Feasibility of 4D IMRT Delivery for Hypofractionated High Dose Partial Prostate Treatments R.A. Price Jr., Ph.D., J. Li, Ph.D., A. Pollack, M.D., Ph.D.*, L. Jin, Ph.D., E. Horwitz, M.D., M. Buyyounouski, M.D., C-M. Ma, Ph.D. Fox Chase Cancer Center, Philadelphia, PA *University of Miami Miller School of Medicine, Miami, FL
Proposed IMRT Dose Escalation Trial Intermediate Risk Stratify PSA Gleason ±STAD R a n d o m i z e SIMRT 76 Gy in 38 (2.0 Gy) fxs SIMRT + IMRT Boost Boost bulky tumor 76 Gy in 38 (2.0 Gy) fxs + 10 Gy Boost (single fraction)
Rationale Local persistence after RT remains a problem, even at high doses Confirmed by prostate biopsy Appears related to dominant lesion (hypoxia?) Builds on prior FCCC randomized trial
FCCC Experience with 10 Gy/fx In-house protocol; 46 Gy to pelvis (IMRT) 9.75-10.75 Gy HDR boost weeks 1 & 3 ~45 men over last 9 years <10% risk of rectal bleeding/urethral strictures Same short-term term side effects as IMRT
We need advanced imaging for Targeting (what part(s) ) of the prostate do we need to boost) Treatment Planning (we need to reduce PTV margins to stay below critical structure tolerances) Treatment Delivery (we need to know where the target(s) ) are during treatment delivery, e.g. tracking)
MRS of Prostate Citrate Cho Cr Citrate levels with prostate Ca PPM 3 2 Cho Cr Citrate Choline levels with prostate Ca High (choline+creatine)/citrate ratio Cancer PPM 3 2 Courtesy of Radka Stoyanova, Ph.D. (original data from UCSF)
MRS Correlate MRS findings with high tumor density regions prior to treatment planning May define based on palpation Additionally, use non-invasive MRS in lue of 2-2 year follow-up biopsy (initially we ll correlate results with biopsies)
Hypointense regions (indicative of Ca) choline choline citrate choline Courtesy of Radka Stoyanova, Ph.D.
Problems Limiting dose to rectum during the 1 st 76 Gy Limiting dose to rectum during the 10 Gy boost Evaluating rectal constraints during the planning of the 10 Gy boost Evaluating the rectal constraints of the composite plan
DVH Acceptance Criteria PTV 95 % 100% Rx R 65 Gy 17%V R 40 Gy 35%V B 65 Gy 25%V B 40 Gy 50%V FH 50 Gy 10%V Good DVH R 40 = 22.7% PTV 95 = 100% R 65 = 8.3% R 40 = 19% B 65 = 8.4%
Good plan example (axial) 100% 90% 80% 70% 60% 50% CTV Effective margin The 50% isodose line should fall within the rectal contour on any individual CT slice The 90% isodose line should not exceed ½ the diameter of the rectal contour on any slice
R65 with PTV reduction 25 38cc prostate 3mm PTV 66cc prostate 20 20.2 3mm PTV 79cc prostate 3mm PTV Percent of Rectum at 65 Gy 15 10 13.4 7 16.3 6.8 13.7 8.9 7.5 16.1 5.9 9.2 101cc prostate 3mm PTV 127cc prostate 3mm PTV 214cc prostate 3mm PTV 5 1.1 0 1 Theoretically, we can limit dose to the rectum by decreasing PTV margins & using Calypso beacons for active tracking
Prostate IMRT Rectal Values Rectal Volume (%) 40.0 35.0 30.0 25.0 20.0 15.0 10.0 5.0 0.0 36.8 28.5 15.4 20.6 14.6 6.6 Average Values Max Values Min Values Average Prescription 79.2 Gy (78-80) Average Rectal Volume 50.4 cc (35.8-78.8) 14.3 R40 R65 R75 R80 Rectal Dose Cutpoints (Gy) 9.3 3.4 10 6.1 1.6
Equivalent dose at 2Gy/fx EQD2 = D[(d + (α/β( ))/(2 + (α/β( ))] D = total dose given with a fraction size of d
Assumptions Overall tx time is relatively unchanged; 76 Gy in 38 fractions followed by a boost of 10 Gy in a single fraction EQD 2 are additive If we limit the R 65 to 17% Vol in 38-40 fxs our results hold α/β = 2Gy (prostate); α/β = 4Gy (rectum) 10Gy boost 30Gy @ 2Gy/fx (prostate( prostate); 76 + 30 = 106 Gy
