Purpose and goals of this symposium
Low Dose Rate Prostate
Brachytherapy Quality Assurance
• Present the rationale for prostate LDR brachytherapy
• Discuss critical physics components of the LDR
brachytherapy process map
and Treatment Evaluation
• Discuss their impact on quality assurance and treatment
evaluation
• Identify factors that require special attention in the
planning and execution of permanent LDR prostate
brachytherapy
Wayne M. Butler, Ph.D.
Zhe Chen, Ph.D.
Schiffler Cancer Center
Therapeutic Radiology Dept.
Wheeling Hospital
Yale University
Wheeling, WV
New Haven, CT
• Show how to implement quality assurance practices in an
LDR prostate brachytherapy program
2
Advantages of permanent seed
LDR prostate brachytherapy
The rationale for permanent
seed prostate brachytherapy
• Dose conformity and sparing of normal tissue
• Continuous low-dose rate irradiation
• Monotherapy dose sufficient to completely ablate
the prostate cancer cells
• One-time, out-patient procedure
• Treats extra-prostatic extension missed by radical
surgery
• Avoids EBRT issues of organ motion and setup
uncertainties
4
1,840 consecutive patients implanted 1995 — 2007
High biochemical survival translates into
high prostate cancer specific survival
(AV Taira et al., IJROBP, 2011, 79:1336-42)
(AV Taira et al., IJROBP, 2011, 79:1336-42)
Very high success rates for all risk groups
100
Low risk
80
60
Low risk
98.7%
98.7%
98.7%
Intermed. risk
96.3%
95.9%
95.9%
High risk
90.9%
90.4%
90.4%
Cause-Specific Survival (%)
Biochemical Progression-Free Survival (%)
100
p <0.001
40
20
80
60
99.8%
99.8%
Intermediate risk 99.7%
99.1%
98.0%
High risk
95.3%
95.3%
98.5%
99.8%
p < 0.001
40
20
0
0
0
2
4
6
8
Years Since Implant
10
12
14
0
16
5
2
4
6
8
10
Years Since Implant
12
14
16
6
1
For high-risk group, BTx biochemical
success rates are unequaled by RP or XRT
Why hasn’t prostate seed brachytherapy
swept aside the competition?
(Similar differences in intermediate-risk group)
• LDR implants have the lowest reimbursement and profit
margin
100
Progression Free Survival (%)
BTx + XRT, n = 390
80
• Not all brachytherapists are equally successful
AV Taira et al., IJROBP, 2011
• Operator dependent learning curve
MSKCC, 81 Gy IMRT, n = 32
60
ZA Alicikus et al., Cancer, 2011
Columbia U, Prostatectomy, n = 306
40
• Regulatory oversight of radionuclide applications are more
stringent than for XRT or surgery
• Each patient carries a permanent record of the implant
quality
R Korets et al., BJU Int, 2011
20
• Subtle complexities in LDR implants must be understood
0
0
2
4
6
8
10
12
14
7
Years
Total treatment costs from diagnosis to 5.5
years later for prostate treatments
Risk group (k$)
Treatment
Overall (k$)
Low
Intermediate
High
Brachytherapy
35
28
41
43
EBRT
60
49
57
73
Radical Prost.
37
33
35
54
Cryotherapy
43
32
33
54
Androgen Dep.
69
45
57
88
8
Technical complexities of low
energy brachytherapy
•
Rapid dose falloff of low-energy photon sources
•
Complex and diverse temporal dose delivery
patterns
•
Induction and resolution of procedure-induced
prostate edema
•
Inherent difficulties in radiation dosimetry for
low-energy photon sources
LS Wilson, et al., Cancer 2007, 109:518-527
9
Typical mono- and boost therapy doses and
seed strengths
Interstitial seed properties
Radionuclide
I-125
Half life (d)
59.4
16.99
9.65
73.8
27
21
29
380
0.96 – 1.04
0.69
~ 1.05
1.12
0.025
0.008
~ 0.035
2.5
Ave. Energy (keV)
Λ (cGy/h U)
½ value layer (mm)
10
Pd-103 Cs-131
Ir-192
Isotope
Pd-103
I-125
Cs-131
11
Therapy
Prescribed Dose
Seed strength (U)
mono
115 – 130
2.0 – 3.3
boost
80 – 110
1.2 – 3.0
mono
140 – 160
0.4 – 0.6
boost
100 – 110
0.3 – 0.5
mono
100 – 115
1.8 – 2.5
boost
70 – 80
1.6 – 2.2
12
2
Dose rate (cGy/day) as a function of time
since implant for monotherapy
Time to deliver relative fraction of
prescribed dose (mPD)
1
Cs-131
Pd-103
I-125
0.8
Cs-131 115 Gy
Pd-103 125 Gy
I-125 145 Gy
600
400
Relative mPD
Dose Rate (cGy/day)
800
0.6
0.4
200
0.2
0
0
0
30
60
90
120
150
180
210
0
30
60
Days since Implant
90
120
150
180
210
Days since Implant
13
14
Point source radial dose functions for
brachytherapy radionuclides
Anisotropy, F(r,θ), is considerably affected
by source construction
(Some variance due to vendor source construction)
(Cs-131 at r = 1 cm)
90
1.2
120
Radial Dose Function
60
Ir-192
1
0.8
0.6
150
30
0.4
0.8
Cs-131
0.6
0.2
180
0
0
0.4
Pd-103
F(θ
θ)
I-125
210
0.2
0
330
240
0
1
2
3
4
5
6
7
300
8
270
Distance (cm)
theta
15
Dose rate in Gy/h for a 1.0 U seed
of each radionuclide
Radial anisotropy functions, F(r,θ)
(Oncura model 6711)
1 .10
90
120
1
60
Dose rate (Gy/h)
anis 2 cm
180
— Cs-131
0
0
— I-125
10
30
0.5
3
100
anis 1 cm
150
16
anis 3 cm
— Pd-103
1
0.1
··· ISL
0.01
1..10 3
anis 7 cm
1..10 4
210
330
1..10 5
1..10 6
240
300
270
0
17
1
2
3
4
5
r (cm)
6
7
8
9
10
18
3
Dose rate in Gy/h for usual monotherapy
strength seed of each radionuclide
Interplay of radionuclide decay
rate and edema magnitude and
its resolution rate makes
implant quality uncertain
1000
100
— 2.0 U Cs-131
Dose rate (Gy/h)
10
— 0.5 U I-125
1
— 3.0 U Pd-103
0.1
0.01
When should the post-implant dosimetric
imaging be performed?
1 .10 3
1 .10 4
1 .10 5
1 .10 6
0
1
2
3
4
5
6
7
8
9
10
r (cm)
19
Exact analytic equation for the relative
dosimetry error (RE) in Dv due to edema at
any post implant CT date (t)
General characteristics of procedureinduced prostate edema
Prostate Volume
(F Waterman et al., IJROBP, 1998, 41:1067-77)
 1 + ∆ ⋅ e − λ ed t p 


