M.Beran 3-rd International Summer Student School, July 2005, Dubna-Ratmino 1

Therapeutic Effects of Beta Radiation in Therapeutic Effects of Beta Radiation in Nuclear MedicineNuclear Medicine

Miloš BERANRadiopharmaceutical Department

Nuclear Physics InstituteCzech Academy of Sciences

Řež near Prague

milber@atlas.cz

M.Beran 3-rd International Summer Student School, July 2005, Dubna-Ratmino 2

General characteristics of nuclear medicine General characteristics of nuclear medicine interdisciplinary positioninterdisciplinary position

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Classification of Classification of ββ--radionuclides for use in nuclear medicineradionuclides for use in nuclear medicinefrom J. Zweit: Phys Med Biol from J. Zweit: Phys Med Biol 41 41 (1996) 1905(1996) 1905--19141914

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M.Beran 3-rd International Summer Student School, July 2005, Dubna-Ratmino 5

Low energy electrons (Auger electrons) emittingLow energy electrons (Auger electrons) emittingradionuclidesradionuclides

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ββ--particles soft tissue range of some radionuclides particles soft tissue range of some radionuclides in radionuclide therapyin radionuclide therapy

J. Carlsson et al., Radiotherapy and Oncology 66 (2003) 107–117

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Therapeutic use of some Therapeutic use of some ββ--radionuclidesradionuclides

J. Zweit: Phys Med Biol 41 (1996) 1905-1914

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Classification of radionuclide therapyClassification of radionuclide therapy

Embolization and necrotization of localized solid tumours• Intra-arterial application of radionuclide-bearing (90Y,

166Ho,…) microspheres (glass, resin, polylactic acid, etc.)• Injection of gel-formating labelled sol (e.g. 166Ho chitosan)

into tumourRadiosynoviorthesis (therapy of arthritic joint diseases) withsuspensions of insoluble radionuclide compounds (90Y citrate colloid,166Ho boromacroaggregates, ferric hydroxide macro-aggregates)Targeted radionuclide therapy using biomolecules• Palliative therapy of bone metastases with 89Sr chloride,

153Sm,186Re phosphonates• Radioimmunnotherapy with „smart“ biomolecules likemonoclonal antibodies (labelled, e.g., with „carrier free“ 90Y)against disseminated cancer cells and metastases

M.Beran 3-rd International Summer Student School, July 2005, Dubna-Ratmino 9

Vascularization of solid tumoursVascularization of solid tumours

Mean diameter of radioactive particles for clogging (embolization) and necrotization of blood capillaries is about 40 µm

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166Ho Poly Lactic Acid (PLA) microspheres

Single 166HoPLA microsphere in normal liverparenchyma (A) and cluster of microspheres

in tumour tissue (B)

F.Nijsen: Eur J Nucl Med (2001) 28: 743-749

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IntraIntra--arterial embolization of head and neck cancer witharterial embolization of head and neck cancer with166166Ho poly(LHo poly(L--lactic)acid microsphereslactic)acid microspheres

R.J.J. van Es et all: Int J Maxillofac Surg 2001; 30: 407-413

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Characteristics of various radioisotopes for use in Characteristics of various radioisotopes for use in radiosynoviorthesisradiosynoviorthesis

Radionuclide Half life (days) Radiation Mean range in tissue( mm )

198Au 2.7 β and γ 1.290Y 2.7 β 3.9 (Knee)

166Ho 1.1 β and γ 3.2 (Knee)169Er 9.5 β 0.3 (Fingers)186Re 3.7 β and γ 1.2 (Elbow)

32P 14.3 β 2.6

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Typical radionuclide carriers for radiosynoviorthesisTypical radionuclide carriers for radiosynoviorthesis

Radionuclides ColloidsSuspensions

(ideal particle size 2-10 µm)186Re

90Y

169Er

166Ho

Sulphide

Citrate

Silicate

Hydroxyapatite particles

Ferrihydroxy macroaggregates

Boromacroaggregates

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Principle of radiation effect in radiosynoviorthesis

A – Radioactive particles (yellow stars) are phagocytosed with proliferatingsynoviocytes (pink) in an inflammed hypertrophic synovia (red)

