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USE OFRADIONUCLIDE
THERAPY:
ACTUAL CLINICALAPPLICATIONS?
J. Boratynski
R. KristensenF. BruchertseiferZurich, 2010
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Outline1. Aim of radionuclide therapy2. Radionuclides for therapy parameters and
characteristics.
3. Linkers parameters and characteristics.4. Carriers parameters and characteristics.
5. Examples.6. Future/Clinical Trials.
7. Summary.
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Aim of radionuclide therapyThe fundamental objectives for radionuclide therapy are:
1. To achieve appropriate treatment of the disease through
delivery of a radiation dose at the desired cytotoxic levelwith the defined endpoints being cure, disease control(stabilization) or palliation.
2. To avoid or minimize toxic effects (spare normal organs),both in the acute time frame and as long termcomplications. The goal of radionuclide therapy is tomaximize the therapeutic index as represented by the
ratio of the radiationdose delivered to the tumor to thatdelivered to normal tissue.
S.R. Thomas, Cancer Biotherapy & Radiopharmaceuticals, 2002, 17, 1, p.71
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Target
Structure
Carrier RadionuclideLinker
Carriers:
Monoclonal antibodies, Peptides (somastotatin analogues), Small
molecules (sugars, amino acids), Liposomes, Microspheres, Particles
Linkers:
DOTA, NOTA, TRITA, DTPA
Radionuclides:
90Y, 177Lu, 186Re, 131I, 153Sm 211At, 212Bi 193mPt Auger
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Radionuclides for therapy
parameters and characteristics
- stable daugher isotope
- a proper type of radiation (, Auger electrons, )
- apropriate physical half-life time (hours, days)
- radiation energy + high LET (effective cell irradiation~300 keV)
- range of radiation:Auger electrons ~ nm
~ m
~ mm
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Linkers parameters and
characteristics
- conjugate metal and carrier bifunctional
- chelate metal
- couple with carrier
- stable in-vivoconditions (kinetically inert)
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Carriers parameters and
characteristics
- reach matastases via blood stream- relatively long biological half-life time
- stable in-vivo
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non-Hodgkins lymphoma (NHL)
Target: CD20 receptor on mature b-cells
Pre-treatment: rituxan (naked antibody)clearing the majority of normal b-cells - the therapeutic radiolabeledantibody is more focused on tumor cells.
Mechanism: the monoclonal antibody recognizes and attaches to theCD20 antigen, allowing radiation emitted by radioisotope to
penetrate and damage the B-cell as well as neighboring cells.
Zevalin: 90YT1/2=2.7 d
Energy: 2,28 MeV
Bexxar: 131IT1/2=8 d
Energy: 600 keV , 364 keV
[http://www.lymphomation.org/compare-bexxar-zevalin.htm]
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ZevalinBexxar
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Neuroendocrine tumours
177Lu-DOTATATE, 177Lu-DOTATOC 90Y-DOTATATE, 90Y-DOTATOC
Target: somatostatin receptors. The somatostatinreceptor is strongly over-expressed in most tumours,resulting in high tumour-to-background ratios.
25% of patietns achieving objective tumour shrinkage
>50%. Serious side-effects have been rare.90YT1/2=2.7 dEnergy: 2,28 MeV
177LuT1/2=6,7 d
Energy: 497 keV
, 208 keV
F. Forrer et al., Best Practice & Research Clinical Endocrinology & Metabolism, 2007, 21,1, p. 111-129
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Thyroid carcinoma
Na131I
in capsules and i.v. (also diagnosis) target: thyroid
mechanism: thyroids iodine uptake
the oldest and most succesful radiopharmaceutical
since: 40
T1/2=8 d
Energy: 600 keV , 364 keV
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Phaeochromacytoma & Neoblastoma
131I-mIBG
Similar tonorepinephrine
Uptake by adrenergicreceptors
123I 159 keV & 27 keV 131I 606 keV 89% IncidencePhaeochromacytoma
2-8/106 pr. Year
Neoblastoma 2/106 pr.
Year
norepinephrine
I-mIBG
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Phaeochromacytoma & Neoblastoma
40 patients received 131I-MIBGtherapy. May 1996 to May 2006
Strong uptake of 123I-MIBG, byScintigraphy.
7.4 GBq pr. treatment cycle.Average 1.8 cycles.
11 patients showed reduction intumour size post-therapy.
27 patients reported improvedsymptoms after 131I-MIBG therapy.
11 patients required hospitalisationas a consequence of complications(bone marrow suppression).