edema evolution
Vmax
• Edema magnitude: ∆ = (Vmax–Vref)/Vref
Vref
•
≥ one month
RE =
V (t ) = Vref + [Vmax − Vref ]e − ( t −tmax ) / TE1 / 2
λ is ⋅
TE1/2 : Edema resolution half-life
−τ / 3
− λ is ⋅
e − λ is t
∞
∫ (1 + ∆ ⋅ e
0
e − λ is t
∞
∫ (1 + ∆ ⋅ e
0
)
− λ ed t τ / 3
)
− λ ed t τ / 3
dt
dt
~ 1 to 2 days
tmax
λed and λis are the edema and isotope decay constants
Time
tp is the time after implant for the “snapshot” CT evaluation
• Severity & resolution pattern vary widely from patient to patient
τ characterizes the isotope-specific dose falloff with radial
• ∆: from 0.2 to >1.0
distance, ~ r−τ
• TE1/2: from 4 to over 25 days
• It forces the implanted sources to vary from their planned locations
(Z Chen et al., IJROBP, 2000, 47:1405-19)
21
22
Maximum under- or overestimation for edema
magnitudes of 10% to 100% and edema half lives of
5 to 25 days for Pd-103
Mean absolute errors versus post implant
dosimetry CT day for Cs-131, Pd-103, and I-125.
(Z Chen et al., IJROBP, 2000, 47:1405-19)
(Z Chen et al., Med Phys, 2006, 33:968-74)
25
50
Relative Dosimetry Error (%)
Mean Absolute Dosimetry Errors (%)
Pd-103
40
30
20
10
0
-10
Maximum Relative Error
-20
Minimum Relative Error
-30
20
Cs-131
15
I-125
10
Pd-103
5
Mean Absolute Relative Error
-40
0
0
20
40
60
80
100
0
Post-implant Dosimetry Time (days)
20
40
60
80
100
Post-implant Dosimetry Time (days)
23
24
4
TG-137 suggested two time points for post
implant dosimetry CT or MRI
• At day 0 or day 1
What can go wrong?
• Logistically favorable for patient and staff
• Early feedback allows timely response to under- or overdose
• Prompt closure of learning loop while memory is still fresh will aid
future patients
• Edema makes implant appear cooler; effects of source migration are
not included
• At isotope-specific optimum dosimetry time
• 10-14 days for
131Cs,
15-21 days for
103Pd
and 35-45 days for
125I
• This may encourage procrastination
• The NRC may define a medical event as failure to obtain post
implant dosimetry within 60 days
25
Basic components of LDR prostate implant
98 seeds implanted, 0 in the prostate
(Limbs and branches where things can go wrong —
details of twigs and leaves not shown)
(Brachytherapist attributed this to seed migration
and did not report this as a medical event!)
TPS
Commission
Patient
selection
Algorithm
validation
PTV margin
Geometric
alignment
Delivery verification
Dose criteria
Preloaded needle
verification
Timing
Imaging resolution
Probe alignment
Strength assay
Leakage test
Imaging
Imaging modality
Equipment
Commission
2 seeds
in penile
shaft
Source delivery
RT history
Tx prescription
Source
handling
penile bulb
Targeting
Planning approach
Loose or strand source
Source
modeling
prostate
Source
Implantation
Pre-implant
Planning
Physician
Consult
Pre-implant
volume study
Ordered vs shipped
Source
Preparation
Interpretation
Source
loss/migration
Timing
Post-Implant
Dosimetry
rectum
27
28
U Penn, which ran the Philly VA program, also
harmed seed brachytherapy in 1998 with their
results for hormone naïve high-risk patients
Philadelphia VA medical events
• Two brachytherapists performed 114 prostate
implants from 2002 – 2008
100
80
bNED Survival (%)
• 97 implants were cited by the NRC as medical
events
• The VA used no outside evaluations
• No post-op dosimetry for last three years
• Some were clearly wrong organ treated
High-risk patients, n = 18
60
40
20
AV D’Amico et al., JAMA, 1998, 280:969-974
• Some of the ME’s identified by the NRC were based on
a new dosimetry regulatory proposal
1
29
2
3
4
5
Time (Years)
6
7
8
9
10
30
5
Why did their high-risk prostate cancer
patients have such poor outcomes?
High risk prostate cancer, comparative
brachytherapy outcomes
(N Bittner et al., Oncology, 2008, 22:995-1004)
100
• Inexperience, still on early learning curve
Merrick
bNED Survival (%)
• Low total implanted activity
• No periprostatic treatment margins
• Absence of post-implant dosimetry
• Inadequacy of brachytherapy technique
• Prostate base and anterior gland intentionally spared
• Failure to use fluoroscopy in the O.R.
80
60
Sylvester
Blasko
40
20
D’Amico
• Small patient population
• High risk men have greater likelihood of subclinical distant mets
Dattoli
Stock
N Bittner et al., Oncology, 2008, 22:995-1004
0
0
2
4
6
8
10
12
14
16
Years since Implant
31
32
The NRC lists 53 non-VA prostate
brachytherapy medical events
• 20 gross target misses or wrong target treated
•
9 wrong strength seed used
•
3 shipping errors
Source preparation and calibration
• 11 leaking sources (mostly Mick jams)
•
8 reports of lost seeds
