The potential future of targeted radionuclide therapy: implications for occupational exposure? P. Covens

Transcription

1 The potentil future of trgeted rdionuclide therpy: implictions for occuptionl exposure?

2 Introduction: Trgeted Rdionuclide Therpy (TRT) Systemic tretment Molecule lbelled with rdionuclide delivers toxic level of rdition to disese sites Cn eliminte both primry tumour sites nd metsttic cells Ionising rdition cn exert bystnder effects Externl bem rdition therpy with high-energy X- rys Tumour-directed drugs nd toxins Current rdionuclide therpies Use b - emitting rdionuclides ( 131 I, 153 Sm, 89 Sr,, 90 Y, 32 P, 177 Lu) b - prticles (electrons) deliver energy to tumour cells Some rdionuclides hve "thernostic" properties ( 131 I, 177 Lu)

3 (More) Trgeted Rdionuclide Therpy b- (electrons) in rdionuclide therpy Emitted electrons do not deposit their min energy to the micrometsttic tumour cells Energy (nd its effects) will be relesed long severl millimetre long electron trck Tumour cell cluster Helthy tissue TRT ELECTRONS TRT, uger electrons Energy deposition electrons from site of decy trck length (mm) 177 Lu I 4 90 Y 11 More specificity? Energy deposition zone electrons Energy deposition zone, uger Alph prticles (rnge µm) Auger electrons (rnge µm)

4 Why -prticles? (1) Typicl -prticles emitted by rdionuclides of interest High Liner Energy Trnsfer (LET): kev/µm Short pth length/rnge in tissue: µm High potency nd specificity! Rdionuclide therpy with b-emitters Long tissue rnge ( > 1 mm), difficult to sterilise individul tumour cells solely Low LET: kev/µm Exception: Auger electrons!

5 Why -prticles? (2) High LET nd RBE Distnce between ionistions ~ DNA High possibility for DSB per unit of bsorbed dose X, g, b High Reltive Biologicl Effectiveness (RBE)! RBE Absorbed _ dose( Gy) _ reference rdition Absorbed _ dose( Gy) _ test rdition Prticle type, LET Totl bsorbed dose Dose rte, frctiontion Biologicl system, biologicl endpoint

6 Why -prticles? (3) RBE() for deterministic effects 5 Bsed on review of literture: 3 < RBE() < 5 for cell killing Recommended for projecting the possible deterministic biologicl effects ssocited with -prticle bsorbed dose! W R ()= 20 (rdition protection) Reltes to stochstic endpoints (e.g. cncer induction) Importnt for occuptionl exposure

7 Why -prticles? (4) Log-liner cell survivl curve Low LET: initil shoulder on the cell survivl curves reflects the repir (Liner-qudrtic model), Qudrtic: ccumultion of dmge High LET: no initil shoulder (log-liner t both high nd low doses) Log-liner reflects reduced repir cpcity (not bsence) Log-liner reflects cell deth from single event (without the need for ccumultion) Po-210 -prticles 250kVp X-rys Absorbed dose (Gy) Sgouros et l., 2010

8 Why -prticles? (5) Oygen enhncement rtio (OER) Importnt fctor in the response of cells to ionising rdition Effect strongly influenced by the LET OER Absorbed _ dose( Gy) _ with Absorbed _ dose( Gy) _ without presence oxygen presence oygen Sgouros et l., 2010 Ability of -prticles to overcome rdioresistnce due to hypoxi!

9 Why -prticles? (6) Sensitivity of cells during cell cycle Low LET: sensitivity vries during cell cycle Reltive Survivbility High LET: sensitivity is less cell cycle dependent G 1 S G 2 M G 1 Delys t checkpoints re less pronounced nd persistent in cells tht re irrdited with high LET Less dependent on ctive cell prolifertion Importnt in clinicl sitution where both tumours nd surrounding norml tissue irrdited with high LET

10 Rdiobiologicl properties -prticles Fvourble with respect to b-prticles Specificity Potency Log-liner cell survivl curve Less dependent on oxygention Less dependent on ctive cell prolifertion Stndrd in trgeted rdionuclide therpy? The vilbility of suitble -emitting rdionuclides -emitting dughters: toxicity helthy tissues (recoil energy breks chemicl bound vector) Mny pre-clinicl reserch nd clinicl trils going on, first trgeted -therpy entered clinicl routine recently

11 -emitting rdionuclides in rdition protection? -emitting rdionuclides re troublemkers! Nucler industry / NORM industry: long lived ctinides, long-lived rdium Potentil dispersion by noble gses (Rn) High rdition weighing fctor (W R =20) for stochstic effects Detection difficulties: specific -detection systems not (yet) vilble in clinicl environment High potentil rdition dose to workers, generl public?