Prostate S Prostate I Boost Target Boost Target 76 Gy, 68, 61, 53, 46, 38 76 Gy, 68, 61, 53, 46, 38
Boost 10 Gy, 9, 8, 7, 6, 5 10 Gy, 9, 8, 7, 6, 5 EQD2 = D[(d + ( / ))/(2 + ( / ))] = 30 Gy { / 30 Gy, 27, 24, 21, 18, 15 prostate 30 Gy, 27, 24, 21, 18, 15 = 2.0 Gy}
Prostate spillover 30 Gy, 27, 24, 21, 18, 15 Boost target Issues of note -spillover dose into non-boost prostate volume (will result in increased overall dose at time of composite plan generation) -there are systems that allow the optimization on previously delivered dose (what happens to the boost dose/fraction?) -compressed dose gradient has been used for critical structure sparing (rectum) -this plan is for evaluation of target(s) only (α/β prostate = 2.0 Gy) -this plan cannot be used to evaluate the rectum (α/β rectum = 4.0 Gy)
106 Gy, 95, 85, 76, 65, 55 Increased overall dose to both targets: 85 Gy 95 Gy 106 Gy 95% of Prostate PTV ~84 Gy (vs 76 Gy) 95% of Boost PTV ~107 Gy (vs 106 Gy) 76 Gy
Volume-based scaling (initial plan) Our normal PTV margins (8 & 5 mm) result in dose-volume limit of 17% rectum receiving 65 Gy. 65 Gy/38 fx = 1.71 Gy/fx EQD 2 61.86 Gy limit P R 65 Gy
Volume-based scaling (initial plan) P R 35.59 Gy With decreased margins (3mm) 17% rectum receives ~ 35.59 Gy in 38 fractions resulting in a dose/fx of 0.9366 Gy. Therefore EQD 2 29.28 Gy (from the rectum s s perspective)
Rectal DVH with PTV Change 100 90 80 PTV 5mm posteriorly (original) PTV 3mm PTV 3mm (rectum EQD2 scaled) 17% Rectal Volume 70 Prostate Volume (%) 60 50 40 30 Rectum 5mm post margin 3mm post margin 20 17% rectal volume 10 0 0 10 20 30 40 50 60 70 80 Dose (Gy)
Rectal dose limit for boost plan The 10 Gy boost plan yields 3.09 Gy to 17% of the rectal volume EQD 2 3.65 Gy 29.28 Gy (EQD 2 initial) + 3.65 Gy (EQD 2 boost) = 32.93 Gy; well below the 61.86 Gy limit Composite plan: 32.91 Gy
Composite to 106 Gy 110 Prostate PTV 100 Prostate Boost Target PTV Percent Volume 90 80 70 60 50 40 Target data taken from composite plan generated using prostate α/β = 2.0 Gy 17% Vol receiving 32.91 Gy Boost Target Rectum 30 20 Rectal data taken from composite plan generated using rectum α/β = 4.0 Gy 10 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Dose (Gy)
Summary Single fraction high dose boosts to the prostate should be possible (dosimetrically( dosimetrically) Important issues with targeting & radiobiology PTV reduction is necessary (but is a 3mm margin necessary? Remember, 17% of rectum at 32.91 Gy only)
Dose Escalation Barriers Goals Highly Conformal Radiation Therapy Use reduced margins Uncertainty of Target Delineation Setup Error Patient and Organ Motion Target Deformation Uncertainty of Beam Delivery System Improve Disease Control Reduce Complications
3D Localization Techniques for Prostate Treatment Skin Markers with portal image verification Ultrasound images BAT, I-BEAMI etc. In room CT/MRI -- CT-on on-rails and Cone beam CT, Tomotherapy,, cobalt machine with MRI Implanted Fiducial markers with OBI Implanted Beacon transponders with Calypso 4D localization system
4D Localization Techniques for Prostate Treatment Orthogonal X-rayX images with implanted fiducial markers Calypso 4D localization system with Implanted Beacon transponders
Calypso 4D Localization Wireless miniature Beacon Electromagnetic Transponders Accurate, objective guidance for target localization and continuous, real-time tracking Actual size: Length = ~8.5mm Diameter = 1.8mm System Beacon Electromagnetic Transponder