B – Necrotized synovial membraneBlue upper layer (cartilage) should stay unaffected

P.Schneider et all: J Nucl Med 2005; 46: 48S-54S

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Overall Overall Success Rates for Radiosynovectomy of Different JointsSuccess Rates for Radiosynovectomy of Different Joints

Joint No. of treated patients

Success rate (%)6 mo 1 y 2 y

Knee 196 77 66 73

Shoulder 56 62 65 54

Elbow 60 51 50 50

Wrist 202 79 67 50

MCP 208 54 38 44

PIP 164 53 47 39

Hip 14 43 40 44

Ankle 58 76 100 96

Total 958 66 58 54

MCP = metacarpophalangeal; PIP = proximal interphalangeal

P.Schneider et all: J Nucl Med 2005; 46: 48S-54S

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Various biomolecules suitable as radionuclide carriersVarious biomolecules suitable as radionuclide carriers

Several different types of substances have been tried for radionuclide therapy. Examples are radioactive ions (e.g. Sr-89), low molecular weight drugs (e.g. I-131-MIBG), peptides (e.g. In-111-octreotide) and several radiolabelled macromolecular substances such as antibody fragments, various proteins, intact antibodies or antibody based conjugates and liposomes. These substances cover, as indicated, a molecular weight (MW) range of several orders of magnitude. The radionuclides are indicated as stars.

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Figure 1. Radioisotope crossfire

Vose, J. M. Oncologist 2004;9:160-172

Copyright ©2004 AlphaMed Press

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Figure 1. The HER (erb) gene family

Ross, J. S. et al. Oncologist 2003;8:307-325

Copyright ©2003 AlphaMed Press

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Figure 4. Simultaneous HER-2/neu gene amplification and protein overexpression determination

Ross, J. S. et al. Oncologist 2003;8:307-325

Copyright ©2003 AlphaMed Press

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Figure 1. Areas of potential therapeutic intervention

Nahta, R. et al. Oncologist 2003;8:5-17

Copyright ©2003 AlphaMed Press

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Most expressed antigens on BMost expressed antigens on B--Cell NonCell Non--Hodgkin Lymphoma Hodgkin Lymphoma with corresponding monoclonal antibodies (with corresponding monoclonal antibodies (mAbmAbs)s)

Target antigen Unconjugated mAb

Generic name (trade name)

Radiolabelled mAb(trade name)

B1 Tositumomab 131I-Tositumomab (Bexxar)

2B8 Ibritumomab 111In/90Y-Ibritumomab tiuxetan (Zevalin)

C2B8 Rituximab(Rituxan)

Epratuzumab (Lymphocide)

131I-Epratuzumab

111In/90Y-Epratuzumab

186Re-Epratuzumab

CD 22 hLL2

CD 20

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First radiopharmaceuticals approved for First radiopharmaceuticals approved for radioimmunnotherapy of Nonradioimmunnotherapy of Non--Hodgkin LymphomaHodgkin Lymphoma

Radiolabelled mAb

(trade name)

Producer (Supplier)

Approving Authority

Date of Registration

Biogen IDECInc.

U.S., FDA February 2002

Schering AG EU, EMEA January 2004

131I-Tositumomab (Bexxar)

GlaxoSmithKline Inc.

U.S., FDA June 2003

111In/90Y-Ibritumomab

tiuxetan (Zevalin)

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BB--cell Noncell Non--Hodgkin Lymphoma treatmentHodgkin Lymphoma treatmentwith ZEVALIN (PETwith ZEVALIN (PET--imaging)imaging)

http://www.queenspetcenter.com/brochure/HQ4101_casestudy_03.pdf

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Comparison of Therapeutic Response of BComparison of Therapeutic Response of B--cell Noncell Non--Hodgkins Hodgkins Lymphoma to Immunnotherapy (Rituxan) and Lymphoma to Immunnotherapy (Rituxan) and

Radioimmunnotherapy (Zevalin)Radioimmunnotherapy (Zevalin)

ResponseIbritumomab

tiuxetan (Zevalin) n = 73

Rituximab (Rituxan)

n = 70P-value

Complete Response 30 % 16 % 0.002

Overall Response(Complete+Partial) 80 % 56 % 0.040

Comment : Clinical Trials, n= number of patients