•
1 prescription error (monotherapy vs. boost)
•
Physicist responsibilities
1 wrong patient (plan for I-125 but implanted with the
next patient’s Pd-103 plan, modified)
33
95% confidence level vs. number of
seeds assayed for various distributions
• TG-138 has reported total brachytherapy source dosimetry
uncertainty < 5%
(LA DeWerd et al., Med Phys, 2011, 38:782-801)
• AAPM Working Group report
(WM Butler et al., Med Phys, 2008, 35:3860-65)
• Although manufacturers or remote 3rd parties may provide
detailed calibration services, the local physicist must still
perform a sample assay
Percent Strength Deviation
of Assayed Source Distribution
18
95% Confidence Level (%)
Physicist responsibilities recognize
uncertainties and chain of custody
15
—— 10 %
12
—— 5 %
9
—— 1 %
6
3
• Assay must use equipment appropriate to the type of source
0
• Equipment must have secondary traceability to NIST
0
5
10
15
20
25
30
35
40
Number of Sources Sampled for Assay
35
(NJ Yue et al., Med Phys, 2007, 34:1975–1982)
36
6
Action level thresholds
Relative strength histograms for all seed
models have 95% CI (k = 2) < 10%
1,200
Source strength used in planning may be either the
manufacturer’s or the user’s
Sample size for source Mean diff.
mfr. vs.
assay by end-user
user
physicist
Mean = 1.00
Pd-103
Std. Dev. = 0.01
≥ 10% but < 100% of
order, or batch
measurements of
individual sterile strands,
cartridges or pre-loaded
needles
1,000
Frequency
n = 3,277
800
600
400
200
Action by end-user medical physicist
≤ 3%
Nothing further
> 3%
Investigate source of discrepancy or
increase the sample size
> 5%
Consult with manufacturer to resolve
differences or increase the sample size.
For assays performed in the OR, consult
with the radiation oncologist regarding
the consequences of proceeding with
the implant using the measured source
strength
0
0.94
0.96
0.98
1.00
1.02
1.04
1.06
Deviation from Mean
37
38
Actions to be taken by the end-user
institution physicist: single seeds
Sample size for
assay of sources
by end-user
medical physicist
Difference of
mean from
manufacturer’s
certificate
Individual source as
part of an order of >
10 sources
≤ 6%
> 6%
Confusion over source strength
labeling has caused significant
treatment errors
Action by end-user medical
physicist
Nothing further
Consult with the radiation oncologist
regarding use: dependent on the
radionuclide, intended target,
source packaging, and the
availability of extra sources
For orders of ≤ 10 sources, the tolerance threshold is 5%
39
Not all vendors use the same units for
seed strength
VariSeed calculates mCi value as U is
entered, and vice versa
Use that as a 2nd check on your physics worksheet
• Some source manufacturers specify seed strength in U and
others in mCi
• Mislabeling will produce ~ 30% error
• Virtually all low dose rate seed brachytherapy treatment
planning uses TG-43
• Source strength, Sk, specified in U
• Dose rate constant, Λ, in cGy/h U-1
• Treatment planning systems allow use of either U or mCi
41
42
7
Commissioning a procedure is
the most important quality
assurance activity
43
Commissioning brachytherapy — Treatment
planning system:
Verify the source calculation algorithm
• Planning system vendors provide user tests for
acceptance
Publicly available AAPM guidance
documents and reports
• TG-40
(1994)
– General radiotherapy QA
• TG-64 (1999) – Permanent prostate seed
brachytherapy
• Better to hand calc from the original TG-43
update documents
• Assign line and point source exercise to students each
year
• TG-43u1 (2004) – Protocol and data for
brachytherapy dose calculations
• LEBSC Working Group (2008) – 3rd party
calibrations and physicist responsibilities
• TG-137 (2009) – Dose prescription and reporting
methods for prostate BTx
45
46
Sample: Calculate point dose at 1.5 cm
from a 200 U 103Pd Model 200 source
Limitations of the TG-43 protocol
• Water is not the same as tissue
• At low photon energies, the mass energy absorption
coefficients are strongly composition dependent
• Absorbed dose of tissue/water may differ by >20%
• At low photon energies, the mass attenuation
coefficients are strongly density dependent
• Attenuation of tissue/water may differ by 10%
• No accounting for calcifications
• No accounting for interseed shielding
47
48
8
Find the radial dose function value
Find the anisotropy value, 0.8625
49
50
Complete the point dose calculation
for dose rather than dose rate
r 
Dose = Sk ⋅ Λ ⋅ g p (r ) ⋅ φan (r ) ⋅Tave ⋅  0 
 r 
Dose = 200U ⋅ 0.686
How to minimize source errors
2
16.991d × 24h / d  1cm 
cGy
⋅ 0.755 ⋅ 0.8625 ⋅
⋅

