Radiopharmaceuticals in Bone Metastasis:
Clinical Trials, Imaging and Dosimetry
John L. Humm & Neeta Pandit-Taskar
Memorial Sloan-Kettering
Disclosures
• John L Humm
– Served on the Scientific Advisory Board
Algeta
of
Objectives of this Presentation
To assess pharmacokinetics, biodistribution and
dosimetry of Ra-223 in patients with prostate cancer
Protocol Design
Ra-223 dose escalation: 50, 100 kBq/kg & 200 kBq/kg
Serial gamma camera images
immediately, post first void (0-6 h of treatment), and 24 6 h, 48 12 h,
96 24 h and 144 24h
Serial whole body counts (NaI probe)
Pre-void, post 1st void (0-6 h of treatment), and 24 6 h, 48 12 h,
96 24 h and 144 24h
Serial blood and serum counts
1m, 5 m, 15m, 30 m, 45m, 1 h, 24 6 h, 48 12 h, 96 24 h and
144 24 h
Radium-223 Decay
Radium-223 decay chain
• Radium-223 in Alpharadin is an
alpha-emitter
• t1/2 = 11.43 days
• Of the total decay energy
– 93.5% emitted as 4 particles
– < 4% emitted as particles
– < 2% emitted as γ or X-rays
223Ra
11.43 d
Decays via a series of α, β,
and emitting daughters
α
219Rn
3.96 s
α
215Po
β−
1.78 ms
α
211Pb
36.1 m
β−
211Bi
α
(99.73%)
4.77 m
516 ms
α
2.17 m
207TI
5
Henriksen G, et al. Cancer Res. 2002;62:3120–3125.
(0.27%)
211Po
β−
207Pb
stable
The Ra-223 Spectrum
Ra-223
11.4 days
Rn-219
4s
84 keV X-rays ~41%
154 keV (9%), 269 keV (14%)
5 energy windows used:
84 keV, 154, 269, 351
and 403 keV
Po-215
1.8 ms
271 keV
10%
Pb / Bi-211
36m * 2.2 m
Nothing
imageable
Pb-207
351 keV + higher
13%
Serial WB Images from Royal Marsden
Posterior Images from Day 0 through 7
Imaging Organs
• Since other centers had focused on acquiring serial whole body scans, our
philosophy was to try to get early organ data.
• Relevant organs would be vertebrae, kidney, liver, G.I. tract.
• Serial ant & post spot views of the abdomen and pelvis following upon the
imaging trial design of an earlier trial with 213Bi-M195 antibodies .
• Images are much more noisy on account of the low administered activity.
Patient at the 50kBq/kg
FDG – D27
Lt fem tu 1.4
Tc-99m MDP –D20 ant & post
Ra-223 ant & post
Patient at the 200 kBq/kg dose level
MIP
FDG -7
Rt hum 1.74
Tc-99m MDP –D 10 Ant & Post
Ra-223 Ant & Post
0-10 m
40-50 m
2d
10-20 m
50-60 m
6d
20-30 m
232 min post
Bone scan –D13
30-40 m
1d
Bone Retention is very long
Posterior View Pelvis
Ra-223 6 d
Bone scan
200kBq/kg (240 Ci)
Ra-223 14 d
Bone scan
Whole Body Clearance
120.0
%WB Activity (ndc)
100.0
80.0
101
102
103
60.0
104
107
40.0
109
110
111
20.0
0.0
0.0
20.0
40.0
60.0
80.0
100.0
120.0
Time (hr)
140.0
160.0
180.0
200.0
Blood Clearance
Blood (%ID/l)
8
102
7
103
6
104
5
106
4
107
3
108
2
109
110
1
111
0
0
5
10
15
20
T1/2 fast (h)
0.19 + 0.18
T1/2 slow (h)
3.99 + 3.27
25
Whole Body Excretion
Urinary Excretion
First void
(%)
Amount in bowel at 1d
(%)
Amount Excreted from Whole
Body at 7d (range 6 - 8)
%ID
4% (range -3.9 - 11%)
51% (range 43 - 59%)
68% (range 44 -78%)
Where does the administered activity go?
Fraction of injected activity in the intestine over time
Time
10 min
20 min
30 min
40 min
2.7 + 0.7 h
23 + 2 h
Uptake in intestine
% mean injected dose + standard
deviation
24 + 3
25 + 3
26 + 3
28 + 3
40 + 6
51 + 8
What happens to the Daughters?
