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 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
PPM
Citrate levels ↓ with
prostate Ca
Cr
3
2
High
(choline+creatine)/citrate
ratio → Cancer
Citrate
Cho
Choline levels ↑ with
prostate Ca
Cr
Courtesy of Radka Stoyanova, Ph.D.
(original data from UCSF)
PPM
3
2
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 2year 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 1st 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
Good DVH
PTV95 % ≥ 100% Rx
R65 Gy ≤ 17%V
PTV95 = 100%
R40 Gy ≤ 35%V
B65 Gy ≤ 25%V
B40 Gy ≤ 50%V
FH50 Gy ≤ 10%V
R40 = 22.7%
R65 = 8.3%
R40 = 19%
B65 = 8.4%
Good plan example (axial)
100%
90%
80%
CTV
70%
60%
50%
“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
38cc prostate
3mm PTV
66cc prostate
3mm PTV
79cc prostate
3mm PTV
101cc prostate
3mm PTV
127cc prostate
3mm PTV
214cc prostate
3mm PTV
25
20.2
Percent of Rectum at 65 Gy
20
16.3
15
16.1
13.7
13.4
9.2
8.9
10
7
7.5
6.8
5.9
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
40.0
Average Values
Max Values
Min Values
Average Prescription 79.2 Gy (78-80)
Average Rectal Volume 50.4 cc (35.8-78.8)
36.8
Rectal Volume (%)
35.0
30.0
28.5
25.0
20.6
20.0
15.0
15.4
14.6
10.0
14.3
9.3
6.6
5.0
10
6.1
3.4
1.6
0.0
R40
R65
R75
Rectal Dose Cutpoints (Gy)
R80
Equivalent dose at 2Gy/fx
EQD2 = D[(d + ( / ))/(2 + ( / ))]
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
EQD2 are additive
If we limit the R65 to ≤ 17% Vol in 38-40 fxs our results
hold
/ = 2Gy (prostate); / = 4Gy (rectum)
10Gy boost → 30Gy @ 2Gy/fx (prostate);
76 + 30 = 106 Gy
Prostate
I
76 Gy, 68, 61, 53, 46, 38
S
Prostate
Boost
Target
Boost
Target
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}
Issues of note
-spillover dose into non-boost
prostate volume (will result in
increased overall dose at time of
composite plan generation)
Prostate
Boost
target
spillover
30 Gy, 27, 24, 21, 18, 15
-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 ( / prostate = 2.0
Gy)
-this plan cannot be used to
evaluate the rectum ( / rectum =
4.0 Gy)
Increased overall dose to both
targets:
106 Gy, 95, 85, 76, 65, 55
95% of Prostate PTV → ~84 Gy
(vs 76 Gy)
95 Gy
106 Gy
85 Gy
76 Gy
95% of Boost PTV → ~107 Gy
(vs 106 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
EQD2 → 61.86 Gy
limit
P
65 Gy
R
Volume-based scaling (initial plan)
P
With decreased margins
(3mm) ≤ 17% rectum
receives ~ 35.59 Gy in
38 fractions resulting in a
dose/fx of 0.9366 Gy.
R
Therefore EQD2 →
29.28 Gy (from the
rectum’s perspective)
35.59 Gy
Rectal DVH with PTV Change
100
PTV 5mm posteriorly (original)
PTV 3mm
PTV 3mm (rectum EQD2 scaled)
17% Rectal Volume
90
80
Prostate
Volume (%)
70
60
50
40
Rectum
3mm post
5mm post
margin
margin
17% rectal volume
30
20
10
0
0
10
20
30
40
Dose (Gy)
50
60
70
80
Rectal dose limit for boost plan
The 10 Gy boost plan yields 3.09 Gy to 17% of
the rectal volume
EQD2 → 3.65 Gy
29.28 Gy (EQD2 initial) + 3.65 Gy (EQD2 boost)
= 32.93 Gy; well below the 61.86 Gy limit
Composite plan: 32.91 Gy
Composite to 106 Gy
110
Prostate PTV
Prostate
Boost Target PTV
Boost Target
Rectum
100
90
Target data taken from composite
plan generated using prostate /
= 2.0 Gy
Percent Volume
80
70
60
50
40
17% Vol receiving 32.91 Gy
30
Rectal data taken from composite
plan generated using rectum / =
4.0 Gy
20
10
0
0
10
20
30
40
50
60
Dose (Gy)
70
80
90
100
110
120
Summary
Single fraction high dose boosts to the prostate should
be possible (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
Uncertainty of
Target Delineation
Setup Error
Highly Conformal
Radiation Therapy
Goals
Improve
Disease
Control
Patient and Organ
Motion
• Use reduced margins
Target
Deformation
Uncertainty of
Beam Delivery
System
Reduce
Complications
3D Localization Techniques for Prostate
Treatment
Skin Markers with portal image verification
Ultrasound images – BAT, I-BEAM etc.
