesy of John Schreiner, Kingston Regional Cancer Centre, Ontario

Dose Sculpting and Painting

2-D Planning

IMRT

3-D

Conformal

Dose

Painting

Why 3D Image-Guided Radiotherapy (IGRT)?

• Eventually, most curative radiotherapy will be IMRT, even many palliative treatments, e.g., re-treatments.

• All IMRT should be image-guided:– IMRT is justified by sparing critical tissues (conformal avoidance) which produces higher dose gradients.

– IGRT enables higher gradients to be delivered safely and effectively.

– IGRT enables a smaller setup margins to be defined.• In some radiotherapy sites, e.g., prostate, IGRT may be more important than IMRT.

• 2D imaging is inadequate to obtain volume information.

“If you can’t see it , you can’t hit it

If you can’t hit it, you can’t cure it”

From Jerry Battista

1 second 1 minute 1 hour 1 day 1 week

Intra-fractional time scale

Inter-fractional time scale

time

respiratory,

cardiac

motion digestive

system

motion

bowel/

bladder

filling

random/

systematic

setup errors

tumor

growth

and

shrinkage

weight

gain and

loss

Radiotherapy Time Scales

Is Daily Imaging Necessary?Translational Setup Error by Disease Site

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

0 1 2 3 4 5

Disease Site

Error (mm)

Rotational Setup Error by Disease Site

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

0 1 2 3 4 5

Disease Site

Error (degrees)

∆ systematic

● random

lateral

longitudinal

vertical

Brain H&N Lung Prostate Brain H&N Lung Prostate

∆ systematic

● random

roll

• Translational corrections smaller for brain and H&N than for lung and prostate treatments

• Rotational corrections greater for brain and H&N than for lung and prostate

• Shows that when we image, we do make shifts. Does this improve outcomes? Can we use this to image less?

Residual Errors For Imaging Protocols

Error As a Function of % Days Image Guidance Used

0

20

40

60

80

100

0 20 40 60 80 100

% Image Guidance

% Times Error

Occurs

Error > 3 mm

Error > 5 mm

Error > 10 mm

Every second day

Weekly

NeverEvery day

Adapted from Zeidan et al, Int. J. Radiat. Oncol. Biol. Phys. 2007; 67:670-677

Head and Neck

Small residualuncertainty

Off-line Adaptive Techniques

• Dose verification and replanning

• Dose reconstruction

• Deformable registration of contours and dose distributions

• Dose trending

Off-Line Adaptive3-D Imaging

OptimizedPlanning

Pre-DeliveryImaging

RadiotherapyTreatment

DoseReconstruction

Setup Adjustment

DeformableDose

Registration

Quantitative Imaging forAdaptive Therapy

• Quantitative images are required for many

Adaptive Therapy Processes:

– Delivery Verification.

– Dose Reconstruction.

– Deformable Dose Registration.

– Re-optimization.

• All of these can be achieved with

tomotherapy’s CT images.

Patient courtesy of Tim Holmes, St. Agnes Cancer Center Baltimore, MD

Re-calculated plan with shifted target

Dose Verification – Recomputing Dose

Planed Dose to the PTV

Delivered Dose to the PTV

Planned Max Cord Dose

Max Cord Dose with Existing Plan

Per-fraction DVH

Re-calculated plan with shifted target

Clinical Adaptive Planning

Patient courtesy of Tim Holmes St. Agnes Cancer Center Baltimore, MD

Patient courtesy of Tim Holmes, St. Agnes Cancer Center Baltimore, MD

Planed Dose to the PTV

Delivered Dose to the PTV

Planned Max Cord Dose

Max Cord Dose with Existing Plan

PerPer--fraction fraction DVHDVH

Revised Plan Revised Plan DVH for DVH for remaining remaining fractionsfractions

Replanning

Revised plan for remaining Revised plan for remaining

fractionsfractions

Max Cord Dose with Revised Plan

Original Planning CT

Original planning CT

Reference CT

Daily CT Daily CT mapped

to Reference CT

Original planning CT

Reference CT

Daily CT Daily CT mapped

to Reference CT

Accuracy of Automatic H+N MVCT contours

kVCT contours: MVCT contours:

