Dosimetry and radiobiology for Peptide Receptor Radionuclide Therapy

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1 Dosimetry and radiobiology for Peptide Receptor Radionuclide Therapy Short-ranged particle emitters for targeted radionuclide therapy require specific dosimetry and radiobiology Mark Konijnenberg Melodi Workshop Brussel, 9 Oct. 2013

2 Peptide Receptor Radionuclide Therapy Targeting for diagnosis and therapy Succesful diagnostic Somatostatin receptor positive tumours SPECT ( 111 In-DTPA-octreotide / Octreoscan) PET ( 68 Ga-DOTA-octreotide) Radiopeptide Succeful therapy neuro-endocrine tumours 90 Y-DOTA-octreotide Receptor OS: 95 months, (A Imhof et al., J Clin Onc 2011) 177 Lu-DOTA-octreotate OS: 128 months, (D Kwekkeboom et al., J Clin Onc 2008)

3 Dosimetry and radiobiology for PRRT Treatment schedule and dose limits current therapy Kidney dosimetry and late renal toxicity Ways to improve radionuclide therapy with PRRT Dosimetry guided treatment planning High LET radionuclides: -emitter 213 Bi Dosimetry and radiobiology models for PRRT Dose rate effect in kidney toxicity: BED Non-uniform dose distributions: DV constraints Small scale dosimetry for nephrons Cellular dosimetry for macroscopic tumours Equivalent Uniform Dose model for PRRT?

4 Treatment schedules in the clinic for PRRT Series of treatment cycles with fixed activity Amino-acid infusion to reduce renal uptake GBq/m 2 90 Y-DOTA-octreotide GBq 177 Lu-DOTA-octreotate Combination of both Absorbed doses in fixed activity treatment schedules 90 Y-DOTAoctreotide 177 Lu-DOTAoctreotate Kidneys 24 Gy (20 38) 18 Gy (14 22) Bone Marrow 2 Gy ( ) 0.5 Gy ( ) Tumour 44 Gy (8 560) 200 Gy (4 600) R Barone et al., J Nucl Med 2005 L Bodei et al., Eur J Nucl Med Mol Im 2008 M Sandström et al., J Nucl Med 2013

5 % Incidence of end-stage renal disease (CLR > 20 % / year) 90 Y-DOTA-octreotide renal toxicity 9% (102/1109) incidence of renal toxicity after 1-10 cycles of therapy A. Imhof et al., J Clin Onc % 75% 50% 25% XRT data NTCP: XRT Barone Bodei NTCP: DCT (MIRD) Threshold for late occuring kidney toxicity after XRT radiotherapy: Gy in 2Gy fractions L Dawson et al., I J Rad Onc Biol Phys % Kidney dose (Gy) B. Wessels et al., J Nucl Med 2008

6 Linear Quadratic model (dose rate effect) explains shift Repair mechanism sub-lethal damage during exponential decay dose delivery Biological Effective Dose BED Nd 1 T eff T T LQ model parameters / = 2.5 Gy: ratio of direct to repairable damage T µ = 2.8 h: repair half life N number of fractions d Absorbed dose per fraction T eff Effective decaytime d / Threshold BED = 40 Gy

7 Radiation exposure is not the only risk factor 90 Y DOTATOC (N=28) 90 Y DOTATOC or 177 Lutate (N=65) Hypertension Diabetes Old age (>60 y) Kidney absorbed dose per cycle > 14 Gy Valkema, J Nucl Med 2005

8 Dosimetry guided treatment planning for PRRT? BED dose limit depends on risk factors for renal radiation damage: 40 Gy without risk 28 Gy with risk Independent of radionuclide, just BED At risk (12 pts), BED limit ~28 Gy M Cremonesi, Q J Nucl Med Mol Im Is the limit for mean kidney dose equally applicable for 177 Lu?

9 No renal toxicity observed after 177 Lu-DOTA-octreotate 2 / 504 patients with renal insufficiency (unrelated to the therapy) Even no toxicity in patients retreated after relapse 35 patients initial therapy 4 x 7.4 GBq 177 Lu-DOTA-octreotate Absorbed dose 1 st therapy: 18 6 Gy Additional cycles salvage therapy: 2 4 x 7.4 GBq Cumulative kidney dose: 26 9 Gy (12 46)

10 Dose volume constraints for renal toxicity risk of < 5% External Beam RT Mean kidney dose <18 Gy Mean BED 32 Gy Dose-Volume constraint V 28Gy < 20% PRRT dose limits 90 Y-DOTA-octreotide (N=2) Mean dose < 23 Gy 177 Lu-DOTA-octreotate (N=4) Mean dose < 28 Gy Dose Volume Histograms? Dawson, Quantec paper IJROBP 2010

