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Adapting radiotherapy usingpatient-specific biological imaging
Mike PartridgeAssociate Professor
Translational Techniques: Up and coming techniques in Medical Physics translated into preclinical and clinical practice.IoP, 80 Portland Place, London Monday 1st December 2014
Lots of technology
• 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
Jaffray, D. A. Nat. Rev. Clin. Oncol. 9, 688–699 (2012);
Personalized Radiotherapy Radiotherapy TodayThe fundamental aims of radiotherapy are independentof 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
Improved TargetingPre-treatment we can use imaging to:
– Better identify the target volume (18FDG PET, MRI, 4D CT)– Better identify radiosensitive normal tissues
Image Plan Treat
Improved DeliveryDuring treatment we can use imaging to:
– Improve day-to-day setup and delivery accuracy– Measure (and correct for) systematic changes in anatomy
Image Plan Treat
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Int J Radiation Oncology Biol Phys 60 1419-1424 (2004)
Fig 2, 3
CT PET Fusion
Target Definition: Head & Neck
I. J. Radiation Oncology Biol. Phys. 59 78–86 (2004)
FDG PET forvolume delineationin non-small-celllung cancer
T1N0M0 stage from CT
T1N2M0 stage from PET
PTVPlanning Target Volume
CTV
Clinical Target Volume
Volume DefinitionIn radiotherapy planning we define a number ofvolumes to account for uncertainties in the planningprocess:
GTV
Gross Tumour Volume
Where next?Use on-line imaging to reduce margins more andmore to allow dose escalation and normal tissuesparing.
– Yes, but with caution Int. J. Radiat. Oncol. Biol. Phys. 74, 388–391 (2009).
Continue to increase PTV dose with protons &carbon ions.
– Yes, but physical dose is not always the limiting factor.
Image every patient with every modality as manytimes as we can.
– Probably not …
CT PET SPECT MRI Linac ?
Oedema
Microscopicextension
Visible tumour mass
Hypoxic region
But tumours are heterogeneous
Necrotic core
Where next?Move away from delivery of a uniform population-derived dose to a (deliberately non-uniform) patient-specific prescription:
– Individualised iso-toxic dose– Biologically-guided using functional imaging– Stratified using gene expression profile
Monitor patient response during treatment to createbiologically 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
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Imaging in Radiation Oncology
Anatomical
Before During After
Targetdefinition
Diagnosis& Staging
Biologicallyadaptive
IGRT
Early Late
Functional
Adapted from a slide by Robert Jeraj
The challenge
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 targetii. dose escalate to a fixed level with a single functional
image defined targetiii. dose escalate to a fixed level with a multiple
functional image defined targetsiv. optimise plan using explicit radiobiological objective
function
? [Gy]
18F-FDG for boost target definition inlocally-advanced pancreatic cancer
Post80%
Post90%
Post60%
Post70%
Pre40%
GTV
Courtesy James Wilson and Maria Hawkins
MR-guided intraprostatic boost
H&E stained section Fresh slice + outline T2 MR + outline
Central gland (red)Tumour (yellow)Prostate (blue)
Diffusion coefficient map Spectroscopy voxels
Integrated area undergadolinium uptake curve
Dynamic coefficient Ktrans Dynamic coefficient Kep
Courtesy Sophie Riches, ICR
MR-guided intraprostatic boostChallenges:• Optimisation & validation of imaging (2 different
clinical trials)• Elastic matching of images pre/post hormone and
with/without endorectal probe (developed in-housesoftware)
• Developing optimum model to segment tumours(developed in-house software)
• Importing segmented template and matching withplanning CT (fiducial markers and in-house software)
MR-guided intraprostaticboost
T2W ADC T2map
Cho+Cr/Cit Ktrans IAUGC
Br J Radiol 2014;87:20130813
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MR-guided intraprostaticboost
T2W ADC T2map
IAUGC
Br J Radiol 2014;87:20130813
FDG-PET guided boost
PTV
FDG-PET guided boostIn radiotherapy planning we define a number ofvolumes to account for uncertainties in the planningprocess:
GTV
“BTV”
PTV
GTV
“BTV”
Same mean dose to PTV
Imaging Protocol & QA
• To ensure that images are consistent, carefulprotocols should be followed for:− Patient immobilisation− Time from injection to imaging (for PET)− Image acquisition protocol− Image processing− Segmentation
• These should be regularly checked usingphantom measurements.