Parotids: Visual inspection of automatic

contours

MVCT to kVCTDeformable Image Registration

kVCT:

PTV

Cord

MVCT:

PTV

Cord

Accuracy of Automatic H+N MVCT Contours

Spinal Cord: Automatic vs. manual contours

Compare dose-based end points: Dmax, Dmean

3 patients:

Dmax %difference: 1.1 + 3.5%

Dmean %difference: 0.1 + 2.5 %

Langen et al., AAPM, 2006

Dmean

0.6

0.8

1.0

0 5 10 15 20 25 30 35Treatment fraction

Dose (Gy)

Automatic Manual

Dmax

1.0

1.2

1.4

0 5 10 15 20 25 30 35Treatment fraction

Dose (Gy)

Automatic Manual

Trending

1st fraction

Cont. to 35 fractions

Trending

Re-plan at 20 fractions

Trending

On-line Adaptive Techniques

• Detection of intrafraction motion

• Methods of motion management• Gating

• Tracking

• Delivery modification

Lung Motion Dynamics

The motion can be complex

Motion close

to diaphragm

Motion mid

lung

Motion tumor

at center

Motion lower

chest

Lung Motion Dynamics

Navotek RealTrack System• Fine radioactive wire is implanted in the patient.• Can see the wire on IGRT systems.• Can track wire position in real time.

Calypso System• Electromagnetic transponders are implanted in the patient.• Can see the transponder on IGRT systems.• Can track transponder position in real time.

Degradation of Alignment Quality after Initial Setup for Prostate Cancer

0

10

20

30

40

50

60

0 5 10 15Time (minutes)

Precentageof observations

Percentage of displacements

observed

over time after initial alignment

>3 mm

>5 mm

>7 mm

>10 mm

17 patients

551 Calypso

sessions

Mean: 32

tracks

per patient

Courtesy of Katja Langen, M.D. Anderson Cancer Center, Orlando, FL

MRI-Guided Systems for Real Time Imaging

View Ray

AlbertaUtrecht

Motion Management

• Margin: Put an ITV on a CTV

• Breath holding: Either active or passive

• Gating: Not very efficient

• Tracking: Move the patient or move the beam

• Delivery Modification: Can also handle non-rigid motion

The Breathing Cycle

Inhalation Inhalation

Exhalation

Gating Paradigm

Assumes no motion

in gated portion

Loss of Efficiency

Motion Management (4D Planning and Delivery)

Treating while the patient breathes is more accurate as compared to tracking, and saves time as compared to gating.

Works in Progress

Nemo Demo

Motion SurrogateNemo

Static Tank

Fish Represents a Moving Tumor

How Necessary is Motion Management?Magnitude of Motion

Tumor Size

< 5 mm > 5mm < 1cm > 1 cm

SmallFraction, Including Margin, of OAR Volume

Not Needed Not Needed

Not Needed Not Needed PerhapsNeeded

LikelyNeeded

PerhapsNeeded

MediumFraction of OAR Volume

LargeFraction of OAR Volume

Not Needed

Not Needed

Why IMRT Is Needed

• 5 IMRT beams is more conformal than 5 conformally-shaped beams.

– If uniform fields were sufficient, the pencil beam weights for each beam would be identical.

54

12

3

54

12

3

Multileaf Collimators (MLC’s)

Siemens Varian NOMOS

• Conventional MLC’s were designed for field shaping

and have limitations when used for IMRT.

BinaryConventional

• Binary (off-on) MLC’s are designed for IMRT and are

the easiest to model and provide high modulation.

Segmental MLC IMRT

• “Step and shoot”.

• Deliver multiple MLC apertures within a field to apply the intensity in a paint-by-number fashion.

• May be a straightforward technique for “forward” optimization.

