Download Lots of technology Personalized Radiotherapy Radiotherapy Today

Lots of technology
Adapting radiotherapy using
patient-specific biological imaging
Mike Partridge
Associate Professor
•
•
•
•
•
•
Linacs with on-board imaging
Cone beam CT
Tomotherapy, Cyberknife, Vero
Fluoroscopy
4D CT
Surrogates for breathing / implanted fiducial
markers
• Gating, tracking, ABC
• Functional imaging PET, SPECT, MRI
• Ultrasound
Translational Techniques: Up and coming techniques in Medical Physics translated into preclinical and clinical practice.
IoP, 80 Portland Place, London Monday 1st December 2014
Personalized Radiotherapy
Radiotherapy Today
The fundamental aims of radiotherapy are independent
of the technology we use:
– to deliver a high enough dose to control local tumour growth,
– to keep normal tissue toxicity within reasonable limits.
Image
Plan
Treat
Jaffray, D. A. Nat. Rev. Clin. Oncol. 9, 688–699 (2012);
Improved Targeting
Pre-treatment we can use imaging to:
During treatment we can use imaging to:
– Better identify the target volume (18FDG PET, MRI, 4D CT)
– Better identify radiosensitive normal tissues
Image
Plan
Improved Delivery
Treat
– Improve day-to-day setup and delivery accuracy
– Measure (and correct for) systematic changes in anatomy
Image
Plan
Treat
1
Target Definition: Head & Neck
FDG PET for
volume delineation
in non-small-cell
lung cancer
T1N0M0 stage from CT
Fig 2, 3
CT
T1N2M0 stage from PET
PET
Fusion
I. J. Radiation Oncology Biol. Phys. 59 78–86 (2004)
Int J Radiation Oncology Biol Phys 60 1419-1424 (2004)
Volume Definition
In radiotherapy planning we define a number of
volumes to account for uncertainties in the planning
process:
Where next?
Use on-line imaging to reduce margins more and
more to allow dose escalation and normal tissue
sparing.
– Yes, but with caution
Int. J. Radiat. Oncol. Biol. Phys. 74, 388–391 (2009).
Gross Tumour Volume
Continue to increase PTV dose with protons &
carbon ions.
Clinical Target Volume
Image every patient with every modality as many
times as we can.
– Yes, but physical dose is not always the limiting factor.
GTV
– Probably not …
CTV
PTV
Planning Target Volume
But tumours are heterogeneous
Visible tumour mass
CT
PET
SPECT
?
Move away from delivery of a uniform populationderived dose to a (deliberately non-uniform) patientspecific prescription:
– Individualised iso-toxic dose
– Biologically-guided using functional imaging
Necrotic core
– Stratified using gene expression profile
Oedema
Linac
Where next?
Hypoxic region
Microscopic
extension
MRI
Monitor patient response during treatment to create
biologically adaptive plans:
– Boost dose to non-responding sub-regions of tumours
– Reduce dose to well-responding areas
– Early prediction (& reduction) of normal tissue toxicity
– Intervene with radiosensitivity modulating drug
2
Imaging in Radiation Oncology
Anatomical
IGRT
Functional
Biologically
adaptive
Before
Diagnosis
& Staging
During
The challenge
? [Gy]
After
Early
Late
Target
definition
Adapted from a slide by Robert Jeraj
18F-FDG
for boost target definition in
locally-advanced pancreatic cancer
How could we use functional data for dose prescription?
i. don’t – dose escalate to a fixed (or iso-NTCP) level
with an anatomically-defined target
ii. dose escalate to a fixed level with a single functional
image defined target
iii. dose escalate to a fixed level with a multiple
functional image defined targets
iv. optimise plan using explicit radiobiological objective
function
MR-guided intraprostatic boost
Post90%
Pre40%
Post80%
Post70%
Post60%
H&E stained section
Central gland (red)
Tumour (yellow)
Prostate (blue)
GTV
Courtesy James Wilson and Maria Hawkins
MR-guided intraprostatic boost
Challenges:
• Optimisation & validation of imaging (2 different
clinical trials)
• Elastic matching of images pre/post hormone and
with/without endorectal probe (developed in-house
software)
• Developing optimum model to segment tumours
(developed in-house software)
• Importing segmented template and matching with
planning CT (fiducial markers and in-house software)
Integrated area under
gadolinium uptake curve
Fresh slice + outline
T2 MR + outline
Diffusion coefficient map
Dynamic coefficient Ktrans
Spectroscopy voxels
Dynamic coefficient Kep
Courtesy Sophie Riches, ICR
MR-guided intraprostatic
boost
T2W
ADC
T2map
Cho+Cr/Cit
Ktrans
IAUGC
Br J Radiol 2014;87:20130813
3
MR-guided intraprostatic
boost
ADC
T2W
FDG-PET guided boost
T2map
IAUGC
Br J Radiol 2014;87:20130813
FDG-PET guided boost
In radiotherapy planning we define a number of
volumes to account for uncertainties in the planning
process:
“BTV”
“BTV”
GTV
GTV
PTV
PTV
Imaging Protocol & QA
• To ensure that images are consistent, careful
protocols should be followed for:
−
−
−
−
−
Patient immobilisation
Time from injection to imaging (for PET)
Image acquisition protocol
Image processing
Segmentation
• These should be regularly checked using
phantom measurements.
