HIT Betriebs GmbH am Universitätsklinikum Heidelberg mit beschränkter Haftung www.med.uni-heidelberg.de/hit
Imaging techniques for in-vivo
treatment verification
Katia Parodi, Ph.D.
Heidelberg Ion Therapy Centre, Heidelberg, Germany
Previously: Massachusetts General Hospital and Harvard Medical School, USA,
and Research Center Dresden-Rossendorf, Germany
Hadron Therapy Workshop 2011
Erice, Italy, May 25th, 2011
Massachusetts General Hospital
and Harvard Medical School
The physical advantages of ion beams The finite range with the characteristic “Bragg-peak”
Depth in water (cm)
Peak-region
Photons
Bragg-Peak
Protons 12C-ions
Plateau-region
Treatment uncertainties in ion beam therapy
Difference TP / delivery
Daily setup variations
Internal organ motion
Anatomical / physiological changes
TPS dose calculation errors
Inhomogeneities, metallic implants
Daily practice of compromising
dose conformality for safe delivery
Conversion HU in ion range
CT artifacts
After Enghardt 2005
Accounting for uncertainties
in the clinical practice
Current approach:
Opposed fields,
overshooting
Protons
Desirable approach:
Different beam angles and
no overshooting
A. Trofimov et al, MGH
? In-vivo verification
Positron-Emission-Tomography (PET)
1) b+-decay A(Z,N) A(Z-1,N+1) + e+ + ne
2) Moderation of e+ in medium (typically few mm in tissue)
e+
Imaging of b+-activity
e-
Eg = 511 keV
g
g
180°
3) Annihilation into 2 opposite g-rays (511 keV each)
Coincidence
processor Image reconstruction
4) Coincident detection and processing
Detector
b+-emitter
or prior to irradiation with same radioactive beam (planned at HIMAC, Japan)
HIMAC, Japan
PET imaging for verification of ion therapy
Injected to the patient via irradiation using primary b+-radioactive ions like 19Ne (T1/2 17s), 11C (T1/2 20 min) and 10C (T1/2 19 s)
Low dose exposure prior to therapy with stable beam (pioneered in 70s at LBL, USA)
In-situ, non-invasive detection of b+-activity
19Ne from 20Ne
LBL, USA
Not (yet?) in clinical routine use
Llacer et al, Nucl. Sci. Appl. 3 (1998)111; Kitagawa et al, Rev. Sci. Instrum 77 (2006)
11C
12C ions in PMMA (A) (D)
PET imaging for verification of ion therapy In-situ, non-invasive detection of b+-activity Formed as by-product of irradiation in nuclear fragmentation reactions
(11C [T1/2 20 min], 15O [T1/2 2 min], …)
Schardt et al, Rev Mod Phys 2010; Parodi et al, IEEE TNS 2005; Enghardt, … Parodi … Nucl Instrum Meth A 2004
g-emission
12C
11C, 10C
15O, 11C, ...
nf ≈0
A(r) D(r)
Dose-guidance from PET surrogate
by comparing measured b+-activity
with expectation as done at GSI
g-emission g-emission (“prompt”)
≠ annihilation
11C 11B+ e+ + ne
T1/2
Eg = 511 keV
<~180°
e+ e-
Annihilation g-rays
g
g
In-beam PET for scanned 12C therapy at GSI
Planned
dose
Once
Measured
b+-Activity
For every fraction
(typically 20 d @ 1Gy)
MC calculated
b+-Activity
Verification of
Beam range
Lateral position
In case of deviation
Timely reaction
Enghardt, … Parodi … Nucl Instrum Meth A 2004; Parodi et al Nucl Instrum Meth A 2005
> 400 patients
Time in s
Beam off (PET signal)
Beam on (noise)
In-beam PET for scanned 12C therapy at GSI
1998
Prediction
Measurement
Since 1999
Prediction
Measurement
Extraction of ion range in-vivo
Validation of the physical beam model of treatment planning
1. Precision measurements:
Range of 12C-Ions in tissue
(D. Schardt et al. GSI) 2. Modification:
R = R(HU)
(E. Rietzel et al. GSI)
Original-CT Modified CT
Fast PET recalculation
b+-activity: prediction b+-activity: measurem.