• Little change in paradigm involved in field boundary verification using portal imaging.

• May be relatively time consuming if field delivery is verified in exactly the same way.

• Only discrete intensity levels can be delivered.

Segmental MLC IMRT

A set of leaf sequences to deliver

an intensity modulated field.Conventional MLC’s have been designed

for field shaping not IMRT.

Dynamic MLC IMRT

• Pairs of MLC leaves are in continuous movement across the field with the intensity at a point equal to the total exposure time of the leaf pair above it.

• Most efficient delivery for modest modulation of intensities.

• High spatial variation of intensities are difficult.

• Continuous intensity levels.

• Difficult to verify with conventional techniques as anatomic details blend into the continuous intensity levels.

Dynamic MLC Leaf Motion

From Paul Keall, Stanford University

Intensity Modulated Arc Therapy (IMAT)

• Collimator leaves move dynamically as the gantry rotates.

• Beams delivered from all coplanar directions. • Requires multiple arc deliveries to achieve intensity modulation.

• Provided field length is not too long, no couch translations are necessary.

• Proposed by Cedric Yu and implemented by Wilfried DeNeve (Ghent, Belgium).

• Single arc IMAT is branded “VMAT” or “RapidArc” and also changes the dose rate during the rotation to achieve some limited modulation.

IMAT

Field shape changes dynamically during rotation.Needs multiple rotations.

IMAT Intensity Levels

i is the number of non-zero intensity levels.n is the number of rotations.

3

n = 2

Two Rotation IMAT

71i

n = 3 n = 1

Three Rotation IMAT

One Rotation

IMAT

2 1ni = −

Following Equation is from Cedric Yu:

3 SeparateRotations with

Different IntensitiesPer Rotation

1 2 3 4 5 6 7

Example of 3 IMAT Rotations

Yields 7 Unique Non-Zero Intensity Levels

From David ShepardAnd Cedric Yu

Tomotherapy

• Tomotherapy is intensity modulated rotational therapy with a fan beam of radiation and is analogous to a CT scanner.

• It utilizes a binary collimator to provide the modulation.

• Serial tomotherapy was first form of IMRT

• In helical tomotherapy, the gantry and couch move simultaneously.

TomoTherapy HI-ART Unit

Linac ShownWithout Shielding

Pulse FormingNetwork andModulator

DetectorBeam StopHigh VoltagePower Supply

ControlComputer

Magnetron

Data Acquisition System

Circulator

Gun Board

How the Intensity is Modulated with Tomotherapy

Open

Closed

For Low Intensity ALeaf Is Open for a Short Time DuringThe Projection

For High Intensity ALeaf Is Open for a Long Time During The Projection

One Rotation is Divided into Angular SegmentsCalled a Projection

Binary leaves were specifically designed for IMRT.

Sample Sinogram

Collimator Position

Angle

A delivery sinogramis a representationof the energy fluence delivered to thepatient. The energyfluence distributionis the realization ofthe sinogram andtakes into accountphoton attenuation.

A Sinogram Specifies the Relation Between Collimators and Voxels

Collimator Index

GantryAngle

Helical Delivery Sinogram

Example with 13 Rotations

GantryAngle

Collimator Index

Darker Is HigherIntensity or LongerOpening Time

AvoidanceOf NormalTissue

The delivery sinogramspecifies the intensity(or leaf opening time) as a function ofgantry angle.

IMRT Requires Optimization

Hard Constraints• cannot be violated

• may not lead to a feasible solution

Soft Constraints• constraints may be violated

• find optimal intensity profile

• may lead to a local minimum

Beamlet-Based Optimized Planning

• Two-step approach to treatment planning:

1. Fluence map optimization – Delivery constraints ignored

2. Leaf sequencing – Accounts for delivery constraints

• Employed by nearly all vendors.