• Nuklearmedizin 2012; 51: 140–153
Acquisition Protocol
H. Zhuang et al J. Nucl Med 42 1412-1417 (2001)
• PET image contrastchanges as afunction of time afterinjection.
• Different types oflesion show differentkinetic behaviour.
• A well-definedprotocol is essentialfor accurateoutlining.
CT DCE MR DW MR FDG PET T2 MR
So which one is the target?
Courtesy Ceri Powell & Kate Newbold
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Daisne Radiology (2004) 223, 93
Histopathological correlation Histopathological correlation
Eur J Nucl Med Mol Imaging (2013) 40:1828–1835
Study of 12 patients with head and neck cancer with 28 metastatic lymphnodes eligible for therapeutic neck dissection who underwent preoperativeFDG PET/CT.
Biological AdaptationUse the imaging to measure biological response totreatment and adapt individual patient treatmentsaccording to response:
Image Plan Treat Image Plan Treat
CT DCE MR DW MR FDG PET T2 MR
Early assessment of responsePre-treatment
Post-treatment
DW-MRI ADC changes at 2 weekspredicts response
Lambrecht et al.Radiotherapy and Oncology (2013)
Median ΔADC in poor responders was significantly lower than ingood responders 2 weeks into treatment (7% vs. 21%; p < 0.001).
Hoeben et al JNM 54 (2012) 532–540
baseline
baseline week 2
baseline week 2 week 4
18FLT as a predictor of response
Stratify by 45% decrease in SUVmax between baseline and week 2(patients treated with radiotherapy)
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Zips et al Radiotherapy and Oncology 105 (2012) 21–28
18FMISO PET as a predictor of response The RHYTHM trial as an example ofimaging biomarker development
• RHYTHM: modulation of Radiotherapy according toHYpoxia: exploiting changes in the TumourMicroenvironment to improve outcome in rectalcancer.
• Objectives: To define the best method of detectinghypoxia in rectal cancer and to develop a method ofdetecting changes in rectal tumour oxygenationduring preoperative chemoradiotherapy
BiopsyBlood sampleFMISO-PET
pCTdce-MRI rectum
Day ‒7: ‒1 0 10-12 6 weeks 8 weeks
Restagingdce-MRIrectum
BiopsyBlood sampleFMISO PET
pCTdce-MRI rectum
Radiotherapy planning feasibility study
RHYTHM-I: Group B
Daily radiotherapyand capecitabinetreatment (Mon-Fri)
Resection
Histologically confirmed locally advanced adenocarcinomaof the rectum: CRM threatened/involved
MRI FMISO PET / CT FMISO PET / MRI
Images before and after 10# RT
Images courtesy of James Wilson
Compare images or doses?Picking a single fixed threshold to define a biologicaltarget volume is hazardous:• Different thresholds give different volumes!• Threshold value changes with object size• Patters of uptake vary with time
Søvik Semin Radiat Oncol 20 138–146 (2010)
Spontaneous canine head and neck tumour treated with3.0 Gy per fraction.
DCE MRI-derived pO2
Optimal dosedistribution given the
above pO2
Compare images or doses?Solution – use doses not images
Søvik Semin Radiat Oncol 20 138–146 (2010)
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http://www.ucl.ac.uk/silva/nuclear-medicine/patients/PETMRschematic.png?hires
PET / MRI
Crijns & Raaymakers PMB 59 3241 (2014)
MRI / linac
Summary I
• Biological information already plays an importantrole in radiotherapy in staging
• It is playing an increasing role in assisting GTVdefinition
• A number of clinical trials are in progress testingfunctional image-guided “boosting” or doseredistribution.
Summary II
• Through observational trials we are learning howto use functional imaging as a quantitative andstandardised “biomarker” of response totreatment.
• This will allow patient-specific adaptation oftreatment according to response to therapy.
• The advent of the PET/MRI and the MR-LINACoffer the opportunity to get more and morepatient-specific biological information duringtreatment.
Challenges
• Knowing the best imaging modality to use andthe best time point to observe response (but stillhave time to intervene) for a particular diseaseand site needs more work.
• The link between functional image “signal” anddose-response is still largely unknown and raisesboth physical challenges (absolute imagequantification, standardisation and QA) andbiomedical challenges (clinical dose-responsestudies using heterogeneous prescriptions).
• There are safe and pragmatic ways to get startedwithout the above …
Acknowledgements
Tim MaughanMaria HawkinsJames Wilson
RHYTHM trial groupSamantha Warren