Download doctorsonly.co.il

Francesco GIAMMARILE
« Aut tace aut loquere meliora silentio »
Presentation Outline
NO CONFLICT OF INTEREST
Introduction
• Bone scan and F-Choline
• Radionuclide treatment
General aspects
Introdiction
• In prostate cancer, bone is the second common site of
metastases (after LN)
• Bone metastases have poorer prognosis and significant
higher morbidity & mortality
- osteoblastic (80 %)
- osteolytic (15 %)
- mixed osteoblastic/osteolytic (5 %)
What is bone scan?
Bone scintigraphy
• Biphosphonates
(bone uptake)
• Labelled with 99mTc
 99mTc-DP

SPECT-CT
Bone PET
What is bone scan?
• 18 Fluorine
 18F-NaF
+
PET-CT
‘historical’ agent (1960)
18F-NaF
18F-FCholine
What is bone scan?
SPECT or PET ?
Characteristics
SPECT PET
Image Quality
++
+++
Availability
+++
+/++
Cost
+
++
Irradiation
=
=
• PET-CT has a better spatial resolution than SPECT-CT
• Bone peripheral reaction is more evident in FNa
imaging
 better detection and analysis of small lesion in FNa
What is bone scan?
Superiority of PET?
 CT add sensitivity (lytic lesion with no osteoblastic reaction)
and specificity (equivocal bone uptake) to functional imaging
Bone scan in metastatic prostate cancer
FCH vs FLUORIDE PET/CT
Benign
Bone
Metastase
FNa and Tc-HMDP
FCH
PET/SPECT
CT
PET
CT
Trauma
+
+
-
+
Arthrosis
+
+
-
+
Sclerotic
+
+
-
+
Mixed
+
+/-
+
+/-
Indolent
+
+
-
+
Bone
marrow
Pure Lytic
-
-
+
-
-
+
+
+
Bone scan in metastatic prostate cancer
FCH vs FLUORIDE PET/CT
FCH PET/CT
True
False
Total
Positive
97
1
98
Negative
95
34
129
Estimated
value
sensitivity
74 %
specificity
99 %
(p < 0.01)
accuracy
85 %
NaF PET/CT
True
False
Total
Positive
108
7
115
Negative
89
26
115
Estimated
value
sensitivity
81 %
ns
specificity
93 %
accuracy
86 %
Beheshti et al, EJNMMI 2008
Bone scan in metastatic prostate cancer
FCH vs FLUORIDE PET/CT
L2
L2
L2
L4
L4
L4
S
S
S
FCH
FLUORIDE
Metastases in L2 and S  FCH, FLUORIDE, BONE TP
Degenerative lesion in L4  FCH TN , FLUORIDE, BONE FP
BONE
Bone scan in metastatic prostate cancer
FCH vs FLUORIDE PET/CT
NaF FP
FCHO TN
CT: degenerative lesion
Bone scan in metastatic prostate cancer
FCH vs FLUORIDE PET/CT
FCHO -
NaF +
CT: densely sclerotic lesion
Bone scan in metastatic prostate cancer
Patterns of bone metastases: phase 1
phase 1
CT -
CHOLINE +
FLUORIDE -
bone marrow metastases
phase 2
CT +
CHOLINE +
FLUORIDE +
phase 3
CT +
CHOLINE -
FLUORIDE +
phase 4
CT +
CHOLINE -
FLUORIDE –
(adapted from Werner LANGSTEGER)
Bone scan in metastatic prostate cancer
Patterns of bone metastases: phase 1
FCH -
phase 0
(no BM mets)
PSA 3,8
FCH +
PSA 13,3
phase 1
(3 month later)
Bone scan in metastatic prostate cancer
Patterns of bone metastases: phase 2
phase 1
CT -
CHOLINE +
FLUORIDE -
CHOLINE +
FLUORIDE +
bone marrow metastases
phase 2
CT +
mixed osteoblastic/osteolytic lesions
phase 3
CT +
CHOLINE -
FLUORIDE +
phase 4
CT +
CHOLINE -
