Transcript Document

ECCO12 Poster No. 543
Tolerability of a novel bone-seeking radionuclide, the alpha emitter radium-223,
in patients with skeletal metastases from breast and prostate cancer
S. Nilsson1, L.Balteskard2, S. D. Fosså3, J.E. Westlin4, K. W. Borch5, R. H. Larsen5, Ø. S. Bruland3
1Karolinska Hospital, Stockholm, Sweden, 2The University Hospital of Tromsø, Norway, 3The Norwegian Radium Hospital, Oslo, Norway, 4Mälarsjukhuset, Eskilstuna, Sweden, 5Algeta AS, Oslo, Norway.
Platelets
- All Dosegroups -
550
Blood clearance after intravenous
administration of Ra-223
Serum-ALP change after intravenous
administration of radium-223
100
110
90
10
ALP (% change)
Percent of injected dose
100
1
0.1
80
70
Men,
n=15
60
50
Women,
n=10
40
0
50
100
150
200
Time after administration (hours)
37 kBq/kg
70 kBq/kg
130 kBq/kg
170 kBq/kg
200 kBq/kg
450
+/- SEM
20
10
20
30
40
50
60
Figure 2. Reduction in serum-ALP
levels in patients given a single
injection of radium-223 (all dose
levels combined)
250
200
150
10
20
30
40
50
60
Results: Dose-limiting haemotoxicity was not observed in the dose escalating part
of the study. Reversible myelosuppression occurred, with nadir 2-3 weeks after
injection and recovery during the follow-up period. Neutropenia of maximum grade
3 occurred in 2 of the 25 patients. For thrombocytes, even at the two highest dose
levels only grade 1 toxicity was observed. See detailed results in Table 1 and Figure
3. Few adverse events were reported, with nausea as the most frequent event (4 of 5
patients) at the highest dose level. Reversible diarrhoea, grades 1 and 2, responding
well to medication, were occasionally observed in all dose groups. Several patients
reported pain palliation. Radium-223 was rapidly cleared from blood; after 24 hours
the blood activity level was below 1 % of the initial level for all dose groups (Figure
1). For all patients a decline in serum-ALP values was observed Figure 2). To date,
no trends towards increased myelosuppression upon repeated dosing have been
observed. In patients were gamma-camera scintigraphy was performed,
accumulation of 223Ra in skeletal lesions in accordance with 99mTc-MDP was seen
(Figure 4).
Parameters
Neutrophile
W BC
Haemoglobin
Single dose
Re-
Multiple dosing
CTC Grade 37 kBq/kg 74 kBq/kg 130 kBq/kg 170 kBq/kg 200 kBq/kg treatment 40 kBq/kg 100 kBq/kg
n=5
n=5
n=5
n=5
n=5
n=2
n=3
n=3
0
5
5
4
5
2
2
2
1
1
0
0
1
0
3
0
3
0
0
4
3
3
2
2
2
1
3
1
0
1
0
1
0
0
0
0
2
1
1
1
2
2
0
2
0
3
0
0
1
0
1
0
0
0
0
4
4
3
2
2
2
1
2
1
0
0
0
0
0
0
0
0
2
1
1
1
2
2
0
2
1
3
0
0
1
1
1
0
0
0
0
4
2
4
2
2
1
0
0
1
0
2
0
2
3
1
2
1
2
1
1
1
1
0
0
1
2
Table 1. Myelotoxicity
Reference 1: Henriksen, Breistøl, Bruland, Fodstad and Larsen, Cancer Res. 62, 3120-3125, 2002
99mTc-MDP
CTC Tox Grade 1
100
Days after injection
Days after injection
Figure 1. Blood clearance of
radium-223
300
0
Platelets
0
350
50
10
0
400
I
II
III
IV
V
9
Figure 3.
Platelets, Single dose
Dosegroup I: 37 kBq/kg
Dosegroup II: 70 kBq/kg
Dosegroup III: 130 kBq/kg
Dosegroup IV: 170 kBq/kg
Dosegroup V: 200 kBq/kg
Toxicity
30
0.01
Dosegroup
Dosegroup
Dosegroup
Dosegroup
Dosegroup
500
Platelet counts (x10 /L)
Background: Pre-clinical dosimetry and experimental therapeutic studies of the alpha emitter
radium-223 (t1/2 = 11.4 days) indicate a significant therapeutic potential against skeletal
metastases (Ref. 1).
Patients and methods: 31 patients (10 breast cancer and 21 prostate cancer patients) have
been enrolled in an ongoing phase I trial. In the first part of the study 25 patients were given a
single intravenous injection of radium-223 as part of a cohort dose escalating design. Cohorts
of 5 patients were followed weekly for 8 weeks. Initial dose level was 37 kBq kg-1 b.w.
increasing to 74, 130, 170 and 200 kBq kg-1 b.w. In the second part of the study, 2 of the
patients were given a second injection, resulting in a total dose of 200 kBq kg-1 b.w. The
tolerability of repeated dosing (100 kBq kg-1 b.w. X 2, six weeks interval, or 40 kBq kg-1 b.w.
X 5, three weeks interval) were studied in 6 prostate cancer patients. The primary objective was
to evaluate the safety and tolerance of the drug. Toxicity was monitored using NCI common
toxicity criteria and quality of life was assessed (EORTC QLQ-C 30) for all patients. Blood
clearance of radium-223 was studied in the initial 25 patients.
223Ra
Anterior
Posterior
Figure 4. Scintigraphic images demonstrating accumulation of 223Ra in skeletal lesions
in accordance with 99mTc-MDP uptake . (Image quality is dependent on dose
administered: 750 MBq 99mTc-MDP vs. 12 MBq 223Ra)
Conclusions: Radium-223 was well tolerated by patients with skeletal
metastases. Surprisingly low haematological toxicity was observed at
potentially therapeutic doses. These results justify further studies to
explore the efficacy of radium-223 as a novel targeted internal
radioisotope treatment.