In room CT/MRI -- CT-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-ray images with implanted
fiducial markers
Calypso 4D localization system with
Implanted Beacon transponders
Calypso® 4D Localization
System
Wireless
Wireless miniature
miniature Beacon
Beacon®®
Electromagnetic
Electromagnetic Transponders
Transponders
Accurate,
Accurate, objective
objective guidance
guidance for
for
target
target localization
localization and
and continuous,
continuous,
real-time
real-time tracking
tracking
Actual size:
Length = ~8.5mm
Diameter = 1.8mm
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 2
Step 1
Response Waveform
Resonator Current
Source Coil Current
Excitation Waveform
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 were then compared with the corrected Calypso
offset reading
Lateral
3
Difference (mm
2
1
0
-1
-2
-3
Longitudinal
Vertical
FCCC patients
Error of skin marker based prostate
localization
lat
long
vert
Setup errorr(mm
20
15
10
5
0
-5
-10
-15
Number of setup
L-R
I-S
P-A
FCCC patients
-1.6
-1.5
2.5
(mm)
2.3
2.6
2.1
σ (mm)
3.2
3.6
3.6
More than 65% of
patients had > 5mm
misalignment at setup
based on skin
markers
Mean (mm)
Beacon migration and prostate size change
Ratio of distance between transponders
Ratio
1.3
1.2
Apex-RB
1.1
RB-LB
1
Apex-LB
0.9
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
Apex-LB
Apex-RB
LB-RB
The First Treatment
0.97
0.97
0.99
The Last Treatment
0.94
0.92
0.96
FCCC patients; can
be >2mm
Intrafractional motion
Long
Vertical
Lateral
Long
Vertical
0.2
Offset (cm
0.8
0.6
0.4
0.2
0
-0.2
-0.4
-0.6
0
-0.2
-0.4
-0.6
-0.8
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
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)
Time (min)
Lateral
Long
Vertical
0.3
0.2
Offset (cm
Offset (cm
Lateral
0.1
0
-0.1
-0.2
FCCC patients
-0.3
0.0
1.2
2.4
3.6
4.8
Time (min)
6.0
7.2
8.4
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
14
Frequency(%
12
10
8
Mean= -1.5 degree
6
4
SD = 6.4 degree
2
0
-20
-16
-12
-8
-4
0
4
8
12
16
20
16
25
14
12
20
Frequency (%
Frequency (%
Rotation angle around the lateral axis (degree)
10
8
6
4
2
15
10
5
0
0
-10
-8
-6
-4
-2
0
2
4
6
8
10
Rotation angle around longitudinal axis (degree)
Mean= 0.0 degree, SD = 2.9 degree
-10
-8
-6
-4
-2
0
2
4
6
8
10
Rotation angle around vertical axis (degree)
Mean= -0.2degree, SD = 1.9 degree
FCCC patients
Translational Error Caused by Prostate Rotation
FCCC patients
∆x
Rotated contour (20
patients) and found
translational error when
matching to planning CT
θ
Translational Error (mm
9
8
7
6
5
4
3
2
1
0
-1 0
y= -0.0024x2 + 0.3226x- 0.0082
5
10
15
Rotation Angle (Degree)
20
25
30
How much does motion tracking help
during prostate treatment?
- Quantitative analysis of potential PTV reduction
Population-Based Margin
Calculation (CTV to PTV)
mPTV * = 2.0 +0.7σ + S
Total systematic error
=
2
del
+
2
int er
+
2
int ra
+
2
mtd
+
2
rot
+
2
bds
+L
Total random error
σ = σ 2 int er + σ 2 int ra + σ 2 mtd + σ 2 rot + σ 2 bds + L
Total mean
S = Sdel + Sinter + Sintra + Smtd + Srot + Sbds + …
* Stroom JC et al, Int. J. Rad. Onc. Biol. Phys 43(4) pp. 905-919,1999
With a criteria of D99 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
Offset (cm
Lateral
Long
Vertical
0.8
0.6
0.4
0.2
0
-0.2
-0.4
-0.6
1. Beam off (gated treatment)
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)
Long
Lateral
Vertical
0.2
0.2
0
0.1
Offset (cm
Offset (cm
Lateral
2. Move prostate back to the base
line by moving the table
-0.2
-0.4
Long
Vertical
0
-0.1
-0.2
-0.6
-0.3
-0.8
-0.4
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
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)
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
4D Tx +
Rotation Correction
5.5
4.5
5.3
4.3
7.8
4.9
8.3
5.3
9.0
6.0
7.6
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)
Left
5.2
Right
5.9
Sup
7.0
Inf
10.0
Ant
7.4
Post
10.6
5mm threshold (intra rotation not
considered)
5.2
5.9
7.1
9.6
8.0
9.3
3mm threshold (intra rotation not
considered)
4D Tx (additional uncertainty for
tracking added; MLC tracking,
couch)
5.3
6.0
7.4
9.1
8.2
8.7
5.5
5.3
7.8
8.3
9.0
7.6
4D Tx +
Rotation Correction (all uncertainties
added)
4.5
4.3
4.9
5.3
6.0
4.6
No intrafractional motion considered
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 thresholdbased 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.