Clinical Procedure for Calypso Patient 1. MRI scan patient 2. Implant Beacon Transponders 3. CT scan patient at least a week later 4. Complete treatment planning, input isocenter coordinates and transponder coordinates into the Calypso system Medium frequency High frequency low frequency Unique Frequencies Identify Location
Electromagnetics Locate and Track Continuously GPS for the Body Step 1 Step 2 Excitation Waveform Response Waveform Source Coil Current Resonator Current Excitation Phase Ring Down Phase
Calypso System Prostate Localization Prostate rotation monitoring Prostate real-time motion tracking
Advantages and disadvantages of the Calypso system Advantages 4D, real-time tracking Localization Fast feed back Less operator dependence No additional dose Efficient workflow Can be used for gating Disadvantages Invasive implant Lack of anatomic information MRI artifacts Limited patient population Anti-coagulant or anti-platelet drug therapy Hip prosthesis, prosthetic implants Patients with large AP separation
Comparison with OBI for patient localization A. OBI images were taken when Calypso motion tracking was on B. Calypso readings were corrected by the amount of the average isocenter offset from morning QA results in the same period C. The OBI based-shifts shifts were then compared with the corrected Calypso offset reading Lateral Longitudinal Vertical FCCC patients 3 2 Difference (mm 1 0-1 -2-3
Error of skin marker based prostate localization lat long vert 20 Setup errorr(mm 15 10 5 0-5 -10-15 Number of setup L-R I-S P-A FCCC patients Mean (mm) (mm) σ (mm) -1.6 2.3 3.2-1.5 2.6 3.6 2.5 2.1 3.6 More than 65% of patients had > 5mm misalignment at setup based on skin markers
Beacon migration and prostate size change Ratio of distance between transponders 1.3 1.2 1.1 Apex-RB RB-LB Ratio 1 0.9 Apex-LB Apex-RB 0.8 RB-LB 0.7 Apex-LB 0.6 1 11 21 31 41 51 61 71 81 91 101 number of patients Ratio of intertransponder distance relative to the planning CT The First Treatment Apex-LB 0.97 Apex-RB 0.97 LB-RB 0.99 FCCC patients; can be >2mm The Last Treatment 0.94 0.92 0.96
Intrafractional motion Offset (cm 0.8 0.6 0.4 0.2 0-0.2-0.4-0.6 Lateral Long Vertical 0.0 0.9 1.8 2.7 3.6 4.5 5.4 6.3 7.1 8.0 8.9 9.8 10.7 Time (min) Offset (cm Lateral Long Vertical 0.2 0-0.2-0.4-0.6-0.8 0.0 1.2 2.3 3.5 4.6 5.8 7.0 8.1 9.3 10.4 11.6 12.8 13.9 15.1 Time (min) Lateral Long Vertical Offset (cm 0.3 0.2 0.1 0-0.1-0.2-0.3 0.0 1.2 2.4 3.6 4.8 6.0 7.2 8.4 Time (min) FCCC patients 3 patients 3 diff fractions
Intrafractional motion (775 fractions of 105 patients) Percentage of fractions that need intervention 29.3% for 3mm threshold 4.8% for 5mm threshold Percentage of time prostate is off the base line 13.4% for 3mm threshold 1.8% for 5mm threshold
Prostate Rotation Frequency(% 14 12 10 8 6 4 2 Mean= -1.5 degree SD = 6.4 degree 0-20 -16-12 -8-4 0 4 8 12 16 20 Rotation angle around the lateral axis (degree) 16 25 Frequency (% 14 12 10 8 6 4 2 0-10 -8-6 -4-2 0 2 4 6 8 10 Frequency (% 20 15 10 5 0-10 -8-6 -4-2 0 2 4 6 8 10 Rotation angle around longitudinal axis (degree) Rotation angle around vertical axis (degree) Mean= 0.0 degree, SD = 2.9 degree Mean= -0.2degree, SD = 1.9 degree FCCC patients
Translational Error Caused by Prostate Rotation θ x FCCC patients Rotated contour (20 patients) and found translational error when matching to planning CT Translational Error (mm 9 8 7 6 5 4 3 2 1 0-1 y= -0.0024x 2 + 0.3226x- 0.0082 0 5 10 15 20 25 30 Rotation Angle (Degree)
How much does motion tracking help during prostate treatment? - Quantitative analysis of potential PTV reduction
