What is radiation therapy (RT)?

• Cancer treatment

• Tumor versus normal tissues

• External photon beam RT

Intensity-modulated RT (IMRT)

• Brahme et al. 1982– Fluence-modulated beams– Homogeneous, concave

dose distributions

• Better target dose conformity and/or better sparing of organs at risk (OARs)

Imaging for RT

Anatomical imaging

• CT• MRI

Biological imaging

• PET• SPECT• fMRI• MRSI

Brain

Tumor

Tumor biology characterization

Radiotracer Characterization

18F-FDG Glucose metabolism

18F-FLT DNA synthesis

11C-MET Protein synthesis

60Cu-ATSM, 18F-FMISO Hypoxia

Radiolabeled Annexin V Apoptosis

Radiolabeled V3 integrin antagonists

Angiogenesis

Apisarnthanarax and Chao 2005

Biological imaging for RT

• Improvement of diagnostic and staging accuracy

• Guidance of target volume definition and dose prescription

• Evaluation of therapeutic response

Target volume definition

• Gross tumor volume (GTV)

• Clinical target volume (CTV)

• Planning target volume (PTV)

Biological target volume (BTV)

Ling et al. 2000

Dose painting

Dose painting by contours

Dose painting by numbers

Dose painting by numbers

Biologically Conformal Radiation Therapy

Dose calculation algorithms

• Speed versus accuracy:– Broad beam– Pencil beam (PB)– Convolution/superposition (CS)– Monte Carlo (MC)

• Monte Carlo dose engine MCDE Reynaert et al. 2004

Accuracy Accuracy ↑↑

Speed ↓Speed ↓

MC dose calculation accuracy

• Cross section data

• Treatment beam modeling

• Patient modeling– CT conversion – Electron disequilibrium– Conversion of dose to medium

to dose to water

• Statistical uncertainties

Implementation of BCRT:Relationship between signal intensity

and radiation dose

Dose

Ilow Ihigh

Dlow

Dhigh

Signal intensity

highlow

lowhighlowhigh

lowlow

IIIfor

)D(DII

IIDD

Implementation of BCRT: Treatment planning strategy

Implementation of BCRT:Biology-based segmentation tool

• 2D segmentation grid in template beam’s eye view– Projection of targets (+)– Integration of signal intensities

along rayline (+)– Projection of organs at risk (-)– Distance

• Segment contours from iso-value lines of segmentation grid

Implementation of BCRT:Objective function

• Optimization of segment weights and shapes (leaf positions)

• Expression of planning goals

• Biological:– Tumor control probability (TCP)– Normal tissue complication probability (NTCP)

• Physical:– Dose prescription

1

D

D

2

1

D

DF

imean

dev

imean

dev

ii

Implementation of BCRT:Treatment plan evaluation

0

20

40

60

80

100

0 0.5 1 1.5

Q

Re

lativ

e v

olu

me

(%

)

p

p 1Qn

1QF

presc

pp D

DQ

QVH

Implementation of BCRT:Example

• [18F]FDG-PET guided BCRT for oropharyngeal cancer

• PTV dose prescription:

Dlow = 2.16 Gy/fx Dhigh= 2.5 and 3 Gy/fx

Ilow = 0.25*I95% Ihigh = I95%

Implementation of BCRT:Example

Implementation of BCRT:Example

0

20

40

60

80

100

0.85 0.9 0.95 1 1.05 1.1 1.15Q

Vo

lum

e (

%)

2.5 Gy/fx

3 Gy/fx

Implementation of BCRT:Conclusions

• Technical solution– Biology-based segmentation tool– Objective function

• Feasibility– Planning constraints OK– Best biological conformity for the lowest level

of dose escalation

BCRT planning study:Set-up

• BCRT or dose painting-by-numbers (“voxel intensity-based IMRT”) versus dose painting (“contour-based IMRT”)

• 15 head and neck cancer patients

• Comparison of clinically relevant dose-volume characteristics– Between “cb250” and “vib216-250”

– Between “vib216-250” and “vib216-300”

BCRT planning study:Target dose prescription

“cb250”

(cGy/fx)

“vib216-250”

(cGy/fx)

“vib216-300”