FLUORIDE –
Bone scan in metastatic prostate cancer
Patterns of bone metastases: phase 2
FCH +
HU 680
sclerotic lesion
FLUORIDE +
Bone scan in metastatic prostate cancer
Patterns of bone metastases: phase 2
FCH +
lytic lesion
FLUORIDE +
Bone scan in metastatic prostate cancer
Patterns of bone metastases: phase 3
phase 1
CT -
CHOLINE +
FLUORIDE -
CHOLINE +
FLUORIDE +
bone marrow metastases
phase 2
CT +
mixed osteoblastic/osteolytic lesions
phase 3
CT +
CHOLINE -
FLUORIDE +
CHOLINE -
FLUORIDE –
dense sclerotic lesion (HU >825)
phase 4
CT +
Bone scan in metastatic prostate cancer
Patterns of bone metastases: phase 3
FCH HU 1350
HU 550
with increasing HU – FCH becomes NEGATIVE
FLUORIDE +
Bone scan in metastatic prostate cancer
Phase 3: clinical explications
FCH -
HU 3070
FCH -
FLUORIDE +
HU 1250
Beheshti et al, EJNMMI 2008
True negative: non viable sclerosis
apoptosis
therapy response
False negative: reduced sensitivity
tumor density / perfusion 
in dense sclerosis (HU >825)
Bone scan in metastatic prostate cancer
Patterns of bone metastases: phase 4
phase 1
CT -
CHOLINE +
FLUORIDE -
CHOLINE +
FLUORIDE +
bone marrow metastases
phase 2
CT +
mixed osteoblastic/osteolytic lesions
phase 3
CT +
CHOLINE -
FLUORIDE +
CHOLINE -
FLUORIDE -
dense sclerotic lesion (HU >825)
phase 4
CT +
highly dense sclerotic lesion (HU >1000)
Bone scan in metastatic prostate cancer
Patterns of bone metastases: phase 4
FCH -
HU 2400
FLUORIDE -
Treatment in metastatic prostate cancer
Bone metastases: major complications
•
•
•
•
•
Severe pain
Pathological fractures
Spinal-cord compression
Hypercalcemia
Bone marrow infiltration
• Mobility restriction
• Sleep reduction
• → Worsening patient’s quality of life.
Treatment in metastatic prostate cancer
Bone seeking radiopharmaceuticals
Radiopharmaceutical T½
(d)
E
(keV)
Range
(mm)
Nuclide
32P
89Sr
153Sm
166Ho
186Re
188Re
85Sr
117mSn
223Ra
Max Ave
1710 695
1490 583
810
224
1840 665
1080 329
2120 795
15 (e- Auger)
150 (e- Auger)
5.8 ()
Max Ave
7.9 1.85
6.7 1.75
3.4 0.53
9
NA
4.7 0.92
10.8 2.43
10 nm
30 nm
50 µm
Labelled
Phosphate
Chloride
EDTMP
DOTMP
HEDP
HEDP
Chloride
DTPA
Chloride
14.3
50.5
1.95
1.1
3.77
0.71
64
14
11.4
Dose
E
(keV) (cGy/MBq)
103
81
137
155
514
159
154
Lesion
5
23
67
NA
2
NA
8.2
5.4-8
NA
Bone
0.6
1
15
NA
0.1
NA
1.4
0.1-0.2
NA
Treatment in metastatic prostate cancer
Possible effects of the radiometabolic treatment
Antitumoral effect
Antalgic effect
Treatment in metastatic prostate cancer
Contra-indications
• Low blood cell count:
– Hb <90 g/l
– WBC <3.5×109/l
– PLT <100×109/l
• Bone marrow involvement
• Poor renal function:
• if GFR <50 ml/min: halve the dose
• if GFR <30 ml/min (creatinine >180 μmol/l): exclude
• “Chronic” spinal cord compression
• Corticosteroids
• Life expectancy < 4 weeks
 This is the limit, but BSR are more beneficial in patients with
relatively long life expectancy !