Parent and Daughter Sequence
Day 0 Pre-void
Parents
All Counts
Final Daughter
Parent and Daughter Sequence
Day 0 Post-void
All Counts
Parents
Final Daughter
Radium Activity dominated by gut activity
Day 1
Ant
Post
Parent
Daughter
We do not see Pb or Bi daughters leaving gut contents and re-locating in kidney
Parent and Daughter Sequence
Day 1
All Counts
Parents
Final Daughter
Parent and Daughter Sequence
Day 3
All Counts
Parents
Final Daughter
Parent and Daughter Sequence
Day 6
All Counts
Parents
Final Daughter
Ratio of counts from daughter to parents
Ratio of counts within identical ROI drawn over the final Bi-211
daughter to the summed parental emission
G.I. tract
n
10 min
20 min
40 min
1 h (n=1)
4h
1 day
2 days
6 or 7 days
7
0.162±0.011
0.152±0.009
0.147±0.006
0.140
0.151±0.005
0.155±0.005
0.164
0.159
Kidney
7
0.264±0.055
0.243±0.030
0.233±0.024
Liver
6
0.255±0.022
0.260±0.024
0.278±0.047
0.279
Bone lesion
5
0.168±0.010
0.165±0.013
0.169±0.008
0.169±0.045
Ra-223
standard
0.152±0.006
0.153±0.006
0.155±0.006
0.159±0.006
Absorbed doses (Gy/MBq) to different organs
Individual emission contributions
(Gy/MBq)
Target organ
From
George Sgouros
Adrenals
Brain
Breasts
Gallbladder wall
LLI Wall
Small intestine wall
Stomach wall
ULI wall
Heart wall
Kidneys
Liver
Lungs
Muscle
Ovaries
Pancreas
Red marrow
Osteogenic cells
Skin
Spleen
Testes
Thymus
Thyroid
U. bladder wall
Uterus
Whole body
Total
Total
SD
Alpha
Beta
Photon
(Gy/MBq)
(rad/mCi)
(%)
0.00E+00
0.00E+00
0.00E+00
0.00E+00
0.00E+00
3.19E-03
0.00E+00
0.00E+00
1.61E-03
2.99E-03
2.79E-03
0.00E+00
0.00E+00
0.00E+00
0.00E+00
1.32E-01
1.14E+00
0.00E+00
0.00E+00
0.00E+00
0.00E+00
0.00E+00
3.71E-03
0.00E+00
2.22E-02
2.35E-05
2.35E-05
2.35E-05
2.35E-05
4.56E-02
3.60E-03
2.35E-05
3.15E-02
7.07E-05
1.08E-04
1.02E-04
2.35E-05
2.35E-05
2.35E-05
2.35E-05
6.42E-03
1.49E-02
2.35E-05
2.35E-05
2.35E-05
2.35E-05
2.35E-05
1.61E-04
2.35E-05
8.08E-04
9.41E-05
7.52E-05
2.53E-05
2.05E-04
8.49E-04
4.71E-04
1.15E-04
8.24E-04
4.67E-05
1.06E-04
8.22E-05
4.85E-05
9.54E-05
4.62E-04
8.82E-05
2.02E-04
2.98E-04
4.86E-05
6.65E-05
5.96E-05
3.35E-05
4.80E-05
1.56E-04
2.32E-04
1.19E-04
0.00012
0.00010
0.00005
0.00023
0.04645
0.00726
0.00014
0.03232
0.00173
0.00320
0.00298
0.00007
0.00012
0.00049
0.00011
0.13879
1.15206
0.00007
0.00009
0.00008
0.00006
0.00007
0.00403
0.00026
0.02311
0.44
0.37
0.18
0.85
171.88
26.87
0.51
119.58
6.40
11.86
11.01
0.27
0.44
1.80
0.41
513.51
4262.60
0.27
0.33
0.31
0.21
0.26
14.90
0.94
85.50
56
80
120
14
83
45
22
50
42
36
36
90
41
40
43
41
41
79
54
59
109
96
63
28
16
Organ Dose in a 73kg Adult given 50
kBq/kg
Gy
rad
0.0004
0.0004
0.0002
0.0008
0.1696
0.0265
0.0005
0.1180
0.0063
0.0117
0.0109
0.0003
0.0004
0.0018
0.0004
0.5066
4.2050
0.0003
0.0003
0.0003
0.0002
0.0003
0.0147
0.0009
0.0843
0.04
0.04
0.02
0.08
16.96
2.65
0.05
11.80
0.63
1.17
1.09
0.03
0.04
0.18
0.04
50.66
420.50
0.03
0.03
0.03
0.02
0.03
1.47
0.09
8.43
Organs that matter
Target organ
Individual emission contributions
(Gy/MBq)
Alpha
Beta
Photon
Dose to an Adult
given 50 kBq/kg
Gy
rad
Red marrow
1.3E-01
6.4E-03
2.0E-04
0.51
51
Osteogenic cells
1.1E+00
1.49E-02
2.98E-04
4.20
420
Remember - Most of this is α-dose
223Ra
Bone Marrow dosimetry
• Less than 1% of 292 patients treated in phase I & II trials
receiving between 5 and 250 kBq of 223Ra had CTC grade 4
hematological toxicity; 2%-4% had grade 3 toxicity.