h ⋅U
ln 2
 1.5cm 
2
•
Errors in source input can be reduced by having clear
policies on the units for source ordering and planning
system input
•
Check calculation accuracy periodically
• When software is changed
• When a new source model is introduced
Dose = 23,361 cGy
VariSeed dose = 23,317 Gy
•
VariSeed uses 1.44 as a multiplier to calculate Tave
rather than 1/ln2; a 0.187% error
Vendors should not introduce systematic errors by
excessive rounding of mathematical or physical constants
51
52
Guarding against seed loss
All seed loading approaches are
similarly effective
• Account for seeds by loading according to plan
• Manual loading using loose seeds
• Lowest cost solution
• Counting prior to sterilization and loading creates
unnecessary risk
• Seeds in strands
• May or may not improve dosimetry
• Autoradiograph loaded needles
• On-site loading with automated or semi-automated hardware
• Have good detectors handy
• Possible savings in preparation time
• Custom loading by 3rd party vendor
• We take at least one G-M meter and 2 detectors
• Shortest prep time, least flexibility, highest cost
• Scintillator/photomultiplier (high sensitivity)
• Mick® applicator
• Regular G-M tube or Pancake detector (directional)
• Brachytherapist responsible for placing every needle and seed
53
54
9
Up to 30 loaded needles are placed in a slotted
aluminum plate for an autoradiograph
Autoradiograph film folded into sterile paper
55
A smooth aluminum plate is applied on top for
good contact. ~ 10 s exposure
56
The autoradiograph is verified
against the plan
57
58
The needles are moved to templatematched holes in the storage box
59
60
10
Loose seeds versus stranded seeds
Prostate brachytherapy
planning methods
Prostate boundary
at the time of
implant
Edema expands
the prostate ~15%
Edema resolves.
For strands, central
dose ↑ but base
and/or apex dose ↓
61
Various seed and needle placement
approaches
ABS nomenclature for different types of
prostate brachytherapy planning
• Uniform loading
Planning method
• Initial Seattle approach assumed negligible cumulative dosimetric
effects from very low energy seeds
Definition
Preplanning
Creation of a plan hours, days or weeks before
the implant procedure.
Intraoperative
Plan created in the OR. The patient remains
stationary between the time of the volume study
and the implant procedure.
Interactive
The treatment plan is revised periodically during
the implant procedure using image-based
feedback of needle position to recalculate dose.
Dynamic dose calculation
Dose distribution continuously updated using
deposited seed position feedback.
• Patients had very high urinary morbidity
• Nomogram methods
• 75% of volume determined seed strength to be placed on the
periphery
• Modified uniform/peripheral loading
• Basis of most manual planning
• Peripheral loading
• Assumes significant long-range cumulative dose effects: most
appropriate for HDR
63
64
Day zero D90% vs. implant number before
(n = 920) and after (n = 921) we began
hybrid intraoperative planning
Use of both a preplan and a hybrid
intraoperative/interactive approach
may improve implant quality
Intraoperative dosimetry has
added 7 minutes to our total
anesthesia time
(44 min → 51 min)
66
11
Pd-103 implants before and after hybrid
intraoperative planning
(Similar TRUS volume and use of ADT and XRT)
Before Intra-op Planning
2000 — 2005
n = 920
Mean
Parameter
Number of needles
Mean
± SD
33
3
± SD
39
4
14
123
17
109
Seed strength
(U)
2.59
.35
2.77
.42
Total strength
(U)
320
65
306
71
Prostate V100
(% Vol.)
97.6
2.4
97.6
2.0
9
Number of seeds
Dosimetry and quality
After Intra-op Planning
2006 — 2011
n = 921
Prostate D90
(% RD)
123
11
120
Rectum @ 110%
(cm³)
.085
.189
.021
.065
Urethra D50
(% RD)
113
14
110
10
Use planning parameters as
adjustable choices to achieve
good post implant dosimetry
67
Dose response thresholds for various
structures
Sagittal schematic of the prostate and
nearby structures
Structure
Outcome