Treatment in metastatic prostate cancer
Procedure: patient preparation
• Bone pain
– limiting normal activities
– not easily controlled by analgesics
• Recent bone scan (<4 weeks)
• Exclude:
– neurogenic pain
– pathological fractures
• Wait:
– ≥3 mo after wide-field RT
– ≥ 4 weeks after chemo
• Recent full haematological and
biochemical profile (<7 days)
– clotting tests if DIC suspected
Treatment in metastatic prostate cancer
Bone pain palliation
Dose
E
(keV) (cGy/MBq)
Radiopharmaceutical T½
(d)
E
(keV)
Range
(mm)
Nuclide
32P
89Sr
153Sm
166Ho
186Re
188Re
85Sr
117mSn
223Ra
Max Ave
1710 695
1490 583
810
224
1840 665
1080 329
2120 795
15 (e- Auger)
150 (e- Auger)
5.8 ()
Max Ave
7.9 1.85
6.7 1.75
3.4 0.53
9
NA
4.7 0.92
10.8 2.43
10 nm
30 nm
50 µm
Labelled
Phosphate
Chloride
EDTMP
DOTMP
HEDP
HEDP
Chloride
DTPA
Chloride
14.3
50.5
1.95
1.1
3.77
0.71
64
14
11.4
103
81
137
155
514
159
154
Lesion
5
23
67
NA
2
NA
8.2
5.4-8
NA
Bone
0.6
1
15
NA
0.1
NA
1.4
0.1-0.2
NA
Lewington VJ, et al. Eur J Cancer 1991;27:954-8
Sartor O, et al. Urology 2004;63:940-5
Treatment in metastatic prostate cancer
Bone pain palliation
•
•
•
•
•
•
•
Analgesics
Bisphosphonates
Chemotherapy
Hormonal therapy
External beam radiotherapy
Surgery
BONE SEEKING RADIOPHARMACEUTICALS
- Simultaneous treatment of multiple sites
- Concentrate at sites of increased bone turnover (selectively sparring
healthy bone and associated bone marrow)
- Control metastatic bone pain and improve quality of life as an effective
alternative treatment to conventional therapies (analgesics, external
beam radiotherapy)
- Repeatability
- Potential integration with the other treatments
Treatment in metastatic prostate cancer
Bone pain palliation
Recommended activities
• Slow intravenous infusion, followed by saline flush, of
– 89Sr-chloride: = 150 MBq
– 153Sm-lexidronam = 37 MBq/kg,
– 186Re-etidronate = 1,295 MBq
• The amount of activity to be administered should be checked
with an isotope calibrator ( emission)
Treatment in metastatic prostate cancer
Bone pain palliation
Efficacy
• Improved pain control and reduction of analgesic
consumption
– Unlikely immediately after therapy
– More probable 2 weeks after therapy
– Delayed even to 4 weeks, especially with 89Sr-chloride
• Duration of response
– Prolonged: up to 12 months with 89Sr-chloride
– Shorter duration: up to 5-9 months with 153Sm-lexidronam
and 186Re-etidronate
Modified from Lewington V. J Nucl Med 2005
Treatment in metastatic prostate cancer
Bone pain palliation
Side effects
• “Flare” phenomena, usually within 72 hrs, in 10% of pts
• Myelotoxicity: decrease in PLT and WBC
– 3-5 weeks nadir for 153Sm-lexidronam or 186Re-etidronate
– 12-16 weeks nadir for 89Sr-chloride
– bone marrow reserve
Retreatment
• In responding patients when pain recurs
• Quality of response may decrease
• Haematological parameters must be recovered:
– 8 weeks for 153Sm-lexidronam
– 6-8 weeks for 186Re-etidronate
– 12 weeks for 89Sr-chloride
Treatment in metastatic prostate cancer
Combined treatment
Loberg, R. D.
J Clin Oncol; 23:8232-8241 2005
Ricci, S.
