- 1. Prostate Cancer Radiotherapy: Image Guidance Patrick
Kupelian, M.D.Professor and Vice Chair University of California Los
Angeles Department of Radiation
[email protected] 2013
2. Prostate as a model for IGRTCLINICAL NEED:DOSE
ESCALATION:Smaller margins are a necessity (with or without
IMRT)HYPOFRACTIONATION:Increases the importance of individual
treatment accuracyCHANGES DURING THERAPY DO
OCCUR:Motion:SignificantDeformation: Minimal for the prostate gland
SVs / LNs problematicNATURE OF CHANGE: MOSTLY RANDOM(Unlike
anatomic changes due to tumor shrinkage, weight loss) 3. Image
Guidance MethodsDifferent Guidance Methods Generate Different Types
of Images 4. GUIDANCE TECHNIQUES Soft tissue imaging: Ultrasound CT
Large Inter / Intra user variability Fiducial based:X-rays CT
Electromagnetic 5. Implantation of metallic markers
Prep:Antiobiotics day before, am and pmEnema day of insertion
Insertion: Transrectal Ultrasound guidance(Biopsy probe) Needles:
18G needles Pattern: 3 markers (R base, L base, R apex) Time:5
minsShinohara et al.Technique for Implantation of FiducialMarkers
in the Prostate.Urology 71, 196-200, 2008. 6.
PROSTATE:MARKERPatients Markers Intermarker distanceSTABILITYnn
variationDehnad et al. 9 19 SD: 0.5 mmPoggi et al.9 45Mean: 1.2
mmSD: 0.2 mmAubin et al.7 21Mean: 0.01 mmSD: 0.87 mmLitzenberg et
al. 1030Range SD: 0.7 - 1.7 mmPouliot et al.1133Mean SD 1.3 mmRange
SD: 0.44 - 3.04 mmKupelian et al. 56168 Mean: 1.01 mmSD: 1.03
mmRange SD: 0.3 - 4.2 mm 7. IMPLANTED FIDUCIALS MV X-rays kV
X-rayskV Cone Beam CT Helical MV CT MV Cone Beam CT VISIBLE ON
X-RAY BASED IMAGING SYSTEMS 8. ARE IMPLANTED FIDUCIAL
REQUIRED?Megavoltage CT (MV CT)Cone Beam CT (CBCT)
TransverseTransverse CB CTMV CTSagittalSagittalMV CT CB CT 9.
Prostate alignment studyMVCT scans Radiation Therapist vs Physician
Alignment methods:Marker Anatomy Contours 3 patients, 112
scansLangen et al., IJROBP, 62, pp 1517 10. Therapist vs Physician
RegistrationDifferences 5 mmMarkerAnatomyContour A/P: 1 % A/P: 5 %
A/P: 17 % S/I: 2 % S/I: 10 %S/I: 31 % Lat: 1 % Lat: 0 %Lat: 3
%Markers decrease interuser variabilityLangen et al., IJROBP, 62,
1517, 2005 11. Marker LocationShould be representative of relevant
anatomy (prostate/rectum interface)Inadequate PlacementAdequate
Placement(Anterior)(Posterior) 12. Interfraction MotionGeometry
versus DosimetryDosimetric Impact of Motion 13. Interfraction
Motion Need for Daily Imaging?74 patients, 2252 fractions, all IGRT
with daily shifts.Replay different alignment strategies;Check
residual errors vs actual daily shifts.Significant proportions of
residual errors with any scenario.Example:Every other day imaging +
apply running average;Residual errors > 3 mm in ~40% of
fractionsResidual errors > 5 mm in ~25% of fractionsSignificant
random component: Need daily imaging Kupelian et al., IJROBP, 70:
1146, 2008 14. Interfraction Motion CorrectionsClinical Impact 15.
