Joint ICTP-IAEA Advanced School on Internal Dosimetry. Trieste, April 2010

Transcription

1 Joint ICTP-IAEA Advanced School on Internal Dosimetry Trieste, April 2010

2 Dosimetry in PRRT: what for

3 Dosimetry has the purpose to address

4 %&!"# '!&!"#!(%)* $ *!$+

5 Most Used Radiopeptides for PRRT ) β ' 0 :+. '!β // ; /0 1;!" ) β',-+. ) γ,//!, 0/+. '!β 0 /0 12 # $ imaging/ therapy with the same complex 3! 4, 56788)!79

6 γ, β To simulate 177Lu-PRRT ' >/223 6% Aug 2004 < & 3 Nov 2004 Feb 2005 May 2005 = & > >

7 How to simulate 90 Y-PRRT?

8 How to simulate 90 Y-PRRT? #! " is recommended /// 6 The same compound used for PRRT labelled with 111 In is a good surrogate for dosimetry purposes gamma emission; T phys close to 90 Y, compatible with peptide T biol SPECT resolution!

9 To simulate 90 Y-PRRT %& γβ?1 56 behaviour identical to 90 Y; PET resolution as compared to peptide T biol, T phys (14.7 h) low Low abundance A(%) * Scarse availability days #$$ % &' ( )* + ), High energy γ rays prompt ) %,! "#$#%&'()$*+ E max 1.2, 1.5, 2.0; E γ 0.6, 1.1, 1.2, 1.9MeV

10 90 Y-Bremsstrahlung >>>!B>9 9 & /// 6 "7 #?1 56 /// 6 1? C6 ()$%&&'*+,-.' " #$%&'

11 Bremsstrahlung imaging: work in progress 5)"6."6 / " 23 '*4.4* Octreoscan MBq 90 Y-DOTATATE GBq / ) ',' )'( 7)$%&&'8-- "-.'/ 0#1234

12 further processing Bremsstrahlung images Lund University, Sweden & 5&2',4-,.49+ & 5&2'4,9+.4,,+ $ 8!( 8!(!* N:not corrected; A:attenuation, S:scatter, C:ollimator /// 6> A 90 Y-imaging is most promising and might become the future standard approach

13 What s well known

14 Typical blood clearance of peptides A (%) in the blood hours A blood ND blood A red marrow ND RM peptides f ~ 1 (MoAbs f ~ 0.3) ND peptides ND MoAbs ~ 0.2 h ~ 2.5 h / / ) $%&&::'

15 Typical elimination of peptides Urine collection peptides fast and prevalent elimination trhough the urine: MoAbs-Zevalin hours % A cumulative elimination % A in the urinary bladder (u. bladder dynamic model MIRD 14) not negligible absorbed dose to U. bladder KIDNEY

16 '( ) * (( 111 In-DOTATOC )(*+,-.( #.- /&-0)1(. 1( #!" # $ 1 h 3 h 24 h 48 h % %% %% 2 &&&!" ' (&%& A(%) days

17 Mean Doses / Activity major characteristics 177 Lu-DOTATATE 90 Y-DOTATOC for both radiopeptides: kidneys spleen liver RM testes u.bladder TB Dose / activity _Gy/GBq KIDNEYS are the critical organs, despite the renal uptake reduction reduction of 25% - 65% relatively low dose to RED MARROW (RM) Tumours (2-42) (0.6-56) Gy/GBq large variability in tumour doses Typically, for cumulative activity of 11 GBq Kidneys 27 Gy with protection RM 0.4 Gy " #$%&'

18 90 Y- & 177 Lu-PRRT schemes commonly applied Injected activities, number of cycles, time interval between cycles -. (#$$ // 0#$$ ) 3 12).-45&5 1 " ) 12) 1 " 4/&6/ '- 3 6// '+7 ' '- 3 54/ '+7 &4 4 4-'555+7 '- 3/ 6/54+7 &4 3 6-& ' '± &5+7 /3+7 ' All these are empirical schemes, mostly based on standard activities However, in PRRT, dosimetry evaluations have been seriously taken into account to plan therapy, due to some first serious side effects.this has allowed to improve information for future therapies. Cremonesi et al. QJNM 2010

19 + >? Absorbed Dose evaluations for 90Y-DOTATOC (mgy/mbq) nean values different authors mgy/mbq Kidneys Liver Spleen RM U.Bladder TB To optimise risks vs. benefits balance, TREATMENTS NEED TO BE PERSONALISED

20 What s new! improvements open questions future aims

21 1. Which peptide? dosimetry providing information

22 DOTATOC or DOTATATE? ) )$%&&'-+*-.4 &5 6τ7 & $) ',+-. τ ;6<6<6) : : : 99 7 ;6<6<6) 0: ;6<6;"

23 1. Which peptide Lu or 90 Y dosimetry providing information

24 344 5 % + From previuos experimental data: Tumor/kidney dose ratio is not always in favour of the same radionuclide 177 Lu- vs. 90 Y- DOTA-peptide However, it was noticed an advantageous ratio for Lu in 2 879: 7: 7:7;;5 case of smaller tumours, for Y for bigger tumours the answer: it depends! Tumours Kidneys

