IGRT in Gynecologic MalignanciesArno J. Mundt MD

Professor and ChairDepartment of Radiation OncologyUniversity of California San Diego

La Jolla CA

Image-Guided RT?

“Image guided” is non-informativeRT has always been guided by imagesDefinition of IGRT is not standardized and is open to various interpretationsGlobal definition might include any aspect of RT involving imaging, from fluoroscopic simulation to CT-based planning, to weekly port films

RTOG Research Plan 2002-2006IGRT Committee ReportMichalski J, Purdy JA, Gaspar L, et al.

Int J Radiat Oncol Biol Phys 2001;51:60-5

“IGRT refers broadly to treatment delivery using modern imaging methods, such as CT, MRI, PET and Ultrasound, in target and non-target structures and in RT definition, design and delivery…”

“IGRT includes, but is not limited to, 3DCRT, IMRT, stereotactic radiosurgery, stereotactic RT, and brachytherapy….”

IntroductionRecommend a more focused definition

Highlight the 2 most important roles of imaging in modern RT:

Improved Target DelineationImproved Treatment Delivery

IGRT DefinitionUse of modern imaging modalities, especially those incorporating functional or biological information, to

augment target delineation

and

Use of imaging, particularly in-room approaches, to adjust for target motion and positional uncertainty,

and, potentially, to adapt treatment to tumor response

New FrontierImage-Guided Radiotherapy

Strong rationale in gynecologic tumors, particularly when IMRT is used

CT is not ideal for imaging tumors and normal tissues Gynecology patients often difficult to setupConsiderable organ motion existsTumors shrink rapidly

Target DelineationTraditional method planar (flouroscopic) x-raysExternal beam fields based on visualized bony anatomyContrast used to define normal tissuesBrachytherapy doses prescribed to specified “Points” based on applicator position

2D planning → Poor target coverage and excess normaltissue exposure compared to 3D planning

Red Journal2006

43 cervical cancer ptsEvaluated adequacy of coverage of pelvic vesselsSurrogate for lymph nodesAdequate: >15 mm vessel to block edge

41/43 (95%) inadequate coverage with 2D based fields24/43 (56%) too generous (> 2 cm)Excess normal tissue exposure

Beyond CT ImagingInterest now focused on more sophisticated imaging for treatment planning

Magnetic Resonance Imaging (MRI)With ultra-small iron oxide particles (USPIO)Positron Emission Tomography (PET)18F-Deoxyglucose (FDG)Or combined PET/CT units

Red Journal (2005)

Fe Oxide nano-particleTaken up in benign lymph nodes by macrophages

7 mm margin around vessels encompassed 99% of pelvic nodes

FDG-PET particularly useful to identify involved nodesBoost to higher doses with IMRT

Ahmed Red Journal (2004)PET+ nodes: 60 Gy/2.4 Gy fxPET- nodes: 45 Gy/1.8 Gy fx

Mutic Red Journal (2003)PET+ Nodes: 59.4 Gy/1.8 Gy fx

PET- Nodes: 50.4 Gy/1.53 Gy fx

More Advanced Imaging

Dynamic-Contrast MRI (tumor hypoxia)

Cooper et al. RadiotherOncol (2000)

1H-MR spectroscopy (tumor vs normal tissue)

Okada et al. J MRI (2001)Okada (2001)

Alternative PET TracersMetabolic Abnormalities or Hypoxia11C-Choline (tumor vs normal tissue)11C-Methionine (amino acid transport)60Cu-ATSM (hypoxia)

Torizuka J Nucl Med (2003)11C-Choline imaging

MRI FDG-PET 11C-Choline PET

Less uptake in normal tissues

Tumor hypoxia inversely correlated with DFS and OS3y PFS normoxic (71%) and hypoxix (28%)Could be used to dose paint during external beam and brachytherapy

Normal Tissue DelineationNovel imaging techniques also valuable for normal tissue delineation

Roeske (2003)MR-Spectroscopy to identify active(red) marrow sites

Roeske (2005)SPECT also useful for

active bone marrow delineation

SPECT-Guided BM Delineation

Roeske (2005)

T2* Pulse Echo MRI“Fat Fraction”

Used to differentiate between redand yellow marrow

Information then used to dose paintIMRT plans minimizing red marrowirradiation

Loren Mell MDUC San Diego

ASCO Young InvestigatorAward

Image-Guided Target DelineationBrachytherapy

Growing interest in using imaging to break away from Point AMost attention on MRI

Radiother Oncol (2006)

PET-Guided Brachytherapy

MalyapaRed Journal (2002)

Intravenous FDG+ FDG inserted into tandem and ovoids

Used to conform dose to shape of the cervix and uterusExcellent correlation with MRI