Population-Based Margin Calculation (CTV to PTV) m * = 2.0 + 0.7σ + S PTV Total systematic error = 2 del + 2 int er + 2 int ra + 2 mtd + 2 rot + 2 bds +L Total random error 2 2 2 σ = σ 2 int er + σ 2 int ra + σ mtd + σ rot + σ bds +L Total mean S = S del + S inter + S intra + S mtd + S rot + S bds + * Stroom JC et al, Int. J. Rad. Onc. Biol. Phys 43(4) pp. 905-919,1999 With a criteria of D 99 of CTV > 95% of the nominal dose on average
Geometrical Uncertainties 1. Delineation Error (C. Rasch et al) (del) L-R 1.7mm; S-I 2-3.5mm; A-P 2mm; 2. Geometrical Uncertainty of the beam delivery system (bds) bds = 0.5mm, δ bds = 0.7mm 3. Uncertainty of localization and motion tracking system (mtd) 4. Uncertainty caused by Beacon migration and prostate size change -- not included in the margin calculation 5. Geometrical Uncertainty Caused by Prostate Rotation (rot) 6. Setup residual error included in the intrafractional motion 7. Geometrical Uncertainty caused by intrafractional motion
Geometrical Uncertainty Including Intrafractional Motion and Resultant PTV Margins 105 patients with no intervention (mm) Mean (S) Left -0.05 Right 0.19 Sup 0.25 Inf 0.91 Ant 0.47 Post 0.55 (total) 2.12 2.12 2.94 2.94 3.02 3.02 σ (total) 1.66 1.66 2.88 2.88 3.19 3.19 Margin 5.3 5.6 8.2 8.8 8.8 8.8 How to reduce the effects of intrafractional motion?
Threshold-based Intrafractional Intervention Lateral Long Vertical Offset (cm 0.8 0.6 0.4 0.2 0-0.2-0.4-0.6 0.0 0.9 1.8 2.7 3.6 4.5 5.4 6.3 7.1 8.0 8.9 9.8 10.7 Beam Off Time (min) 1. Beam off (gated treatment) 2. Move prostate back to the base line by moving the table Lateral Long Vertical Lateral Long Vertical Offset (cm 0.2 0-0.2-0.4-0.6-0.8 0.0 1.2 2.3 3.5 4.6 5.8 7.0 8.1 9.3 10.4 11.6 12.8 13.9 15.1 Time (min) Offset (cm 0.2 0.1 0-0.1-0.2-0.3-0.4 0.0 1.2 2.4 3.7 4.9 6.1 7.3 8.5 9.8 11.0 12.2 13.4 14.6 Time (min)
4D treatments moving the couch and/or using DMLC 1. Correction of the translational error only 2. Correction of the translational error plus rotation
PTV Margins for Various Uncertainty Conditions 105 patients with/without intervention (mm) No intervention Left 5.3 Right 5.6 Sup 8.1 Inf 8.8 Ant 8.8 Post 8.8 5mm threshold 5.3 5.6 8.1 8.8 8.7 8.7 3mm threshold 5.3 5.6 8.0 8.5 8.8 8.3 4D Tx 5.5 5.3 7.8 8.3 9.0 7.6 4D Tx + Rotation Correction 4.5 4.3 4.9 5.3 6.0 4.6
Intrafractional motion (61 fractions of 7 patients who exhibited the largest intrafractional motion) The percentage time of prostate off the base line 41% for 3mm threshold 15% for 5mm threshold
PTV Margins 7 patients with/without intervention (mm) No intrafractional motion considered Left 5.2 Right 5.9 Sup 7.0 Inf 10.0 Ant 7.4 Post 10.6 5mm threshold (intra rotation not considered) 3mm threshold (intra rotation not considered) 4D Tx (additional uncertainty for tracking added; MLC tracking, couch) 4D Tx + Rotation Correction (all uncertainties added) 5.2 5.3 5.5 4.5 5.9 6.0 5.3 4.3 7.1 7.4 7.8 4.9 9.6 9.1 8.3 5.3 8.0 8.2 9.0 6.0 9.3 8.7 7.6 4.6
Conclusions Calypso 4D localization system is an accurate and convenient system for prostate localization and real-time motion tracking The prostate translational intrafractional motion is not a major contributor to the geometrical uncertainty for the general patient population and motion tracking during treatment plays a small role in treatment margin reduction. A small fraction of patients who have large intrafractional motion can benefit significantly from real-time motion tracking and threshold- based intervention. Effects caused by prostate rotation are more significant than the translational intrafractional motion. Rotation correction could help more on treatment margin reduction. One should use caution when reducing the treatment margins even with prostate motion tracking.