• Nuklearmedizin 2012; 51: 140–153
Same mean dose to PTV
Acquisition Protocol
• PET image contrast
changes as a
function of time after
injection.
• Different types of
lesion show different
kinetic behaviour.
• A well-defined
protocol is essential
for accurate
outlining.
H. Zhuang et al J. Nucl Med 42 1412-1417 (2001)
So which one is the target?
CT
DCE MR
DW MR
FDG PET
T2 MR
Courtesy Ceri Powell & Kate Newbold
4
Histopathological correlation
Histopathological correlation
Study of 12 patients with head and neck cancer with 28 metastatic lymph
nodes eligible for therapeutic neck dissection who underwent preoperative
FDG PET/CT.
Eur J Nucl Med Mol Imaging (2013) 40:1828–1835
Daisne Radiology (2004) 223, 93
Biological Adaptation
Early assessment of response
Pre-treatment
Use the imaging to measure biological response to
treatment and adapt individual patient treatments
according to response:
Image
Plan
Treat
Image
Plan
Treat
Post-treatment
CT
DW-MRI ADC changes at 2 weeks
predicts response
18FLT
DCE MR
DW MR
FDG PET
T2 MR
as a predictor of response
baseline
baseline
Median ΔADC in poor responders was significantly lower than in
good responders 2 weeks into treatment (7% vs. 21%; p < 0.001).
Lambrecht et al.Radiotherapy and Oncology (2013)
week 2
Stratify by 45% decrease in SUVmax between baseline and week 2
(patients treated with radiotherapy)
Hoeben et al JNM 54 (2012) 532–540
baseline
week 2
week 4
5
18FMISO
PET as a predictor of response
The RHYTHM trial as an example of
imaging biomarker development
• RHYTHM: modulation of Radiotherapy according to
HYpoxia: exploiting changes in the Tumour
Microenvironment to improve outcome in rectal
cancer.
• Objectives: To define the best method of detecting
hypoxia in rectal cancer and to develop a method of
detecting changes in rectal tumour oxygenation
during preoperative chemoradiotherapy
Zips et al Radiotherapy and Oncology 105 (2012) 21–28
RHYTHM-I: Group B
Biopsy
Biopsy
Blood sample
Blood sample
FMISO PET
FMISO-PET
pCT
pCT
Daily radiotherapy
dce-MRI rectum and capecitabine dce-MRI rectum
treatment (Mon-Fri)
Images before and after 10# RT
Restaging
dce-MRI
rectum
Resection
MRI
FMISO PET / CT
FMISO PET / MRI
Radiotherapy planning feasibility study
Day ‒7: ‒1 0
10-12
6 weeks
8 weeks
Histologically confirmed locally advanced adenocarcinoma
of the rectum: CRM threatened/involved
Images courtesy of James Wilson
Compare images or doses?
Picking a single fixed threshold to define a biological
target volume is hazardous:
• Different thresholds give different volumes!
• Threshold value changes with object size
• Patters of uptake vary with time
Compare images or doses?
Solution – use doses not images
DCE MRI-derived pO2
Optimal dose
distribution given the
above pO2
Spontaneous canine head and neck tumour treated with
3.0 Gy per fraction.
Søvik Semin Radiat Oncol 20 138–146 (2010)
Søvik Semin Radiat Oncol 20 138–146 (2010)
6
PET / MRI
http://www.ucl.ac.uk/silva/nuclear-medicine/patients/PETMRschematic.png?hires
Summary I
• Biological information already plays an important
role in radiotherapy in staging
• It is playing an increasing role in assisting GTV
definition
• A number of clinical trials are in progress testing
functional image-guided “boosting” or dose
redistribution.
Challenges
• Knowing the best imaging modality to use and
the best time point to observe response (but still
have time to intervene) for a particular disease
and site needs more work.
• The link between functional image “signal” and
dose-response is still largely unknown and raises
both physical challenges (absolute image
quantification, standardisation and QA) and
biomedical challenges (clinical dose-response
studies using heterogeneous prescriptions).
• There are safe and pragmatic ways to get started
without the above …
MRI / linac
Crijns & Raaymakers PMB 59 3241 (2014)
Summary II
• Through observational trials we are learning how
to use functional imaging as a quantitative and
standardised “biomarker” of response to
treatment.
• This will allow patient-specific adaptation of
treatment according to response to therapy.
• The advent of the PET/MRI and the MR-LINAC
offer the opportunity to get more and more
patient-specific biological information during
treatment.
Acknowledgements
Tim Maughan
Maria Hawkins
James Wilson
RHYTHM trial group
Samantha Warren
7