Hypothesis on the reason for the deviation from the treatment plan
Dose recalculation
Modified CT Original-CT
Original-CT Modified CT
Interactive CT manipulation
New CT CT after
PET findings
Parodi Ph.D. Thesis, 2004; Enghardt, Parodi et al, Radiother Oncol, 2004
Indirect PET-guided dose quantification
Indirect estimation of 12C dose deviation from in-beam PET
g-emission
12C
Parodi et al PMB 2002, Parodi et al IEEE TNS 2005
PET monitoring of proton therapy?
Ap ~ 3 A12C
at same range and dose
(but ~102 lower than in nuclear
medicine PET for typical
therapuetic ion doses)
12C ions
11C, 10C
15O, 11C, ...
In-beam phantom (PMMA)
experiments at GSI
(A) (D)
protons
15O, 11C, ...
(A) (D)
Proton
(Projectile fragmentation only for Z>1)
g-emission
Offline PET/CT for scattered p therapy at MGH
Passive beam delivery at MGH Boston
Proton Irradiation… 14-20 min elapsed…
PET/CT @ MGH Radiology
Offline PET/CT
Only long-lived isotopes
(11C: T1/2 20 min
15O: T1/2 2 min)
Full ring tomograph
CT for co-registration
Phys. MC PET
Bq/ml
Clinical case of clival chordoma
Field 1: 0.87 Gy, DT1 ~ 26 min
Field 2: 0.87 Gy, DT2 ~ 16 min
Parodi et al Int J Rad Oncol Biol Phys 2007
Offline PET/CT for scattered p therapy at MGH
TPS
Field 1
Field 2
mGy
PET/CT Meas.
Bq/ml
MC dose
mGy
Range monitoring: possible in well co-registered low perfused tissues
Challenges: washout, S/N, and (extra-cranial sites) motion, registration
MC PET + washout
Bq/ml
# of patients Dose / field [GyE]
head 12 0.9-3
eye 1 10
C-spine 3 0.6-2.5
T-spine 1 1.8
L-spine 2 0.9-2
sacrum 2 1-2
prostate 2 2
TOTAL 23 0.6-10
Offline PET/CT clinical experience at MGH
Parodi et al, IJROBP 68, 2007; Knopf, Parodi et al, PMB 54, 2009; Knopf, Parodi et al, IJROBP 72, 2011
Direct PET-guided dose quantification Mathematical formalism towards dose deconvolution in proton therapy
Planned dose Filter-PET
11C activity
+ washout
Convolution with filter functions (cross-section dependent)
Deconvolution would enable direct dose quantification from measured
PET images, but issue of statistical noise, washout, motion
Parodi and Bortfeld PMB 2006; Parodi et al AAPM 2006; Attanasi, … Parodi … IEEE 2009
Need for improved imaging strategies
MC-PET
(offline PET/CT scan)
b+-activity
+ washout
Short delay DT improves S/N, reduces washout
Short scan time tmeas minimizes motion artifacts
and maximizes patient throughput
Towards better imaging strategies
Shakirin, … Parodi … PMB 2011; Parodi et al IJROB 2008; Parodi et al NIMA 2005
But optimal solution depends on
Development and integration efforts
Patient throughput in treatment room
Beam macro- and micro-structure
Worldwide active research on novel
dedicated in-beam PET scanners
Time in s
Beam on (noise)
Beam off (PET signal)
-200 -190 -180
Single g-RF time correlation experiments at GSI
Random correction failure due to „prompt“
(sub-ns) radiation correlated with RF (problem even worse for cyclotron)
Dedicated data acquisition needed (Enghardt, Crespo, Parodi, Pawelke, patented)
Distance between two opposing detector heads of 30 - 100 cm
Icentric rotating of 0 -360 deg.