Dosimetric Threshold
Prostate
BPF Survival
D90 > Reference Dose on day 30
D90 > 90% of RD on day 0
Urethra
Morbidity
U·D10 > 150% of Reference Dose
Membranous urethra Stricture
U·D50 > 95% of Reference Dose
Rectum
Morbidity
R·D100 > 1 cm³
Penile bulb
Erectile dysfunction PB·D50 > 30 Gy
Bladder
Corpora
cavernosum
Prostate
Reference Dose is the monotherapy or boost therapy dose recommended by the
ABS for the specific radionuclide
Seminal vesicle
Penile
bulb
Urethra
Corpora
spongiosum
69
70
Prostate implant plan evaluation parameters
(Schiffler Cancer Center)
Adjust to meet your post implant dosimetry goals
Evaluated quantity
Parameter
What is the target volume?
Value
Patient specific needs
PTV, TURP, etc.
Planning volume coverage
V100
> 99.8% PT volume
Planning volume dose
D90
120% – 130% RD
Urethral volume coverage
Urethral V125
Urethral V150
10% – 50% volume
< 15% volume
Urethra dose
Mean
110% – 140% RD
Homogeneity
V150
30% – 45% plan vol, 125I
45% – 60% plan vol, 103Pd
High dose volume
V200
< 15% plan volume, 125I
< 25% plan volume, 103Pd
Target volume / US volume
Ratio
1.85 ± 0.3
• Prostate only — or less
Primary importance
• Biochemical outcome will be no better than surgery
• Prostate plus dosimetric margin
• Inconsistent in interpretation and application
• Explicit Planning Target Volume (PTV)
• Clearly documents your planning goals
• May produce incrementally better bNED results
• Treatment margin may be the best predictor of success
in implants with "good" dosimetry
Try to minimize the number of seeds, needles, and specially loaded needles
71
72
12
Brachytherapy can treat extracapsular
disease more effectively than surgery
How much margin is necessary?
• Mayo Clinic: BJ Davis et al., Cancer,1999, 85:2630-2637
5 mm margin
• ECE in 28% of 376 patients
• 5 mm margin encompasses 99% of locally confined ECE
• Cleveland Clinic: C Sohayda et al., Urol, 2000, 55:382-386
Prostate capsule
• ECE in 35% of 265 patients
• 5 mm = 90th percentile distance
• Wm Beaumont: KK Chao et al., IJROBP, 2006, 65:999-1007
2 mm ECE
• ECE in 33% of 371 patients
• 5 mm = 90th percentile distance
• ECE occurrence and distance increased with PSA and Gleason
score
Note: The XRT dose needed to salvage residual disease
after radical prostatectomy is the same as XRT monotherapy.
73
Where do local BTx failures occur?
MSKCC salvage prostatectomy series
74
Transverse ultrasound:
seminal vesicle seeds
(WC Huang et al., J Urol 2007;177:1324-1329)
• Whole mount pathology of 47 failures
• 93% of patients had cancer foci at the apex
• Seed migration reduces apical dose
• 65% of patients had cancer within 5 mm of the
urethra
• 7% had cancer directly involving the urethra
4 SV seeds
• Urethral sparing does not mean giving the urethra less
than the prescribed dose but < 150% RD
• 50% of patients had extraprostatic disease
• Insufficient planning margins
75
76
Composite sagittal plot of prostate and dosimetric
margins of 103Pd patients
(GS Merrick et al., Am J Clin Oncol, 2003, 26:e178–189)
Brachytherapy
dose matters!
ANT
50
—— 100%
40
---
Bladder
•••
30
90%
75%
20
10
Seminal
vesicles
Base
0
Apex
INF
(D90 = minimum dose in the hottest 90%
of the target volume)
Mean 100% margin
> 6 mm
POST
77
13
Dose matters:
Low-risk randomized trial
(A Herstein et al., Am J Clin Oncol, 2008, 31:6–10)
Progression-free Survival
The role radiobiological modeling in
relative comparison of implants using
different sources and strategies
D90 > 100%
1.0
0.8
0.6
D90 < 100%
0.4
0.2
0
0
1
2
3
4
5
6
7
Years since Implant
79
Full radiobiological calculation with cell
repopulation and sub-lethal damage repair as
recommended by AAPM TG-137
Basic rationale and AAPM TG-137
recommendations
• Implants using different sources and loading patterns
exhibit diverse spatial and temporal dose delivery patterns
• However, physical dosimetry alone do not fully capture the
interplay between the spatial-temporal dose delivery
patterns and the underlying cellular kinetics
  β 