Eur J Nucl Med; 34:1023-30 2007
Treatment in metastatic prostate cancer
Bone pain palliation
Advantages
• Stabilization and reduction of tumour markers
• Delayed occurrence of new painful sites and new metastases
• Better response in patients with few metastases
Disadvantages
• The exposure of surrounding tissues to β-emissions can be
associated with toxicity (relatively long range of the radiation)
• The consequent myelosuppression limits the dosages that can be
given and the use of repeated therapy
• Beta-emitters produce low LET radiation which has a low probability
for inducing double strand DNA breaks
• Prejudices: myelosuppression, high costs
• The late use is associated with an unlikely benefit
• Neither drug confers a survival advantage
Finlay IG, et al. Lancet Oncology 2005;6:392-400
Nilsson S, et al. Clinical Cancer Research 2005;11:4451-4459
Treatment in metastatic prostate cancer
Alpha treatment
Radiopharmaceutical T½
(d)
E
(keV)
Range
(mm)
Nuclide
32P
89Sr
153Sm
166Ho
186Re
188Re
85Sr
117mSn
223Ra
Max Ave
1710 695
1490 583
810
224
1840 665
1080 329
2120 795
15 (e- Auger)
150 (e- Auger)
5.8 ()
Max Ave
7.9 1.85
6.7 1.75
3.4 0.53
9
NA
4.7 0.92
10.8 2.43
10 nm
30 nm
50 µm
Labelled
Phosphate
Chloride
EDTMP
DOTMP
HEDP
HEDP
Chloride
DTPA
Chloride
14.3
50.5
1.95
1.1
3.77
0.71
64
14
11.4
Dose
E
(keV) (cGy/MBq)
103
81
137
155
514
159
154
Lesion
5
23
67
NA
2
NA
8.2
5.4-8
NA
Bone
0.6
1
15
NA
0.1
NA
1.4
0.1-0.2
NA
Radium-223-chloride (Xofigo)
39
Radium Ra 223 Dichloride:
γ-Decay appearance
Tc
Ra
Radium-223-chloride acts as a calcium mimic – hence it is
incorporated into the bony matrix and directly targets new bone
formation in and around bone metastases
41
Short Range of α-Emitters Reduces Bone
Marrow Exposure1
Marrow
Marrow
Radium Ra 223
dichloride
β-emitter
Bone
Range of α-particle:
(short range – 2 to 10 cell diameters2)
Bone
Range of β-particle:
(long range – 10 to 1000 cell diameters2)
1. Henriksen G, et al. Cancer Res. 2002;62:3120–3125. 2. Brechbiel MW. Dalton Trans. 2007;43:4918-4928.
42
Radium 223 Dichloride:
Tumour
cells
Osteoblast
Bone
marrow
Calcium analogue
(eg Radium 223)
Attached to
phosphate
Osteoclast
Targets newly formed bone,
eg bone metastases
Bruland et al. Clin Cancer Res 2006;12:6250s
Alpha particle irradiates
adjacent tumour cells leading
to highly localized tumour cell
killing
43
ALSYMPCA Updated Analysis:
Radium-223 Significantly Improved Overall Survival
The updated analysis confirmed the 30% reduction in risk of death (HR = 0.70)
for patients in the radium-223 group compared with placebo.
100
MEDIAN OS (months)
— Radium-223: 14.9
— Placebo: 11.3
Survival, %
80
HR (95% CI): 0.70 (0.58–0.83)
OS
∆=3.6
mos
60
P <0.001
40
20
0
0
3
6
9
12
15
18
21
24
27
30
33
36
39
7
4
1
2
0
1
0
0
Months Since Randomization
— Radium-223
— Placebo
614 578 504 369 274 178 105
307 288 228 157 103 67 39
60
24
41
14
18
7
CI, confidence interval; HR, hazard ratio; OS, overall survival.
SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213-23.
44
Poster ASCO 2013
45
Dose protocol
The patient dose is specific for each patient:
50 kBq per kg of body weight
Volume to inject (mL) =
Body weight (kg) × 50 kBq/kg body weight
DK × 1000 kBq/mL
The treatment is repeated 6 times
Complete treatment = 6 injections at 4-week intervals
46
Radium Ra 223 Dichloride Is Administered as a
Simple IV Injection in an Outpatient Setting
• Administered at a
licensed facility
• No shielding required
• Note: Before and after
injection, the cannula
is flushed with saline
• Patient comes in for injection
and can leave right afterwards—no shielding or monitoring of the
patient required
• No restrictions with regards to contact with other people
IV, intravenous.
47
Take home messages: diagnosis
• What is bone scan?
 Radionuclide imaging of bone activity with 99mTc-DP or, better, 18F-NaF
• What is the use of bone scan?
Conclusions
 Detection of bone lesions with high sensitivity and poor specificity
• Bone scan in prostate cancer
 Detection of osteoblastic activity around metastasis
 Particularly useful in case of choline negative and highly dense sclerotic
lesions
Conclusions
Take home messages: treatment
• Systemic radionuclide therapy represents a feasible, safe, effective,
well tolerated and cost-effective palliative treatment in patients with
refractory bone pain
 Only patients with a reasonably good general condition should be
candidate for this treatment (radioprotection rules)
 Patients at an early stage of metastatic disease benefit the most from
treatment
• However,
 the evaluation of the pain relief is difficult (subjectivity, placebo), the
dosimetric calculations are not implemented yet
 the competition with chemotherapy/bisphosphonates is strong
• Radium-223 dichloride (novel alpha emitting radiopharmaceutical)
showed a significant prolonged OS in CRPC patients with bone
metastases
 Xofigo may provide a new standard of care
Radioactivity to Cure Cancer