Image-GuidedTreatmentDelivery

Cancer Center Corridor

Strong RationaleImage-Guided Treatment Delivery

Patient setup is difficult

Tumors and normal tissues move

Tumors shrink

RationaleAll 3 issues are a problem for IMRTRapid dose gradients very unforgivingInaccurate setup, organ motion and regression all may lead to underdosageof the tumor and overdosage of the normal tissuesIGRT has the potential to overcome all three problems

Image-Guided Treatment DeliveryImaging Modalities

IGRT Technologies

UltrasoundBAT

SonArrayI-BeamRestitu

VideoVideo subtractionAlignRTPhotogrammetryC-Rad

VolumetricIn-Room CT (FOCAL)CT-on-Rails

Primatom, EXaCTTomotherapyMobile C-ArmSiemens (MVCT)Elekta, Varian (kVCT)

PlanarEPID

CyberKnifeNovalis

RTRTVarian, Elekta

Ultrasound-Based IGRTCervical Cancer

Little dataSurprising given popularity in prostate cancerBut useful for difficult implants

Good Bad

Video-Based IGRTCervical Cancer

No dataAppealing given ability to monitor intra-fraction patient position in real-time without x-raysClinical trial planned at UCSD

Align RT systemCeiling-mounted camerasReal-time 3D surface image

Popular in breast and lung cancer

Planar-Based IGRTCervical Cancer

Most studied IGRT approach in cervical cancerLong history using electronic portal imaging devices (EPID) to monitor patient setupMV image of bony anatomy or implanted markers

Antonuk (2002)

EPID-Based IGRTImplanted Fiducials on Cervix

Kaatee (2002)10 cervical cancer ptsRadiopaque tantalum markers on cervix

Used to track cervix positionImage quality good-excellent½ lost before end of RT

Red J (2000)14 gynecology ptsOn-line EPID IGRTBased on boney landmarksAction level > 4 mm

57% re-positionedAverage time ~ 3 minutesAcquisition and adjustment

↓PTV margins to 5 mm

Real-Time Tumor Tracking (RTRT)

Four sets of diagnostic x-raytubes and imagers

1.5 MHU x-ray tube and a fixedfloor-mounted collimator

Corresponding ceiling-mountedimager

Mitsubishi Electronics Co Ltd, Tokyo, Japanhttp://global.mitsubishielectric.com/

RTRT System

Harada (2002)

During treatment,2 of the 4 x-ray systemsTrack an implanted markerUsing motion tracking software

Tracking is continuous

If the marker coordinates arewithin a permitted distance,the beam is triggered on

Marker position calculated0.03 seconds

Green Journal (2004)10 gynecology patients with implanted fiducials

Necessary CTV-PTV margin using real-time RTRT tracking:6.9 mm (right-left), 6.7 mm (sup-inf), 8.3 mm (ant-post)

No data using other popular planar systems(CyberKnife, Novalis)

Planar-IGRT SystemsSeveral vendors have mounted kV sources on gantry opposite amorphous silicon (aSi) flat panel detectorsCapable of generating high quality kV planar imagesBetter image quality and less dose than EPIDEmerging data using both approachesNone focused solely on gynecology patients

Commercial Gantry-Mounted SystemsPlanar IGRT

Varian On-Board Imaging (OBI)www.varian.com

Elekta Synergywww.elekta.com

kV SourceEPID aSI Detector

Varian OBI planar-IGRT systemOn-line patient setup correction based on bony landmarksVariety of tumor sites including gynecologyFeasibleEntire process < 1 additional minute

Planar kV Commercial Systems

Planar IGRT On-Line Setup

Process FlowPlanar IGRT (Gynecology-Pelvis)

Day 1MD and RTTs meet at console

Discuss anatomy, special issues, etc.

Day 2 thru Completion

All shifts ≤ 1 mm LR shift > 15 mmSI or AP shift > 15 mm

Any concerns

Other shifts

Make no shiftsand treat Call MD

Make all shiftsand treat

Offer the potential to trackImplanted fiducials

Analogous to on-line techniques popularized in prostate cancer

Potentially useful to deliver a high dose conformal boost in patients unable to receive brachytherapy

Planar kV Commercial Systems

Volumetric-Based IGRTInterest is now turning to volumetricIGRTSeveral vendors offer volumetric solutions using the MV treatment beam

Tomotherapy, SiemensOthers generate kV cone-beam CT (CBCT) scans by reconstructing multiple planar kV images

Varian, Elekta

Volumetric-IGRTHigh quality kV CBCT scans can be producedUseful now to monitor target coverageIn future, opens door to adaptive RT

Planar KV Imaging Align boney anatomy(↓CTV-PTV margins around NodesGenerous margins around cervix)

↓Video Imaging Monitor Patient Position during Tx

↓Volumetric ImagingOff-line monitoring of target CoverageAdjust margins if necessary