Position resolution of 1.6-2.1 mm FWHM
Detection area of 164.8×167.0 mm2
Novel PET systems for in-room imaging
Courtesy of T. Nishio NCC Kashiwa, Nishio et al IJROBP 2010
Dual-head scanner mounted on rotating gantry in Kashiwa, Japan
- Planar imaging starting immediately after end of irradiation (cyclotron)
- A(r) ≠ D(r): Daily measurement compared to reference activity (reproducibility check)
Planning dose daily activity Reference activity
Similar finding as for GSI (e.g., detection of anatomical changes)
- > 50 patients of H&N, Liver, Lung, Prostate and Brain from 2007/10
Closeby PET/CT at HIT Heidelberg
Newly installed PET/CT next to the treatment rooms
Tx room
Tx room
Tx room
PET/CT
Biograph mCT
Combs,…, Parodi MIRANDA clinical study; Visualization / Analysis tools within BMBF project DOTMOBI
Establishment of clinical workflow at HIT
Adaptation of MC to handle facility-, patient- and
plan-specific information for automated dose calculation
Extension / validation of MC
for calculation of
b+-emitter yields
Unholtz, …. Parodi, DGBMT 2010; Bauer, …., Parodi, PTCOG 2011
Sommerer et al, Rad Oncol 2010
supported by EU-project PARTNER
Merging MC utilities for
patient calculations
of dose and PET
GUI for automated simulation
data management,
visualization,
data exploration and analysis
Establishment of clinical workflow at HIT
Unholtz, …. Parodi, DGBMT 2010; Bauer, …., Parodi, PTCOG 2011
Implementation realized via
„SimInterface“
(Software developement within the BMBF DOTMOBI project)
Towards 4D PET-guided in-vivo verification
Static absorber
Dynamic wedge
Moving target
(PMMA)
Motion sensor
Dipole magnets
Parodi et al Med Phys 2009, in collaboration with GSI (Bert), FZD (Enghardt), SAG (Rietzel), patent pending
12C ion tracking experiment with time-resolved in-beam PET at GSI
Planned dose
Planned delivery of homogeneous extended dose
Irradiation to static (ref.) and moving (~3cm in 1.5s) target
Correlation of dynamic PET acquisition with motion
Target
Absorber
Wedges
Moving
platform
12C beam PET
Dipole magnets
Static absorber
Dynamic wedge
Moving target
(PMMA)
Motion sensor
Proof-of-principle of 4D in-beam PET
Static reference
3D PET (motion uncorrected) m
oti
on
Static reference
3D PET (motion uncorrected) 4D co-registered PET
Ongoing / planned investigations
Experiments at GSI / HIT to compare in-
beam vs offline PET for monitoring of
motion-mitigated ion beam delivery
(gating, tracking,…)
Explore benefits from advanced internal
motion sensors (ultrasound-based)
Extrapolation to clinical cases
Parodi et al Med Phys 2009; collaboration HIT/GSI/FZD/Siemens/Mediri funded by EU Project ENVISION
4D co-registered PET
mo
tio
n
Real-time prompt gamma imaging
Testa et al, Applied Physics Letters 93 (2008)
Carbon ions in PMMA
Protons in water
Experimentally verified correlation
between 90 angled prompt g profiles
and p / 12C ions ion range
g-emission nf ≈0
g-emission g-emission (“prompt”)
≠ annihilation
(Z>1) 12C or p
Promise of real time in-vivo range
verification insensitive to washout
Challenge of efficient detector solution
(Anger or Compton camera)
=> Next talks!