 
δ

BEDEBRT = D1 +  d − ln 2
 α ⋅ d ⋅ Tpot  
  α 


 Teff ,i 


BEDi = DTeff ,i ⋅ RETeff ,i − ln 2
 α ⋅ Tpot 


• To facilitate the proper use and to increase the
comparability of radiobiological indices reported by
different institutions, the AAPM believes that it is important
to establish a consensus model and its associated
parameters for reporting biophysical indices.
81
Radiobiological parameters for prostate
recommended by AAPM TG-137
125
Description, Units
-1
I
103
− λ ⋅Teff ,i 
DTeff ,i = Di 1 − e



&




1
 β  D 
1 − e − 2λ ⋅Teff ,i −  2λ 1 − e − (µ + λ )Teff ,i 
RE Teff ,i = 1 +   0,i 

 α  µ − λ  1 − e − λ ⋅Teff ,i 
 µ + λ 
• Radiobiological modeling can help quantify the interplay
and its potential clinical impact
Variable
 α ⋅ Di ⋅ Tpot 
Teff ,i = Tavg ln 

T½


BED = −
N

1 
v i ⋅ e −α⋅BEDi 
ln

α  i

∑
{
( − α⋅BEDi )
TCPi = e − vi ⋅K clon ⋅e
}
N
TCP =
∏ TCPi
i
82
Radiobiological advantages or
disadvantages for radionuclides
Pd
Parameter
Order
α
linear component of cell kill, Gy
0.15
0.15
β
quadratic component of cell kill, Gy-2
0.05
0.05
Lower α/β means less repair, favors high dose rate
Cs > Pd > I
δ
d
protraction factor for XRT, d
1.4
1.4
High tumor repopulation rate favors short t½
Cs > Pd > I
daily XRT fractionation dose, Gy
1.8
1.8
Slower normal tissue repair rate favors long Tx
I > Pd > Cs
Tpot
Cell potential doubling time, d
42
42
µ
Kclon
cell repair constant (t½ = 1 h), d-1
16.64
16.64
Greater tumor hypoxia favors greater dose
I > Pd > Cs
clonogen number
5 x 106
5 x 106
Greater normal tissue sparing favors lower energy
Pd > I > Cs
λ
D
radionuclide decay constant, d-1
0.01167
0.04079
Greater biological effect favors lower energy
Pd > I > Cs
total dose, Gy
(145)
(125)
Edema affects BED less for long t½ and higher E
I > Cs > Pd
Ď0
initial dose rate, Gy/d
(1.70)
(5.10)
vi
fractional volume increment
(ZJ Chen et al., Phys Med Biol, 2011, 56:4895-4912)
83
84
14
Composite BED volume histograms
Histograms of BED for biochemical failures
(n = 55) and matched non-failures (n = 110)
Total BED for the 55 failed men was 144 ± 27 Gy. Total BED for the 110
matched controls was 143 ± 23 Gy (p = 0.803)
(WM Butler et al., Med Phys, 2009, 36:776-787)
(WM Butler et al., Med Phys, 2009, 36:776-787)
100
Percent
Prostate Volume (%)
bNED
Failure
30%
All patients, n = 165
80
60
Failed, n = 55
bNED, n = 110
20%
40
10%
20
0%
0
70
100
150
200
250
300
350
BED (Gy)
Total BED (Gy)
85
BED calculated from point D90 dose by TG-137
approach vs. Stock&Stone no repair approach
D90 Dose
Nuclide
(Gy)
I-125
Implant only BED
TG-137
145
125
115.1
144.1
Cs-131
110
106.3
136.0
XRT
45
I-125
110
77.4
Pd-103
100
Cs-131
90
TG-137
Low-risk patients, n = 506
D90 based BED cut point = 116 Gy
(WM Butler et al., Brachytherapy, 2011, 10:16-28)
100
S&S
80
152.4
Pd-103
86
Combined XRT + BTx
S&S
110.5
80 90 100 110 120 130 140 150 160 170 180 200
400
68.1
85.5
114.2
145.5
199.7
89.5
112.2
157.7
197.7
85.1
107.4
153.3
192.9
bNED Survival (%)
50
Low Risk
60
— BED < 116 Gy, n = 109, 95%
— BED ≥ 116 Gy, n = 397, 99%
40
p = 0.012
20
0
0
2
4
Intermediate-risk patients, n = 701
D90 based BED cut point = 169 Gy
8
10
12
88
High-risk patients, n = 266