On-Line Planar, Off-line Volumetric IGRTCervical Cancer

Day 1 Day 2

Day 3 Day 4

Day 5

Day 1

Day 3

Day 2

Day 4

Day 5

Day 3Day 4

Day 595%90%85%80%

Day 1 Day 2

Day 1

Day 3

Day 2

Day 4

Day 5

Volumetric-based IGRTCervical Cancer

Off-line monitoring of target coverage is very useful Particularly important if modest margins are used around the cervix and fundusWe used 1.7 cm marginsModifications are still common to ensure coverage

CBCT Cervical Cancer StudyMargin % Fx Volume Location(mm) CTV Missed Missed Fundus Cervix0 100% 45.3 cc 100% 95.2%3 98.7% 24.8 cc 89.0% 79.5%5 95.4% 20.3 cc 83.6% 65.1%7 87.2% 13.9 cc 71.2% 50.0%10 59.3% 9.3 cc 54.0% 35.6%15 32.1% 4.0 cc 24.0% 18.5%20 19.3% 1.7 cc 11.6% 10.9%25 14.0% 0.7 cc 7.5% 6.9%30 6.7% 0.3 cc 4.1% 0.7%

Image-GuidedAdaptive RT

Aerial View, Inner Garden and Cafe

Adaptive IGRTTumors shrinkAnd often quite quickly with chemotherapy plus RTShrinkage is a double-edged sword

Reduces the conformity of the

original plan

Reduces the chance of a

geographic miss

Tumor ResponseMany investigators have quantified the rate of response in cervical cancersUniversity of Utah used physical exam measurements and found by 30.8 Gy tumors reduced by 50%MD Anderson used weekly conventional CT and noted a mean reduction of 64%Others have used IMRT to better calculate tumor regressionLee et al. Red Journal 2005;58:625Beadle et al. ASTRO 2006Mayr et al. Am J Roentgenol 2006;187:65Van de Bunt et al. Red Journal 2006;64:189

14 cervical cancer patientsMRI prior to RT and after 30 Gy external beamGTV decreased (on average) by 46% Decrements in CTV and PTV were 18% and 9%

Does Re-Planning Help?Re-optimizing the IMRT plan at 30 Gyimproved the sparing of the rectumAverage rectal volume receiving ≥ 95% of the prescription dose

75 cc (range, 20-145 cc) (No Re-planning)67 cc (range, 15-106 cc) (Re-planning)P = 0.009

Improved bowel sparing seen in women with bulky (> 30 cc) tumors

Does Re-Planning Help?

Currently analyzing a large dataset of daily CBCT in cervical cancer patients undergoing IMRT and chemotherapy

Daily imaging data allows us to not only ask whether re-planning helps, but the optimal frequency and timing of re-planning

Adaptive IGRTMany technical obstacles stand in the way of adaptive IGRT, particularly if performed on-lineNew software tools: image deformation and automated segmentationBetter quality CBCT imagingNew rapid, accurate QA approaches

Adaptive IGRTOnce technical obstacles are overcome, numerous clinical questions remain

Does adaptive IGRT help? Does it hurt?Should it be performed on-line or off-line?How often should it be done? Weekly? Daily?

Such questions can only be addressed in carefully designed clinical trials

Bladder

Rectum

Tumor

Bladder

Tumor

Rectum

Week 1 Week 3

Adapt to What?

Adaptive IGRTNecessary tools being developed at UCSD in collaboration with the San Diego Super-Computer Center and Varian Medical Systems

On-Line Setup, Off-Line Adapt On-Line Setup, On-Line Adapt

Setup to Marks

On-LinePlanar IGRT

Deliver TreatmentReal-time Video

IGRT

Off-LineAnalysis

Re-Plan asneeded

On-LineCBCT

Re-plan if necessary

Deliver TreatmentReal-time Video IGRT

“Re-Plan If Necessary”Need to decide on the table within minutes!Not an simple taskCould involve target and normal tissue delineation, re-planning and evaluating potential benefitA more elegant solution may be to use the CBCT image itselfAnalyzed using Machine Learning

Machine LearningRapid Interpretation of 3D Image

Machine LearningRapid Interpretation of 3D Image

Yes Yes No YesYes No

Adapt????

On-Line AdaptationDeform simulation CT anatomy into all potential anatomical changesGenerate 1000+ IMRT plans using supercomputer computational powerImage patient on the table each day and select most similar planTreat with new plan

Daily Re-PlanningHigh speed computer processing is essentialNeed to move from sequential processing to parallel processingNever been applied to radiation oncology

1.5 M Grant Awarded

Acknowledgement

UCSDCome Visit!

= Original space (2 vaults, 1 CT sim)

Southbay

ProtonCenter

BasicScienceInstitute

Encinitas

MexicoColima