Pre- (intra-?) treatment ion-based imaging Imaging residual range of high energy transmitted ion beams for
- Validation of CT-range calibration curve
- Assessment of range variations in motion cycle
- Low dose verification of patient position at the treatment site
Pioneered since the 60’s, but no routine clinical application yet
Issue of high energies required and Coulomb scattering (esp. for protons)
Several groups are now working on
small scale systems based on (single)
ion tracking and residual range
measurement via range telescopes or
thick energy detectors
Major efforts towards tomographic
imaging to eventually replace X-ray
CT for treatment planning
Proton radiograph of a phantom measured
with in-house developed prototype at PSI
Schneider et al 1990s, www.psi.ch (Paul Scherrer Institute, Switzerland)
Towards ion radiography / tomography at HIT
• Scanning 0°-180° in steps of 5° 12C pencil-beam 400 MeV/u
3.5 mm Gaussian FWHM
5 x 106 pps
• PMMA phantom D=160 mm
tissue equivalent rods d=28mm
• Multi-channel electrometer
electronics highly integrated
Proof-of-principle 12C
Heavy Ion Tomography
Rinaldi Ph.D. research at HIT/DKFZ (in collaboration with B. Voss, GSI); Voss et al GSI Report 2010, in press
• Simple 2D back-projected
reconstruction
Stack of ionization chambers
(Voss et al, GSI) with new
electronics
Post-treatment magnetic resonance imaging
Radiation induces fatty tissue replacement of vertebral bone marrow
Krejcarek et al IJROBP 2007
Pre-Tx MRI Planned dose Post-Tx MRI (1 month)
Investigations on using this signal as range indicator of TOTAL dose
delivery (not for single fraction) for population-based assessment
The time scales of in-vivo imaging
techniques for in-vivo range verification Time Irradiation
Pre-treatment (-DT ~ min)
Radioactive ion (RI) beams
Ion radiography / tomography
DT
In-beam „real-time“ (DT << ms)
Prompt gamma, emitted particles
In-beam „delayed“ (DT ms - min)
Positron-Emission-Tomography (PET)
Shortly after treatment (DT ~ 2 – 10 min)
In-room or nearby PET(/CT)
Long after treatment (DT ~ 10 – 20 min)
Offline PET(/CT)
Long after therapy (DT days - weeks )
Magnetic Resonance Imaging (MRI)
First or each fraction (Fx)
Each Fx
Each or
selected Fx
Selected Fx
Sum
of Fxs
Each Fx
Conclusion
Full clinical exploitation of ion therapy promises requires
In-vivo imaging of “surrogate” signal, e.g., from escaping secondary
radiation or physiological changes correlated to range / dose
Reliable computational tools for accurate modeling of the
“surrogate” signal in relation to the range / dose deposition
PET is a mature imaging technique for in-vivo treatment verification,
however technological / methodological improvements desirable
In-beam PET would be the method of choice but requires dedicated,
expensive instrumentation: industrial partners?
Alternative or complementary (time scales!) techniques based on
emitted / transmitted radiation or MRI under development / investigation
Outlook
R&D in modeling, detector development, exp. validation,
clinical integration, depending on beam production / delivery
(beam time structure, background radiation, …)
X-ray source
X-ray
imager
Ion gantry
Motion sensor
Transmission (ions, novel X-rays?)
(ions, novel X-
rays?)
Synergy between imaging for (real-time?) verification of
- Patient / tumour position (image-guided-radiotherapy)
PET Prompt g
- Range / dose delivery (towards dose-guided radiotherapy)
Thank you for your attention
The MC-modeling and in-vivo imaging research group at HIT:
J. Bauer, C. Kurz, A. Mairani (now CNAO), I. Rinaldi, F. Sommerer, D. Unholtz
The colleagues at HIT, Universitätsklinikum Heidelberg and DKFZ:
J. Debus, S. Combs, T. Haberer, O. Jäkel and Medical Physics Group
J. Engelke, M. Martisikova
Collaborators / former colleagues:
A. Ferrari, F. Cerutti, CERN Geneva
D. Schardt, C. Bert, B. Voss, GSI Darmstadt
T. Bortfeld, H. Paganetti, MGH Boston
W. Enghardt, F. Fiedler, K. Laube, HZDR Dresden
F. Attanasi, INFN Pisa
Funding:
FP7 EU Project PARTNER
FP7 EU Project ENVISION
BMBF Project DOT-MOBI
Acknowledgements
HIT Start of clinical operation on
15th November 2009
To date: > 400 patients treated