D90 based BED cut point = 165 Gy
(WM Butler et al., Brachytherapy, 2011, 10:16-28)
(WM Butler et al., Brachytherapy, 2011, 10:16-28)
100
100
80
bNED Survival (%)
80
bNED Survival (%)
6
Years Since Implant
87
Intermediate Risk
60
— BED < 169 Gy, n = 547, 97%
— BED ≥ 169 Gy, n = 154, 95%
40
High Risk
60
— BED < 165 Gy, n = 162, 87%
40
— BED ≥ 165 Gy, n = 104, 93%
p = 0.139
p = 0.098
20
20
0
0
0
2
4
6
8
Years Since Implant
10
0
12
89
2
4
6
8
Years Since Implant
10
12
90
15
Outcomes at 6-institutions stratified by high,
intermediate, and low BED (n = 3,928)
Outcomes at 6-institutions stratified by high,
intermediate, and low BED (n = 3,928)
(NN Stone et al., IJROBP, 2007, 69:1472–1477)
(NN Stone et al., IJROBP, 2007, 69:1472–1477)
High BED > 200 Gy
Int BED = 140 - 200 Gy
Low BED < 140 Gy
Low-risk
Intermediate-risk
High BED > 200 Gy
Int BED = 140 - 200 Gy
Low BED < 140 Gy
High BED > 200 Gy
Int BED = 140 - 200 Gy
Low BED < 140 Gy
High-risk
91
92
Low-risk randomized isotope trial: effect of V100 on
bPFS using 125I
(A Herstein et al., Am J Clin Oncol, 2008, 31:6–10)
1
Cancer free (PSA < 0.5 ng/mL)
Brachytherapy target volume
coverage matters!
(V100 = % target volume covered by
100% of prescribed dose)
V100 > 90 % (n = 80)
0.8
0.6
V100 < 90 % (n = 37)
I-125
0.4
0.2
0
0
1
2
3
4
5
6
7
8
Years since Implant
94
Low-risk randomized isotope trial: effect of V100 on
bPFS using 103Pd
(A Herstein et al., Am J Clin Oncol, 2008, 31:6–10)
Cancer free (PSA < 0.5 ng/mL)
1
Brachytherapy treatment
margins matter!
V100 > 90 % (n = 48)
0.8
V100 < 90 % (n = 80)
0.6
Pd-103
0.4
Mean treatment margin from the
prostate to the 100 % isodose surface
0.2
0
0
1
2
3
4
5
Years since Implant
6
7
8
95
16
Treatment margins and bPFS using
125I
Treatment margins and bPFS using
(S Choi et al., Cancer J, 2004, 10:175–180)
TM > 3mm
0.8
TM < 3 mm
0.6
0.4
I-125
0.2
0
0.8
TM < 3 mm
0.6
Pd-103
0.4
0.2
0
0
12
24
36
48
60
0
30
40
50
60
98
Is it possible to match dosimetry with
different seed models?
Low-risk randomized trial: I-125 vs. Pd-103
(K Wallner et al., IJROBP, 2003, 57:1297-1303)
Pd-103 98%
• For the same radionuclide, DVH curves can be closely
matched by adjusting the source strength of different
manufacturers
I-125 92%
80
20
97
Does radionuclide matter?
100
10
Months after implant
Months after implant
Progression-Free Survival
TM > 3mm
1
Freedom from PSA failure
Freedom from PSA failure
1
103Pd
(S Choi et al., Cancer J, 2004, 10:175–180)
• For different radionuclides, only two points on a DVH curve
can be matched, but multiple DVH curves (prostate,
urethra, rectum) may have points matched
60
40
P-FS ≡ PSA < 0.4 ng/mL
20
p = 0.059
0
0
1
2
3
4
5
6
7
8
9
10
Years Since Implant
11
99
100
Cs-131
All DVH V100 = 100%, D90 = 120%, Urethra D50 = 118%
22 needles, 91 seeds
28 cm³ prostate, 52 cm³ PTV (83 cm³ Rx volume)
Which plan uses which
isotope?
100
Pd-103
I-125
Cs-131
% Volum e
80
Pd-103
60
I-125
PTV
Urethra
40
20
— 100 %
— 150 %
— 200 %
0
80
100
120
140
160
180
200
220
240
% Prescribed Dose
101
102
17
Why dose should not be a
regulatory metric
Dosimetry parameters are good
quality assurance tools but they
should not be used as
regulatory targets
• No medical radiation society has published