• Corvus (NOMOS)• Eclipse (Varian) • XiO (CMS)• Pinnacle (Philips)• Oncentra (Nucletron)• Hi-Art (TomoTherapy)

Field Divided into a Grid of Beamlets

From Cedric Yu, U. of Maryland

2

1

1

1

1

1

2

2

2

1

1

1

2

1

1

2

1

1

2

2

1

3

21 1 32

3 12

3

2 1

3 1 11

11 11

21111

1

2

1

1

2

2

21111 2

Optimized Fluence Map


Leaf Sequencing

2

1

1

1

1

1

2

2

2

1

1

1

2

1

1

2

1

1

2

2

1

3

21 1 32

3 12

3

2 1

3 1 11

11 11

21111

1

2

1

1

2

2

21111 2

Optimized Fluence Map

Deliverable Apertures


Beamlet IMRT Approach for Conventional MLC IMRT

Clinical Objectives, Constraints

Intensity Maps

MLC Segments1

654

32


Aperture-Based IMRT

Clinical Objectives, Constraints

MLC Segments1

654

32

Shepard, Earl, Li, Naqvi, Yu

“Direct aperture optimization”

Med. Phys. 29(6):1007-1018, 2002


Delivery Type Dictates IdealOptimization Type

√

X

IMAT

XX√Aperture

√√XBeamlet

Tomotherapy

(Binary MLC)

DMLC (Dynamic MLC)

SMLC

(Step and Shoot)

Delivery Type

Ideal Optimization Type

Inadequateangularsampling

Inadequateintensitysampling.

Inadequatespatial (pixel)resolution.

Spatial and Angular ResolutionAngular sampling interval, ∆Φdominates image resolution at the peripheryof an axial image.

Pixel size, ∆ldominates imageresolution at thecenter. ∆l

∆Φ

FOV

Angular Sampling Required for CT

FOV is the field of view.

∆l is the spatial resolution.

1260 views

FOV = 40 cm

∆l = 0.1 cm

Large FOV

630 viewsRequirement

FOV = 20 cm

∆l = 0.1 cm

Small FOV

# / oFOV

Viewsl

ππππ

∆∆∆∆====360

Angular Sampling Required for Radiotherapy

FOV is the field of view (max field width)

∆l is the spatial resolution (collimator

resolution)

51 views

FOV = 40 cm

∆l = 0.6 cm

Tomotherapy

25 viewsRequirement

FOV = 15 cm

∆l = 0.5 cm

Conv. IMRT

# / o FOVViews

l

ππππ

∆∆∆∆====360

Brahme‘s Classic 1982 Paper on Rotational IMRT

Phantom

Target OAR

Dose

Rotating

Source

From Tomas Bortfeld

Fluence

Sufficient Modulation and Beam Numbers Are Needed to “Construct Dose”

1 Beam 5 Beams 11 Beams

17 Beams 25 Beams 51 Beams

mm mm mm

mmmmmm

Notice the High Degree of ModulationRequired Even if Rotation is Used

Discretization Error

i is the number of non-zero intensity levels.N is the number of beam directions.

2.2%

i = 1

N = 180

Single Arc

VMAT

0.04%2.2%1 S.D. Error

i = 100

N = 51

i = 5

N = 7

Helical Tomotherapy

Step and Shoot

IMRT

σσσσ ====1

12 i N

Following Equation is from Imaging Theory:

Conventional IMRT Delivery Time Analysis

From Sha Chang, UNC

Average Tomo

Tomo’s Time In Room and Treatment Time

Ave = 5 min

Treatment Time = Beam on Time = Time for Treatment Irradiation

Ave = 17 min

• Other studies have put the average beam on time at 7 minutes for tomotherapy

• Depends on the amount of modulation

• Shorter tumors like prostate have shorter beam on time

• Longer tumors like cranial spinal have longer beam on times

Re-treatments, using tomotherapy for patients not eligible for conventional photon radiation therapy due to cord tolerance.