(cGy/fx)

PTVPET 250

PTV69+PET 216 - 250 216 - 300

PTV69 216

PTV66 206 206 206

PTV62 194 194 194

PTV56 175 175 175

BCRT planning study:“cb250” (blue) versus “vib216-250” (green)

0 30 60 90 120 150 180 210 240 270 300 3300

20

40

60

80

100

Fraction dose (cGy)

Vo

lum

e(%

)

Surr

PTV56

Spared parotid

PTV69+PET

Spinal cordPTV

PET

PTV66

PTV69

MandiblePTV

62

BCRT planning study:“vib216-250” (green) versus “vib216-300” (orange)

0 30 60 90 120 150 180 210 240 270 300 3300

20

40

60

80

100

Fraction dose (cGy)

Vo

lum

e (%

)

MandiblePTV

62

PTVPET

PTV69+PET

PTV66

PTV69

PTV56

Spinalcord

Sparedparotid

Surr

BCRT planning study:Example

2.11.2

2.5

2.16

2.22.4

1.6 1.4

2.3

2.11.2

2.5

2.16

2.22.4

1.6 1.4

2.3

2.1

2.5

2.162.2

2.4

1.61.4

2.32.1

2.5

2.162.2

2.4

1.61.4

2.3

2.1

2.5

2.2

2.4

1.62.3

2.1

2.5

2.2

2.4

1.62.3

BCRT planning study:QF

"cb250"

PTV69

"cb250"

PTVPET

"vib216-250"

PTV69+PET

"vib216-300"

PTV69+PET

0

0.5

1

1.5

2

2.5

3

3.5

QF (%)

BCRT planning study:Conclusions

• BCRT did not compromise the planning constraints for the OARs

• Best biological conformity was obtained for the lowest level of dose escalation

• Compared to dose painting by contours, improved target dose coverage was achieved using BCRT

MC dose calculations in the clinic

• Comparison of PB, CS and MCDE for lung IMRT

• Comparison of 6 MV and 18 MV photons for lung IMRT

• Conversion of CT numbers into tissue parameters: a multi-centre study

• Evaluation of uncertainty-based stopping criteria

• Feasibility of MC-based IMRT optimization

CT conversion: multi-centre study

• Stoichiometric calibration

• Dosimetrically equivalent tissue subsets

• Gammex RMI 465 tissue calibration phantom

• Patient dose calculations

• Conversion of dose to medium to dose to water

CT conversion: example

CT conversion: conclusions

• Accuracy of MC patient dose calculations

• Proposed CT conversion scheme:

Air, lung, adipose, muscle, 10 bone bins

• Validated on phantoms

• Patient study:

Multiple bone bins necessary if dose is converted to dose to water

Biologically conformal RT

• Technical solution– Bound-constrained linear model– Treatment plan optimization

• Biology-based segmentation tool• Objective function

– Treatment plan evaluation

• Feasibility of FDG-PET guided BCRT for head and neck cancer

MC dose calculations

• Individual patients may benefit from highly accurate MC dose calculations

• Improvement of MCDE– CT conversion– Uncertainty-based stopping criteria

• Feasibility of MC-based IMRT optimization

• MCDE is unsuitable for routine clinical use, but represents an excellent benchmarking tool

Adaptive RT:Inter-fraction tumor tracking

• Anatomical & biological changes during RT

• Re-imaging and re-planning

• Ghent University Hospital: phase I trial on adaptive FDG-PET guided BCRT in head and neck cancer

Summation of DVHs

CT 1 Dose 1 CT 2 Dose 2

Registration

Structure 1

Points

P Doses

TPoints

TP Doses

Total dosesTotalDVH

Structure 2

Summation of QVHs

CT 1 Dose 1 CT 2 Dose 2

RegistrationStructure 1

Points

P Q-values

TPoints

TP Q-values

Total Q-valuesTotalQVH

PET 1 PET 2

Registration Registration

Disregard TPointsoutside structure 2

Structure 2

Treatment planning and delivery

•Biological optimisation

•Adaptive RT

Biological imaging

•Tracers

•Acquisition, reconstruction, quantification

Clinical investigations

Fundamental research in vitro, animal studies

Treatment outcome