consensus recommendations for post implant
dosimetric parameters
• The Mt. Sinai D90 dose response study was for
implants through 1996.
• More recent studies find D90 cut points of about
125%.
• Cut points in terms of biologically effective dose
increase with patient risk status.
104
Further problems with dosimetry as a
regulatory target
Schematic of a plot of Vd versus Dv
with a local definition of adequacy
• Patient-specific factors prevent replication of the
planned dosimetric values
100
Possible
data points,
implant adequate
• Each dosimetric parameter has a mean ±
standard deviation
v
• The SD of many parameters are comparable to
the NRC’s 20% tolerance
Possible
data points,
implant inadequate
Vd
• If coverage is important, it is physically
impossible for V100 = 100% if D90 = 100%
0
d
Dv
105
ProQura database implant quality
106
Implants in the ProQura database that would be
medical events using a ± 20% threshold for V100 of
100% volume and D90 of 100% prescribed dose
Mean V100 = 89.2% ± 8.9%
Mean D90 = 103% ± 16%
Prostate
Parameter
D90
V100
Either
Both
n = 6,600
Low Side (-20%)
n
383
723
767
340
%
5.8
11.0
11.6
5.2
High Side (+20%)
n
796
%
12.1
High or Low
n
1,179
%
17.9
Total implants, n = 6,600 by 129 community-based
brachytherapists
107
108
18
A regulatory specification of D90 = 100%
makes no radiobiological sense
Implant quality at Schiffler Cancer Center
Jan 2000 – Feb 2011, n = 1,894.
Mean V100 = 97.6% ± 2.2; Mean D90 = 121% ± 10%
(TG-137 radiobiological parameters)
1
100
1,875 adequate
TCP low U,
overall = 0.970
0.995
19 inadequate
I-125
Tumor Control Probability
% Volume
80
60
PTV high U
Urethra
high U
40
Urethra
low U
20
PTV low U
0.98
TCP high U,
overall = 0.798
0.97
80
100
120
140
160
180
200
% Prescribed Dose
Same prostate planned to
D90 = 125% with either high
or low strength seeds
There is a learning curve as well as variation
Day 0 D90 vs. implant number through 2006
I-125
0.985
0.975
0
109
0.99
60
80
100
120
140
160
180
200
% Prescription Dose
Differential TCPs. TCP = 1 for
dose > 140%, but high U
implant has poorer coverage
< 125% and poorer control
110
Procedures that may reduce errors
(Dosimetric feedback within 24 hr)
Prostate D90 (%mPD)
180
160
• Define and enforce team roles that are invariant for
all participants
140
• Brachytherapist must be an expert on prostate
ultrasound and CT anatomy
• Dozens of penile bulbs have been implanted
120
• Brachytherapy accreditation should be sought
• Use sagittal ultrasound (and fluoroscopy)
100
• Several instances of more than a dozen seeds recovered from
the bladder
80
bNED
Failure
• Seeds not extruded as trains but expelled in piles
– MMF Fit
60
0
250
500
750
1000
1250
• Use intraoperative planning in conjunction with preplan
1500
Implant Number
111
112
Conclusions
• Brachytherapy is the ultimate conformal therapy
• Generous and variable periprostatic treatment margin
possible
• Extracapsular extension is easily treated
• Highly effective for all risk groups
• Most patients may be treated with monotherapy
• Very favorable morbidity profile
• Post implant dosimetric quality trends should be used in a
feedback loop to modify planning indices
113
19