25 ," + ( Dosimetry 90 Y-DOTA-peptide for big lesions 177 Lu-DOTA-peptide for small lesions Dose factor S ratio 0,7 0,6 0,5 0,4 0,3 0,2 Dose factors S Dose factor S T (Lu) / S T (Y) 177 Lu 90 Y ' Morfology, receptors # # 3 = > < &= 3 6 "&>5::& & 26>? ; 0, ,5 2 2,5 T radius (cm) Cross fire properties could compensate non uniformity Lu 90 Y

26 Cross-fire contribution? Dose profile (Gy) Lu 90 Y uniform activities for equal mean doses mean dose isoactivity isodose Mean dose representativity very radionuclide dependent hardly influenced by activity distribution 90 Y Tumour edge higher dose in the core edge: dose < mean dose (cm) 90 Y cross-fire can be a trump card to be played against non uniformity in tumours Lu higher UNIFORMITY inside inside: dose mean dose 2/)$%&&',+4?'@8 '

27 ," + 6 # # # #7 BC < &D BC E < &D A@ *@ //2 3 4, 5 //2 3 4, * + + * *+ '"C # '"C # The model would indicate : &F & &> F??? To be verified >A :$%&'9+*.*'B$%&',,,*. " )<%&'

28 1. 2. which peptide? 177 Lu or 90 Y? 3. dose distribution advances in dosimetry 89 # 83

29 looking for activity distribution 6 : 8 Standard dosimetry Voxel dosimetry BG 7 "'&# =Α ο τ '! ( "'& '# mean doses dose distribution at voxel level &392$%&.+-

30 A new tool available for voxel dosimetry 3(6>>' > B 8>B+ * -* * (6'>> ' (link: Research Voxel Dosimetry ) 0 ::!:!;!; ;0!;?! -!1!1?!4 0? E %%. / ######## 0/. %& 1 %% $)E "$ 7$()I2 $(& 7 $ &5H7& #&# # H :# 7#:H#

31 towards dosimetry distribution,') 5.,2 feasible ' Vol % Dose %

32 6 '+ *>>' These are still open questions in PRRT... work in progress... ))<!) >

33 radiobiological model equations ( # : # 5; # ## Biological-Effective-Doses(BED) Surviving-Fraction curves (SF%) 6 BED i = D i + β/α T 1/2rep D 2 i T 1/2rep + T 1/2eff SF = exp(-α BED) or, to consider in detail the variation of dose vs. time (D t ): Tumour (including repopulation" T 1/2rep BED = D+ β/α D 2 ln2 T 1/2rep + T 1/2eff T α T av SF(D t ) = exp(-αd t -g(t) β D t ) g(t) = A [1-E t +F t ]/H t A=λ e /(λ e +µ); E t =2 λ e /(λ e -µ) exp(-(λ e +µ) t); F t =(λ e +µ)/(λ e -µ) exp(-2λ e t); H t =(1-exp(- λ e t) 2 ) : CC 6 T repair α/β 2 h 2.5 Gy α cortex 0.06 Gy -1 ( T av α/β 10, 30, 60 days 10 Gy α tum 0.3 Gy -1 clonogenic doubling time 2&3$%&'++.*9 5&2-,9.,* B&3'$%&',,,*.

34 1. which peptide Lu or 90 Y 3. dose distribution 4. Any Correlation Radiobiological Models vs. Clinical Outcomes

35 radiation nephropathy any correlation? * ' dose rate radiosensitivity repair capacity repopulation clinical data, RT 90 Y-PRRT unique NTCP curve for RT & PRRT E()JE&77(&5 ):: B$%&',,,*.

36 cycles for safety 27 )$%&&',,*9.4-50: D : : $ BED (d n) > n BED (d) fractionation: 8 higher A tot, same damage improved response lower IA/cycle less damage similar response BED (Gy) SF (%) Gain on Surviving BED sparing Fraction (Gy) for renal cortex 35 18% 30 15% % 15 9% 10 6% 5 3% 0 0% KIDNEY - dose tot (Gy) KIDNEY - dose tot (Gy) 6 cy 4 cy 3 cy 2 cy Multicycles allow a renal cell sparing up to 15%

37 Kidneys: side effects any further correlation? renal toxicity remains the major concern < >> >% % >)F;,C &! &>"!# " )F 0?C # > years 57!;797!? / > EF@ 2 )$%&&',,*9.4-

38 Red Marrow - side effects no correlation...yet.$ G 2)$%&&',,* Y-DOTATOC - mild but progressive depletion of RM resources 177 Lu-DOTATATE - lower RM toxicity, usually / )$%&&'+,.*- < 3& % :: 3& % 03&:

39 Men sterility - side effects consistence 177 Lu-DOTATATE FSH dose to the testes: 0.16 Gy/GBq Gy / cycle Inhibin-B K!99:&L#L( - D7*+ - alteration - reversible These doses are consistent with the effects observed... sterility thresholds, ICRP 60 men temporary 0.2 Gy permanent Gy women permanent Gy

40 Efficacy a correlation? )>> >%"G0-D 7 # 9 8 tumour grading, DNA repair capacity concentration, T 1/2 eff dose rate, dose Radiobiological studies are warrented 2$) '+-.50$%&'4,9'., & "23'9.'+

41 Future directions The clue: + "#* Optimised Trial Design

42 a personal message, out of the rules %) )89: Still in too many countries, scientific contributes are hold back because of governments putting funds and resources far from real progress, research, medical care There are also many countries offering today an example of what willing people can do, once relieved from a totalitarism 8 ; = =

43 ?, #! " # # " " # " $ ( >