12 How to tckle? Be wre of the source chrcteristics nd potentil exposure pthwys! Dedicted risk nlysis

13 -emitter cndidtes for TAT Pre-clinicl phse Clinicl routine 225 Ac 213 Bi 211 At 212 Bi 223 R T 1/2 10d 45.6m 7.2h 60m 11.4d Equilibrium dughters Imging potentil <1h <1s <1m <1h <1d x x x x x Reltively short hlf-live Dughter rdionuclides in equilibrium Presence of other emissions (b, g, X)

14 -emitter cndidtes for TAT Pre-clinicl phse Clinicl routine 225 Ac 213 Bi 211 At 212 Bi 223 R T 1/2 10d 45.6m 7.2h 60m 11.4d Equilibrium dughters Imging potentil <1h <1s <1m <1h <1d x x x x x

15 Dughters in equilibrium: 223 R 5.78 MeV 6.88 MeV 7.53 MeV 223 R 11.43d 219 Rn 3.96s 215 Po 1.78ms 211 Pb 36.1m b 1.37 MeV 211 Bi 2.17m 6.68 MeV 207 Tl 4.77m b 0.58 MeV 211 Po 5.16ms 6.68 MeV 207 Pb b stble 1.43 kev Dughter nuclides with very short hlf-lives re very fst in equilibrium (~ 5 h fter production) 1 kbq 223 R fter equilibrium: 1 kbq 219 R 1 kbq 215 Po 1 kbq 211 Pb 1 kbq 211 Bi ~1 kbq 207 Tl Totl: ~ 6 kbq 4 -emitters 2 b-emitters In prctice ll dughters hve the sme hlf-live of dys!!!

16 Dughters in equilibrium: 211 At 211 At 7.2h 58% EC Brnching decy of mother rdionuclide 42% 5.87 MeV 207 Bi 38y EC 211 Po 2.17m 207 Po stble 7.45 MeV Dughter nuclide 211 Po with very short hlf-live is very fst in equilibrium (< 1 min fter production) 1 kbq 211 At fter equilibrium: 0.58 kbq 211 Po <<<< ctivity 207 Bi (not in equilibrium) Totl: 1.58 kbq In prctice 211 Po hs the sme hlf-live of 211 At (7.2h)

17 Other emissions (b, g, X)? The decy of specific rdionuclides denoted s certin prticle emitter is rrely chrcterised to solely the emission of tht certin prticle! Presence of other emissions (b,g,x) during decy of mother rdionuclide nd/or dughters Disdvntges Medicl bsorbed dose to helthy tissues Potentil for incresed rdition exposure stff, public Advntges Imging cpbilities phrmcokinetics ptient dosimetry Clibrtion of therpeutic ptient doses Detection cpbilities in the frmework of rdition protection (exposure stff nd public, wste mngement,...)

18 Ptient references ctivities Therpy Ref. Activity Sr-89 Pllition bone metstsis 150 MBq I-131 Hyperthyroidism MBq I-131 Thyroid cncer MBq Sm-153 Pllition bone metstsis 2600 MBq R-223 Pllition bone metstsis 3.5 MBq At-211 Dignoses Clinicl tril in tretment of recurrent brin tumor Ref. Activity F-18 FDG PET-scn 250 MBq Tc-99m Bone scintigrphy 740 MBq MBq Unusul low ctivities! Dnger of bnlising -therpy in the frmework of rdition protection?

19 Evlution of rdition protection dt Externl rdition to workers (no contribution of -prticles) 223 R (3.5 MBq ptient dose) 211 At (100 MBq ptient dose) Dose rte ptient 1 m Dose rte unshielded syringe in contct 0.2 µsv/h <0.1 µsv/h 100% b/g 100% X 90 msv/h ~10mSv/h >90% b 100 % X Very low compred to typicl bone scintigrphy procedure Comprble to or lower thn typicl bone scintigrphy procedure

20 Evlution of rdition protection dt Rdition to workers (very lrge contribution of -prticles) 223 R (3.5 MBq ptient dose) 211 At (100 MBq ptient dose) Dose rte droplet (20µl) in contct with the skin (1% injected ct.) Effective dose fter ingestion of ctivity in 20 µl droplet (1% injected ct.) 120 msv/h 5 msv/h >95% b 100% X 6 msv 11 msv >95% >99% Comprble to typicl bone scintigrphy procedure Very high compred to typicl bone scintigrphy procedure Effective dose fter inhltion of ctivity 240 msv!!! 110 msv!!! in 20 µl droplet (1% injected ct.) >95% >99% Very high compred to typicl bone scintigrphy procedure Hygienic mesures/contmintion checks: cornerstone rdition protection procedures!

21 Hygienic mesures in hndling -emitters Importnt hygienic mesures should be tken Production Preprtion Administrtion Ptient cre Focus Stndrd Operting Procedures Prevention Contmintion mngement Contmintion survey Content of the SOP should be "especilly -emitter dedicted" (different from dily routine SOPs)

22 Contmintion surveys of -emitters Run to the shop for -counter? Use other emissions in your dvntge 5.78 MeV 223 R 11.43d 219 Rn 3.96s Severl X-rys, g-rys Geiger-Müller counter 42% 5.87 MeV 211 At 7.2h 58% EC 211 Po 2.17m X-rys NI-scintilltion counter 6.88 MeV 7.53 MeV 215 Po 1.78ms 211 Pb 36.1m b 1.37 MeV 211 Bi 2.17m 6.68 MeV b 211 Po 0.58 MeV 5.16ms 6.68 MeV b 1.43 kev 207 Pb stble NI-scintilltion counter 207 Bi 38y EC 207 Po stble 7.45 MeV 207 Tl 4.77m 2 b-emitters Absolute efficiency for 223 R NI-scintilltion counter < Geiger-Müller counter < Alph counter Advntge only t short distnce (< 1 cm)! Advntge only if loction contmintion is known Suitble for quntifiction but not for workplce survey

23 To conclude Bsed on the rdiobiologicl properties of High LET rdition, TAT hs lrge potentil Severl trils going on using typicl rdionuclides suitble for TAT 223 RCl 2 Alredy entered in clinicl routine First routinely use of -emitters in medicine Despite the reltively low reference ctivities, dedicted rdition protection ttention is needed

24 Thnks for the ttention!