Median survival increased by 37months (symptomatic responders).
norepinephrine
I-mIBG
Nwosu et al. British Journal of Cancer (2008) 98, 1053 1058
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Synoviorthesis
Hydroxyapatite particles (HA)
90YCI3
90Y-Colloid
For Rheumatoid Arthritis,Osteoarthritis and others.
Mainly used in knee's. In practice since the 60's.
Principle:The colloidal particles arephagocytized by the synovial liningcells. The energy released effects a
therapeutically active irradiation of thesurrounding synovial tissue, resultingin a fibrotic and sclerosed synovialmembrane.The inflammatory and destructive
processes is stopped, which leads toan alleviation of the pain and effision,followed by an occlusion of superficialcapillaries.
90Y citrate or silicate colloid 111-
222MBq.
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Synoviorthesis
Review of articles from 1975-2006. (Medline, Embase,Biosis, Derwent Drug file,SciSearch)
Conclusions:
Minimally invasive therapy.
Treatment is efficacious
In view of benefits, tolerabilityand safety are very good
Important!
Post-treatment immobilizationand the co-administration ofcorticoids, to minimize the riskof leakage and of efflux through
the puncture channel.Review article by Kampen et al.,Rheumatology 2007;46:1624
90YCI390YCI3
Hydroxyapatite particles (HA)
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Hepatoma
Sirtex particles
Gastric Mucosa
90Y- micro Particle
TheraSphere - Glass particles
Sirtex - Polymer particles
Principle:Solid particles are inserted into the
hepatic artery of the tumor,cause embolisation in the
tumor microvasculature andtumor irradiation.
Normal liver parenchyma ispredominantly supplied with
blood from the portal vein.
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Hepatoma
Sirtex particles
Gastric Mucosa
Lim et al. BMC Cancer 2005, 5:132 doi:10.1186/1471-2407-5-132
30 patients Jan 2002-Mar 2004
Hepatic metastasis
from colorectal cancer
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Bone Metastasis
153Sm-EDTMP
Ethylenediaminetetra(methylenephosphonic acid)
Approved for palliativetreatment in the USAsince 1998
Standard palliativedose 1mCi/kg
T=46,27h
Bind to Ca2+
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Bone Metastasis
Review of:Three randomized phase III trials,Two randomized phase II trials
Metastatic Breast prostate and
lung cancer. Conclusion: Samarium-153
should be considered as apossible optionfor the palliationof multiple sites of bone pain frommetastatic cancerwherepain
controlwith conventionalanalgesic regimens isunsatisfactoryand where activityon a bone scan of thepainfullesionsisdemonstrated. Ongoingclinical research should seek toestablish the benefit of newerradiopharmaceuticals andradiopharmaceuticals incombination with other systemictherapies
Bauman et al. Radiotherapy and Oncology 75 (2005) 258.e1258.e13
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clinical trials - At-211-MX35 F(ab)2 [phase I]
Aim:- to determine the relevant pharmacokinetics for assessing absorbed dose tonormal tissues and investigating the toxicity
Methods:
-appr. 500 MBq of 211At was labeled to 0.7 mg of MX35 F(ab)2 using the reagentN-succinimidyl 3(trimethylstannyl) benzoate
- 50 MBq (3 patients) or 100200 MBq (6 patients) in 12 L of Extraneal was infusedvia the peritoneal catheter
Results:
- At-211 was found peritoneal fluid, serum (to 6% IC after 30 h) and thyroid to127 63% at 20 h without blocking < 20% IC with blocking
- no other organ uptakes could be detected
- estimated absorbed dose to the peritoneum was 15.6 1.0 mGy/(MBq/L)
- no adverse effects were observed either subjectively or in laboratory parameters
Conclusion:- intraperitoneal administration of 211At-MX35 F(ab)2 it is possible to achieve
therapeutic absorbed doses in microscopic tumor clusters without significant toxicity
Andersson et al, Journal of Nuclear Medicine 2009;50:11531160
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clinical trials - I-131-Labetuzumab [phase I/II]
Liersch T, et al Ann Surg Oncol 2007;14:2577
Aim:- RIT using I-131 labetuzumab (anti-CEA) after the salvage resection ofcolorectal (CRC) liver metastases (LMs)