Interfraction Motion / Clinical ImpactChallenges to document
clinical impact: Endpoints: Cure; Long timeline, few events
Toxicity: Low number of significant events Dose
escalationImplemented Decreasing marginssimultaneously Image
Guidance Independent effect of image guidance?? 16. Image Guidance:
Avoiding Systematic ErrorsIMPACT ON CLINICAL OUTCOMES: TUMOR
CONTROLImpact of Rectal Distention at the Time of Initial
PlanningMDACCDutch Trialde Crevoisier et al, IJROBP, 62, 965-973,
2004 Heemsbergen et al., IJROBP, 67, 14181424, 2007 17. NO IMPACT
OF RECTAL DISTENTION ONRELAPSE FREE SURVIVAL IN PATIENTS TREATED
WITH IMAGE GUIDANCECleveland Clinic Rectal volume at simulation
Biochemical Relapse Free SurvivalN=4881 50 100 ccRectal volume.6on
Planning CT .4Med FU: 60 mos .2p=0.18 00 12 24 36 48 6072 8496Time
(months)Kupelian, IJROBP (70), 1146, 2008 18. TREATMENT MARGINS TOO
SMALL:INCREASED FAILURES ??Engels, IJROBP, 74: 388-391, 2009 19.
TREATMENT MARGINS TOO SMALL??N=2136 mm lateral, 10 mm otherwiseNo
guidanceN=25 3 mm lateral, 5 mm otherwise Fiducial/GuidancebNED at
5 years (median follow-up 53 months): No guidance (large margins):
91% Guidance (small margins):58% p=0.02On multivariate analysis,
biochemical failure predictors were; High Risk Group Low RT Dose
Rectal Distention Guidance (small margins) Engels, IJROBP, 74:
388-391, 2009 20. CHHiP TrialLocalized Prostate Cancer; N=30261st
randomization: Dose: 74 Gy at 2 Gy per fx vs 60 Gy at 3 Gy per
fx2nd randomization: Image Guidance:Image Guidance vs no Image
Guidance3rd randomization:Margins 21. INTRAFRACTION MOTION 22.
Prostate Real Time Motion StudiesAdapted from Ghilezan, IJROBP, 62,
406417, 2005Author (year)ObsMethodSampling Motion (mm)Kupelian
(2005)1157 Calypso 9-11 min >3 mm motion for >30 secs in 41%
Continuous>5 mm motion for >30 secs in 15%Ghilezan (2005)
18Cine MRI 1hr q 6 sec Range S.D.: 0.7-1.7Mah (2002)42Cine MRI9 min
q 20 s Range S.D.: 1.5-3.4Padhani (1999)55Cine MRI 7 min >5 mm
motion in 29%Khoo (2002) 10MRI 6 min q 10 s Range S.D.: 0.9
-1.7Kitamura (2002) 50Fluoro 2 min Range S.D.: 0.1-0.5Dawson (2000)
4 Fluoro 1030 sec Range S.D.: 0.95.3Malone (2000) 40Fluoro q 20
s>4-mm motion AP 8% SI 23%Nederveen (2002) 251Fluoro23 minRange
S.D.: 0.3-0.7Shimizu (2000)72Fluoro 9 min Median: AP 0.7, SI
0.9Vigneault (1997) 223EPID --No displacementHuang (2002)20US (2)
1520 min apart Range S.D.: 0.4 1.3 23. Intrafraction
MotionElectromagnetic Tracking (Prostate)Calypso
MicroposWirelessWirePermanent Removable 24. Kupelian, IJROBP, 67:
1088-1098, 2007HighContinuous TransientPersistent Frequency Drift
Excursion StableExcursionExcursion Erratic 25. MONITORING
INTRAFRACTION MOTION IN THE CLINIC Calypso, Electromagnetic
trackingClinical protocol: 3 mm threshold Realignment only between
beamsPatients N=29Fractions: N=963, mean= 33 /patientEvents:Mean
Frequency Range(indiv pt)No motion >3 mm, no intervention 59%
