1. IMRT: Where next?Image guided Radiotherapy Dr. A. W. Beavis PhD Principal Physicist,Hull and East Yorkshire Hospitals (NHS) Trust (Hon) Senior Research Fellow,University of Hull

2. Thank you for this honour!

Mme Naudy and the organisers of this training meeting

Great honour for me and my hospital to be invited back to speak on this course for a second time

Hope you enjoy my lecture!

www.hullrad.org.uk

3. IMRT is possible in any clinic!

Now have the weaponry to treat small volumes of tissues to high(er) doses

Need to develop the intelligence to find the tissue to target!

• Recall that target volume delineation is as bigger part of the prescriptionas defining the doses

Need to ensure we are treating the right tissues!

4. Limitation of current IMRT planning at PRH and world-wide

CT imaging does not show the position or viability of tumour

Solutions:

Advanced MR techniques

• Spectroscopy/ T2 mapping

• DCE

Also PET imaging

5. CMS:Focal FUSION used to fuse T2-weighted images with CT data set Use of T2 weighted images routine in our department for planning purposes 6. Can we just add images together from different modalities?

Do we expect the prostate on a CT scan from Monday to overlay on the prostate on an MR scan acquired the next Thursday?

No, because organs move, fill-up/ empty and generally try to confuse us!

Courtesy Di Yan, William Beaumont and Marcel Van Herk, NKI Amsterdam 7. GE Lightspeed CT-PET combined scanner Should we obtain images at same point in time? So we KNOW the anatomy is registered. 8. But just discussed organs move...?

So information about position and magnitude of motion is required

So in planning we either need to build in motion margins (ICRU50) or know precisely where each organ is during treatment

maybe stratify patients as good/ bad Conformal RT candidates

T = 0 T = t Z = z 1 Z = z 2 Z = z 3 9. PTV is an envelope within which the CTV is present with 100% certainty

Cannot assume any edge of the PTV is less at risk from being under-irradiated

DEFINE MARGINS CAREFULLY EVEN WITH ADVANCED IMAGING! + + 95% isodose = + 10. Where are we going?Image guided radiotherapy

Planning the treatment

11. Defining the Boost target in IMRT ?

Much interest in Magnetic Resonance Spectroscopy MRS for this purpose

• UCSF: Pickett et. al.IJROBP44 (4) 921-929 (1999) and references therein.

Look for decreased Citrate and enhanced Choline traces in the spectra

MRS is not simple to do and it is time consuming to perform necessary studies

12.

IMRT offers the capability to BOOST the dose to the actual tumour potentially increasing the tumour control probability

+?= PTV1: Prostate PTV2: Boost the conventional dose?? 55 Gy covering PTV1 65 Gy covering PTV2 PTV2is coveredby 60 Gy 13. Spectroscopy data for Peripheral Zone (PZ) Carcinoma and normal PZ data

Single voxel measurementsshowing normal PZ Citrate sample and that fordiseased (Ca.) tissue

tumour normal Choline Citrate Choline Citrate

• G.P. Liney et al. NMR in Biomedicine1239-44 (1999)

T2 image showing MRS sampled voxels 14. Tumor Necrosis Normal NAA Cr Cho Cho Combination ofMRI and 3D-MRSI >>> acquisition ofan image of spectra MR-Spectroscopy Imaging (MRSI) Courtesy of Prof. Lynn Verhay, UCSF 15. Voxel size 1cc MRSI 3D contours Abnormality-Index2 , 3 , 4 Courtesy of Prof. Lynn Verhay, UCSF 16. Our approach

Though our MR group has experience in single voxel MRS they opted for the use of T2 maps rather than expanding to multi-voxel MRS

• G.P. Liney et al. Proton MR T2 Maps correlate with the Citrate Concentration in the Prostate NMR in Biomedicine959-64 (1996)

T2 map is a plot of the absolute T2 value/ relaxation time (rather than signal intensity)

17. T2 map .v. spectroscopy (MRS)

Advantages:

• short acquisition time compared to MRS

• produces anatomical image withmmresolution

• • no need for registration to T2 weighted image

• modern scanners produces T2 map image as part of programmed sequence (Philips Intera 1.5T)

Disadvantage:

• dont see Choline data (not clear if this is important)

• biopsy false-negatives - blood and urine in Prostate will cause high T2 signal!

• Biopsy false-positives this high signal will fade with time (darken image) as fluid disperses

18. T2 maps:of volunteer and patient alternative to MRS and potentially directly applicable into RT planning.

T2 map ofhealthy volunteer with normalPeripheral Zone image

T2 map ofpatient with tumourin Peripheral Zone Dark area indicates disease

Advantages of T 2mapping over MRS:

short acquisition time compared to MRS

produces anatomical image withmmresolution (no registration needed)

Absolute T2 value .v. Citrate concentration

• G.P. Liney et al. NMR in Biomedicine959-64 (1996) Proton MR T2 Maps correlate with the Citrate Concentration in the Prostate

19. Dynamic contrast-enhanced-MRI

Gadolinium: Gd-DTPA

Shortens the T1 and T2 signal enhances image on a T1 weighted image

Basically, it enhances the signal from the dense vascularisation (and poor integrity) typical of neoplastic (tumour) tissue

Normal tissue does NOT enhanceas quickly

Relevant to most solid tumours

• Citrate chemistry is unique to prostate.