11 Dose Volume Histogram 90 Y-DOTA-octreotide macrodosimetry scale SPECT/CT uptake 111 In-DTPA-octreotide in kidney cortex Isodose curves for 90 Y absorbed dose (27 Gy) Reduction to DVH 111 In 177 Lu 90 Y similar DVH? S. Baechler et al., Med Phys 2012

12 Dose distribution in the kidneys on smaller scale Ex-vivo autoradiography kidneyuptake 111 In-DTPA-octreotide Different dose distributions M.Melis et al., J Nucl Med 2010 M.Konijnenberg et al., J Nucl Med 2007

13 Dose Volume Histogram for mean kidney dose of 27 Gy activity distribution following autoradiography XBRT Dose Volume constraint V 28Gy <20% 28 Gy in Gy BED 42 Gy 90 Y (T 1/2 = 64 h) Volume with dose > 33 Gy V 33 = 21% 177 Lu (T 1/2 = 160 h) Volume with dose > 38 Gy V 38 = 12%

14 Method to improve efficacy of PRRT: - emitters High LET: > 500x that of β-emitter Difficult-to-repair DNA double strand breaks Short range: 2-10 cell diameters Minimal damage to surrounding normal tissue 213 Bi easy obtainable from 225 Ac generator Also effective against radio-resistant cells and under hypoxic conditions. F. Giesel et al., Exp Oncol 2013

15 Effect of short-ranged -emitters Dose distribution kidneys on functional subunit scale Dosimetry for -particle emitters 225 Ac / 213 Bi Range -particles: 5.9 MeV 225 Ac: 47 m 8.4 MeV 213 Bi: 85 m Size human nephron: Glomerulus 150 m Tubule lumen 33 m S-value 213 Bi human Cortex: 6.9 Gy/MBq.s Glcprt: 1.5 Gy/MBq.s R.Hobbs et al., Phys Med Biol 2012

16 Absorbed doses in neuroendocrine tumours PRRT in comparison to adjuvant XBRT radiotherapy PRRT ( 90 Y-octreotide) Median absorbed dose Responding: 232 Gy Non-responding: 37 Gy Median volume 24 ml External beam radiotherapy after surgery Median absorbed dose to tumour 50 Gy 1.8 Gy fractions Residual disease < 10 ml Arvold, Int J Rad Oncol Biol Phys 2012 S Pauwels et al., J Nucl Med 2005

17 Dose distribution PRRT for heterogeneous models Disease Cure Probability DCP = TCP i 1 Large tumour (8 g) 5, 3 & 1 mm cold spheres +10 Small lesions (1 mm) TCD 50 = 60 Gy a = -12 (~minimum dose) 50 = 2 DCP model, at 28 Gy kidney dose favours combination of 177 Lu with 125 Sn (0.8 MeV ) Walrand, Phys Med Biol. 2012

18 Use of Equivalent Uniform Dose for radionuclide therapy SF 131 I Tositumab therapy NH Lymphoma i = 0.22 Gy -1 / = 10 Gy exp( d N 1 EUD ln EUD from tumour DVH Correlation between tumour shrinkage and EUD i ) exp( EUD) i exp( di ) N H Amro et al., J Nucl Med 2010

19 Tumour Cure Probability 177 Lu-DOTA-octreotate can cure large tumours at absorbed doses below 200 Gy 95 Gy in 200 g tumour 90 Gy in 1 kg (13 cm!) tumour 16-Jul-04 5-Aug-05 L Bodei, J Endocrinol Invest 2009, Aug-08, 3 yrs. 1 0,8 0,6 0,4 0,2 homogeneous 10% variance 15% variance 20% variance Tumor control probability 200 g tumour = 0.3 /Gy / = 8 Gy Mass 100 g Uniform dose distribution by 177 Lu-DOTA-octreotate Absorbed dose (Gy)

20 Cost function for EUD calculation FSU-based dosimetry? XRT: Beam configuration defined absorbed dose to OAR or PTV PRRT: Physiologically defined absorbed dose in OAR Receptor density and perfusion defined target dosimetry

21 Dosimetry and radiobiology for PRRT Summary and conclusion 1. Dose-effect relation for late kidney damage after PRRT with -emiters Dose rate dependence by LQ model: BED limit 40 Gy 90 Y (T 1/2 64h) lower threshold than 177 Lu (T 1/2 160h) Possibly dependant on dose distribution 2. Improvement of therapeutic efficacy PRRT Dosimetry guided treatment planning What is the absorbed dose-volume limit for 177 Lu? What tumour dose is needed and which non-uniformity acceptable? Therapy with -emiiter 213 Bi labelled peptides Small scale dosimetry model at functional sub unit level Incorporation of FSU dosimetry into EUD model

22 Acknowledgements: Marion de Jong, Roelf Valkema and all colleagues at nuclear medicine

23 The Theranostic Approach : YouTube Movie Action BM0607, raise interest of the public