- liver is the only metastatic site in 30%40% of CRC patients
- 5-year survival rate is 0%3%
Method:-40-60 mCi/m
I-131 labetuzumab-2x40-50 mCi/mI-131 labetuzumab
Outcome:Safe, feasible, well acceptedProloged survival time
Phase III
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clinical trials - Lu-177/Y-90 PRRT
http://www.carcinoid-call-point.de/assets/Patienteninformation_RRT_fuer_INTERNET_2006-08.pdfD. J. Kwekkeboom et al, Eur. J. Nucl. Med. Mol. Imag. 30/2003, 417-22Waldherr C et al, Ann Oncol. 2001 Jul;12(7):941-5
Frilling et al, Surgery, 2006, 140(6), 969
Aim:- peptide radioreceptor therapy (PRRT) with Lu-177/Y-90 for neuroendocrine tumors- peptide [DOTA0,Tyr3]octreotide (DOTATOC) and [DOTA0,Tyr3]octreotate(DOTATATE), specific for somastotatine receptors
Method:- 3 +/- 2 GBq Y-90 peptide- 7 +/- 3 GBq Lu-177 peptide
Outcome:According WHO criteria- CR 2%- PR (more 50%) 22%- PR (25% - 50%) 12%- SD 49%
http://www.carcinoid-call-point.de/assets/Patienteninformation_RRT_fuer_INTERNET_2006-08.pdfhttp://upload.wikimedia.org/wikipedia/commons/2/2b/DOTATOC.pnghttp://www.carcinoid-call-point.de/assets/Patienteninformation_RRT_fuer_INTERNET_2006-08.pdf8/4/2019 10 Radionuclides for Therapy
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clinical trials - Ac-225/Bi-213 CD33 [phase I/II]
Phase I:
18 patients with relapsed and refractory AML (acute myelogenousleukemia) or CML (chronic myelomonocytic leukemia)
0.3 - 1.0 mCi/kg body weight of 213Bi-HuM195 (anti-CD33) no significant toxicity 14/18 patients responded
Phase I/II (ongoing):
elimination of residual disease after partial cytoreduction using cytarabine > 30 AML patients treated so far 0.5 1.25 mCi/kg body weight of 213Bi-HuM195
MTD 1 mCi/kg 24% of patients receiving 1 mCi/kg (n=25) responded (2 CR, 2 CRp, 2PR)
T. Rosenblatt et.al. submitted
J. Jurcic, Blood 2002
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clinical trials - Glioma/Glioblastoma [phase I]
At-211-labeled chimericantitenascin antibody, 81C6
Outcome:
- 97% of At-211 occurred in thesurgical resection cavity
- survival increased to 52 weeks inglioblastomas and 97 weeks innonglioblastoma tumors 77
- historic control of 31 weeks
- limitation in the specific activity
Zalutsky et al J Nucl Med 2008;49:30
Substance P labelled with Lu-177/Bi-213
(Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH-R)Outcome:
- only transient toxicity was seen as symptomatic radiogenic edema in one patient
- disease stabilization and/or improved neurologic status was observed in 13 of 20 patients- resection disclosed widespread radiation necrosis with improved demarcation
TAT with diffusible peptidic vectors for local control of malignant gliomas
Kneifel et al Clin Cancer Res. 2006 Jun 15;12(12):3843-50
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clinical trials - melanoma [preclinical/phase I]
Rhenium-188
- Re-188 sulfur colloid, tin colloid or microspheres on carrier e.g. filter paper, emulsion- doses appliceted 50 to 100 Gy
Jeong et al, Appl RadiatIsot 2003;58:551
Bismuth-213
- Phase I study on grade IV malignant melanoma / in-transit metastases usingBi-213 labelled mAb 9.2.27
Results: 48 patients treated with 1.5 to 27 mCi Bi-213-9.2.27
- 12% partial response
- 50% stable disease- 38% progressive disease- no signs of adverse effects
C. Raja et al, Cancer Biology & Therapy 6:6, 846-852; 2007
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Summary
- long tradition of radionuclide therapy- radionuclide therapy especially the radioimmunonuclide therapy large potential
- use of beta and alpha emmiting radionuclidese.g. Y-90, I-131, Sm-153, Lu-177, Re-186/188, At-211, Bi-213 etc.
-commercially used vectorse.g. Zevalin, Bexxar, EDTMP, HDEP
-Variety of clinical trials with further AB and peptidese.g. CD33, Labetuzumab, Substance P, DOTATOC, DOTATATE
Outlook
- more specific targeting- use of alternative radionuclides specifically for the type of tumors (
or Auger-
emiters)
- combination of antibodies and peptides (pre-targeting)
e.g. modified CD22 with IMP-288 (B-cell cancer)
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