10-100%Motion >3 mm, transient, no intervention 14% 0-42%Motion
>3 mm, realignment between beams25% 0-85%MD disagree with
therapist intervention1%0-8% (interuser variability)Kupelian 2009
26. Intrafraction Motion: Dosimetric Consequence FRACTIONATION,
Cumulative doses, D95%MDACCO: N=16 patients, full course Prostate -
No Delay Pat. 15 Pat. 2a n g e fr o m p D95 Pat. 3%P DosechChange,
la n Pat. 40 Pat. 5 Pat. 6-5 Pat. 7 Pat. 8 Pat. 9 -10 e r ce n t
Pat. 10 Pat. 11 Pat. 12 -15 Pat. 13 Pat. 14 -20 Pat. 15 05101520 25
3035Pat. 16 Fract ion number Langen, IJROBP, 2009 27. Intrafraction
Motion: Dosimetric Consequence FRACTIONATION, Cumulative doses,
D95% MDACCO: WORST CASE (WORST INTRAFRACTION MOTION) P rostate -
Delay (Pat. 8) 5 Fractions 10P erc en t c h an g e from p la n %
Dose Change, D95 5 0 -5- 10- 15Cumulativedaily- 20- 25 0 510
15202530 35Fraction numberLangen, IJROBP, 2009 28. INTRAFRACTION
MOTION CLINICAL IMPACT 29. CORRECTION OFINTERFRACTION AND
INTRAFRACTIONMOTIONCLINICAL IMPACTAIM STUDY 30. Intrafraction
Monitoring Correction Clinical Impact?Assessing the Impact of
Margin (AIM) Reduction Study Sandler, et al. Urology:75(5):1004-8,
2010Acute toxicity comparison (PreRTand End of treatment QOL
scores):Group 1Group 2 (Historical control)Sanda et al., NEJM 2008
358(12) 1250-61EM tracking (Calypso)Guidance method, if any, not
reported (2 mm threshold:Institutional normsrealigned in 57% of
fx)3 mm post marginsVarying margins 5-10 mm81 Gy~ 75-80 GyN=64
patientsN=153 patientsIMRT, no hormonesIMRT, no
hormones2008-20092003-2006 31. Intrafraction Monitoring Correction
Clinical Impact?PreRT PostRT Difference (Post Pre)Benefit from
smaller margins oron EPICDomainStudyMeanEPIC Mean EPIC95% CI
Differencemotion management? DifferenceScoreScore AIM91.8 89.8
-1.9[-9.0, 5.1]Bowel / rectal NEJM94.4 78.5
-16.0[-19.4,-12.5]Control Urinary AIM84.5 80.6 -4.0 [-10.0, 2.1]
irritation /obstruction NEJM86.6 70.1 -16.5 [-19.8, -13.3]Control
Assessing the Impact of Margin (AIM) Reduction Study Sandler, et
al. Urology:75(5):1004-8, 2010 32. Reducing anatomic variations:
Intrarectal balloonImmobilization? Unclearvan Lin et al, IJROBP,
61, 278, 2005Court et al, RO, 81, 184, 2006Wang et al, RO, 84, 177,
2007Heijmink et al, IJROBP, 73, 1446, 2009Improve rectal dosimetry
/Decrease late rectal bleedingPatel et al, RO, 67, 285, 2003Teh et
al, Med Dosim, 30, 25, 2005van Lin et al, IJROBP, 67, 799, 2007 33.
DAILY POSITIONAL VARIATIONBALLOON VERSUS PROSTATE GLANDDay 53214
34. BALLOON: INTRAFRACTION MOTION DURING PROSTATE SBRTTime = 0 mins
+38 +28 +10 mins +18 +5 35. ENDORECTAL BALLOON: DECREASE IN
INTRAFRACTION MOTION?Nijmegen + MDACC Orlando: Smeenk et al. ASTRO
2010. Electromagnetic tracks in 30 patients 1143 tracks available
for analysis 15 patients without balloon 15 patients with balloon%
3D motion > 3 mm 20%No ERBBalloon decreases 15%but does not
10%eliminateERB5%intrafraction motion0%200500 1000Time (s) 36.