• G.P. Liney et al. NMR in Biomedicine1239-44. (1999)

Another method (relevant to more tumours): 20. 138 210 453 t = 0 Enhancement factor, EF(t) Tumour (volume) in PZ Benign disease in CG: BPH Normal tissue i.e. RHS of PZ shows no/little uptake T1 weighted imagesat different time intervals post contrast injection. Dont use rectal probe for Radiotherapy sequences! 21. Transfer of information into the Radiotherapy Treatment planning process 2 The data obtained from tracking the progress of the Contrast during the T 1scan (the DCE scan) can be analysed in several ways to extract spatial information to provide the treatment planning process. The simplest is tothresholdthe data set toidentify all pixelsthat enhanced above a certain (pre-determined) value. Plotof enhancement factor .v. time for aT 1 -DCEsequence obtained for a RT patient. A threshold analysis has identified those pixels in theshaded areaas being viable tumour 22. DynamicContrast-Enhancement

Acquire baseline images pre-contrast

Multiphase post-contrast

Uptake of tumour can be analysed

Parameter map produced

23. Threshold the pixels that indicate tumour, XiO/ FOCAL contouring tools can pick it out T2-Weighted FSE Imageoverlay generated from DCE analysis added on Can now contour the tumour without further expert Radiology knowledgeUse automatic contouring tools to pick these areas out and delineate them Transfer the information into the Radiotherapy Treatment planning system 24. Plot of enhancement factor .v. time 1 2 3 1 2 3 ROI 3 (orange) Dark bit of PZ on T2 image could have interpreted as tumour but DCE indicates its a benign problem T2 image with an overlaygenerated fromthe DCE fused on 25.

We are currently already performing (Radiology) DCE method on other sites

Working on their usefulness in Radiotherapy planning

DCE showed nodal involvement and chest wall/ muscle

infiltration not seen on planning CT performed 3 days previously

26. Summary of process 1

Obtain T 2weighted volumetric data set of images

Inject contrast

obtain a time series of T 1weighted images(at same location and resolution as above T 2set)

Analyse data and produce a parameter map providing spatial info of viable tumour

27. Summary of process 2

Fuse the parameter map and the T 2 weighted images to provide tumour and relational anatomy information

DICOM to FOCUS and in FOCALfusion register to planning CT

FOCALSim perform contouring

+ 28. Summary of process 3

Produce inverse plan in CMS: FOCUS/ XiO

Create a simultaneous boost IMRT plan

PTV1: Prostate PTV2: MRI delineateddisease (white = CTV) 60 Gy covering PTV2 52.5 Gy covering PTV1 29. Role of DCE in verification of (conventional) radiotherapy efficacy? Enhancement factor plots .v. time for a patientbeforeconventional radiotherapy. Plotsaftertreatment Plot of PSA level .v. time.Arepresents the time of the pre-Radiotherapy MRI-DCE scan andBthe post-treatment scan. A B A B 30.

Left handed 21 year old with a glioma in the left frontal lobe

T 2 -weighted fast spin-echo (TE/TR=100/3640 ms) 3D T 1 -weighted fast spoiled gradient-echo (TE/TR/flip = 4.2/13.4ms/20 0 )

fMRI acquisition (self-paced finger-thumb opposition with the right hand).T 2 * -weighted (TE/TR/flip=50/300 ms/90 0 )

Activation plot Functional MRI for conformal avoidance 31. 32. 7.2 % 29.6 % 34.6 % MC (IMRT_OAR) MC (IMRT_noOAR) MC (Conv) Dose Volume Histogram 33. Reproducibility fMRI Series 2 Series 1 Series 3 0.605 0.605 0.572 Correlation Coefficient 34. Repeated imaging on volunteers

Area highlighted is consistent with patient data

Intra session repeats show consistent data

Inter session repeats show consistency

Developing this further to create tests to feed probability density maps into inverse planning driven by biologically defined cost functions (EUD approach)

• Wiesmeyer and Beavis AAPM abstract

• ESTRO abstracts .

35. Conclusion

Inverse planning/ IMRT allows us to deliver different dose levels to multiple targets simultaneously

Using MRI - We are developing methods to enhance the identification of diseased sites and definition of boost target volumes for IMRT

Concentrating on Prostate, Brain and Head and Neck (YCR grant) but any solid tumour is possible!

36. Thanks to:

Dr. Gary Liney

Prof. Lindsay Turnbull MRI/ Radiology

My colleagues in Hull

Prof.Lynn Verhay - UCSF

Dr. Andrea Pirkzall - UCSF

CMS for their interest and financial support in our research work Also for funding my participation in this meeting