Patients courtesy of UAB

Re-Treatments

Complex Abdominal/Pelvic

Heidelberg University Clinic

CraniospinalTomotherapyTomotherapy TraditionalTraditional

Craniospinal

TomotherapyTomotherapy

TraditionalTraditional

Total Marrow

Irradiation

(TMI)

From Dr. An Liu,City of Hope, Duarte CA

Conformal Avoidance of:BrainThyroidLungsLiverKidneysSmall Bowel

Strategy for Conformal Avoidance Radiotherapy

• Use generous treatment volumes.• Outline normal sensitive tissues and concentrate on avoiding them.

• Use image-guidance to assure that the normal tissues are being avoided.

• Conformal avoidance radiotherapy is the complement of conformal radiotherapy.

• If you can’t see it you can’t avoid it.• If you can’t avoid it you can’t spare it.

With Better Avoidance of Normal Tissue is Hypofraction Possible?

• In prostate CA, the tumor may repair even better than the normal tissues.

• In lung CA, rapid proliferation reduces the treatment control probability as the treatment is extended in duration.

• Provided better avoidance of sensitive tissues is maintained, fewer fractions of higher dose/fraction will provide both better tumor control and be less expense to deliver.

• Carefulness can be cost effective.

Image-Guided Radiotherapy of the Future

• Image-based staging of the primary and regional field.

– Determine hypoxic and highly proliferative regions using bioimaging and paint in higher dose.

– Conformally avoid sensitive structures in the regional field.

• IMRT with 3-D image verification.

– Less fraction quantity – greater fraction quality.

– Adaptive radiotherapy to provide patient-specific QA of the whole course of therapy.

Image-Guided Radiotherapy of the Future (Cont.)

• Image-based monitoring of outcome.

– e.g., PET scans for regional or metastatic development using a priori information.

• Aggressive treatment of recurrences or distant metastases using conformal avoidance to spare critical structures.

– Better QA of first treatment will allow safer retreatments.

– “Weeding the garden” with image-guided radiotherapy and prevent spread with chemotherapy and immunotherapy.

Oligometastases or “Weeding the Garden”

• Following definitive radiotherapy with local control we often have metastatic progression.

• Chemotherapy (analogous to pre-emergent herbicides) is known to be effective against 100 to 1000 cell tumorlets.

• With PET it is possible to infer the presence of tumorletswith 100,000 to 1,000,000 labeled cells.

• Perform PET scan followups to catch the emergent tumorlets.

• Weed with conformal avoidance hypofractionatedradiotherapy before they can seed more metastases.

• Keep careful track of the cumulative dose delivered so the process can be repeated several times if necessary.

Courtesy of Chet Ramsey, Thompson Cancer Survival Center

Planned Using PET-CT

PET-CT Scans

Treating Multiple Metastases Determined From PET Scans

Tomotherapy Treatment Plan

Visualization Gap

102 103 104 105 106 107 108 109

External Beam

Radiotherapy

Effective

MR/CT Tumor

Visualization

PET Tumor VisualizationChemotherapy

Effective

Tumor Cell Density

(cells/cm3)

1010

Targeted Agents

Effective

101

Visualization Gap

Implications of the Visualization Gap

• Systemic agents are effective for tiny tumorlets.

• Larger tumorlets may shrink so that they are not visible but they are likely to return.

• Systemic agents are more effective when no tumorletsare visible, i.e., used as a prophylaxis agent.

• Radiation therapy is effective for much larger tumors

• If imaging systems were sensitive for smaller tumors, radiation therapy could be used systemically.

• Systemic agents should aim for higher cell kill.

• If the tumor size range of systemic agents and radiation therapy could overlap, cancer could be made a chronic disease.

Conclusions• Setup corrections can correct for translations and

rotations.

• Adaptive therapy accounts for changes in the patient.

• Motion management can accommodate for breathing

and organ filling.

• IMRT and rotational therapy will dominate curative

treatments

• The type of optimization depends on the type of

delivery.

• IMRT takes more time than conventional radiotherapy

• Treatments not possible with conventional

radiotherapy are being done.

• Conformal avoidance enables hypofractionated

treatments.

Applications of Modern Radiotherapy...

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