Deformation / RotationsDosimetric Impact 37. Interfraction Anatomic
Variations: Daily MVCTsAlignment on markersAlignment on mid gland
prostate ProstateProstate Seminal VesiclesSeminal VesiclesCourtesy:
Chester Ramsey 38. DOSIMETRIC IMPACT OF DEFORMATION DOSE
RECALCULATIONPlan TreatmentCHECK ISODOSE
LINESRECALCRECONTOUR:MANUAL OR DEFORMABLE REGISTRATIONCHECK DVHsDVH
39. DOSIMETRIC IMPACT OF INTERFRACTION DEFORMATION Legend Legend10
patientsRectumProstate D95Rectal volume @ 2 Gy (cc)70 Plan
Plan2.3Mean Mean60 SD SDMargins: Fraction D95 (Gy) Max2.250
MinMaxMin6 mm2.1404 mm Posterior302.0201.9400 daily
scans10Alignment on marker 1.8 01.7 12 3 45 6 7 8 9 10Recontours12
3 4 5 6 7 8 9 10 Patient PatientDose recalculationProstate:
Adequate coverageRectum: Large variations in some patientsKupelian,
IJROBP, 66, 876-82, 2006 40. DEFORMATION Challenge: Independent
movement of prostate vs nodesJ. Pouliot, From Dose to Image to
Dose: IGRT to DGRT, Panel on On-Board Imaging : Challenges and
Future Directions,ASTRO 49th Annual Meeting in Los Angeles, Ca,
Oct. 29, 2007.Xia et al., Comparison of three strategies in
management of independentmovement of the prostate and pelvic lymph
nodes. Med Phys. 2010Sep;37(9):5006-13. 41. Independent Motion of
Prostate vs NodesSolution: Dont Treat Pelvic Lymph Nodes!RTOG 9413
RTOG 94-13. N=1323. 4 group randomization.No difference between
Pelvis vs Prostate only RT Biochemical failure free survival
(Phoenix definition) Whole Pelvis Prostate OnlyLawton et al ,
IJROBP, 69, 646-655, 2007 42. GETUG Trial: Prostate only versus
Pelvic RT Pommier et al, JCO, 2007Low Risk High RiskProgression
Free Survival 43. FUTURE: REAL TIME RADIOTHERAPYAdjustments at the
time of delivery (similar to surgery) 44. Ultimate solution for
deformations; Real-Time Radiotherapy Assessment and adjustments:
Daily (all fractions) On-line Intra-fraction variations included
Deformable registration software Dose accumulation
(inter/intrafraction) Real-time adaptationX-rays / CT / PET / MRI
45. Real-Time Radiotherapy:Continuous soft-tissue imaging
withautomated plannning / delivery In-room MRI / MRI
guidanceViewRay system0.35 T on-board MRI 46. Pilot (Navigation)
Scans 20 sec Pilot Scan 47. Automatically Identify & Locate
Tissues 48. Predict Dose On Demand 49. Optimize On Demand 50. Track
Tissues & Control Therapy 51. Physicians Workstation: Overall
review and supervision 52. FUTURE: HYPOFRACTIONATION / SBRT
BOOSTING OF INTRAPROSTATIC LESIONSINCORPORTATING SBRT IN HIGHER
RISK CASESNORMAL TISSUE AVOIDANCE URETHRA RECTUM SUBSECTIONS / ANUS
ERECTILE TISSUES SPHINCTERS 53. TECHNIQUESELECTIVE INTRAPROSTATIC
BOOSTVSFOCAL THERAPY 54. CONCLUSIONSImage Guidance is necessary
with dose escalation.Assessing the dosimetric impact of radiation
deliverytechniques is important, particularly with
hypofractionation.Systematic errors during delivery (e.g. rectal
distention atsimulation) will introduce the most consequential
errors.The dosimetric impact of motion will differ in various
movingand deforming areas: e.g. tumor vs prostate vs SVs vs LNs.In
the future, real time adjustments might be necessary fortight
margin / large fraction treatments. 55. Prostate Cancer
Radiotherapy: Image Guidance Patrick Kupelian, M.D.Professor and
Vice Chair University of California Los Angeles Department of
Radiation [email protected] 2013