Cheetham & Petrylak, Alpha Particles as Radiopharmaceuticals in the Treatment
of Bone Metastases: Mechanism of Action of Radium-223 Chloride (Alpharadin)
and Radiation, ONCOLOGY. Vol. 26 No. 4, 2012.
• Yet individual red marrow absorbed doses based on standard
MIRD estimates were often above 3 Gy.
Marrow Dosimetry
Bone
Bone
R
Trabecular marrow
cavity
• α-emitters deposit energy
uniformly in the marrow space.
• Target marrow cells also
assumed uniformly distributed
From Hobbs, et al. Phys Med Bio ‘12
Trabecular marrow
cavity
• α-emitters mostly on bone
surface and more
concentrated at diseased
sites
• Mean to marrow cavity
won’t predict effect
Autoradiograph of 223Ra in dog
Normal bone
Tumor
Low dose
to bone
marrow
Bone marrow
Courtesy of Oyvind Bruland
Spatial profile of hematopoietic progenitor cells
Bourke et al, Blood, 114: 4077, 2009
Dose-response for toxicity
bone
R

r
Marrow
cavity
400 micron
Hobbs, et al. Phys Med Bio ‘12
Lesion Dosimetry
Radiation dose requires an estimate of the activity AND knowledge of the
tumor mass (or volume of distribution of the radionuclide)
Ratio of counts in bone lesions : normal bone
(uncorrected for partial volume effects)
Subject Number
Hot spot #1
Hot spot #2
101
1.01
L humerus
1.55
L femur
102
1.28
1.19
L iliac
103
1.4
R humeral
head
L femur
1.42
R humerus
104
3.14
1.36
L humeral head
106
1.18
R distal
femur
Sacrum
2.04
107
1.41
Upper spine
1.14
Degenerative disease
R hip
L acetabulum
109
2.03
R scapula
1.23
Thoracic spine
110
2.43
Pubic
1.72
L iliac
111
1.74
R humerus
#107
What can we say about tumor dose?
• Unable to determine tumor doses by
gamma camera imaging.
• Estimates will need to rely on accurate
bone modeling and microdosimetric
calculation.
• Autoradiographs will help but will be
difficult to obtain
• Tumor cells close to bone surface will get
significant doses of α-radiation.
Hobbs, et al. Phys Med Bio ‘12
Dose Rates to the Public from Alpharadin
The administered activities in Alpharadin therapies are
extremely low (50 kBq or 1.35 μCi per kilogram body weight).
Therefore the exposure rates to staff and the public resulting
from patients undergoing this therapy are very small.
Contrast this to the dose rates in µSv/hr to 90 µSv/hr (contact) after a bone scan
Time after
administration
Mean
~0 h
~24 h
T~48 h
T~1 week
Activity
Contact
1m
Contact
1m
Contact
1m
Contact 1 m
50kBq
1.03
0.17
1.8
0.4
2.1
0.1
0.16
0.02
CONCLUSIONS
• PK analysis: rapid blood clearance with little or no binding to
blood elements
• Little urinary excretion based on imaging and wb counts
• Imaging demonstrated bone targeting, and excretion through
small bowel (rapid) with transit through large bowel.
• No significant redistribution of daughters to dose limiting
organs such as the kidney.
• Imaging data can result in mis-leading radiation dose
information to dose limiting tissues such as marrow and G.I.
tract.
• Imaging data unable to estimate radiation dose to metastatic
lesions.
Acknowledgements
• Jorge Carrasquillo, Joseph O’Donoghue, MSKCC, New York
• George Sgouros, Johns Hopkins University School of Medicine, Baltimore
• Wesley Bolch, University of Florida, Gainesville
• Øyvind Bruland, The Norwegian Radium Hospital, Oslo
Question 1
Which organ has the highest amount of 223Ra at 24 hr
post injection?
A. Bone
B. Liver
C. Kidney
D. Large intestine
E. Muscle
Answer 1
A. Bone
B. Liver
C. Kidney
D.Large intestine
E. Muscle
About 50% of the administered activity
is in the large intestine at 24hr
Question 2
The radiation dose to the bone marrow from 223Ra?
A. Uniform and largely a consequence of activity in the
bone
B. Uniform and largely a consequence of activity in blood
C. Uniform and largely a consequence of longer range βemissions
D. Is extremely non-uniform due to the short range of αemissions
E. Is negligible because of the short range of α-particles
Answer 2
A. Uniform and largely a consequence of
activity in the bone
B. Uniform and largely a consequence of
activity in blood
C. Uniform and largely a consequence of
longer range β-emissions
D.Is extremely non-uniform due to
the short range of α-emissions
E. Is negligible because of the short range of
α-particles