Pre-clinical radionuclide therapy dosimetry in several pediatric cancer xenografts

Transcription

1 DEPARTMENT OF Medical Physics UNIVERSITY OF WISCONSIN SCHOOL OF MEDICINE AND PUBLIC HEALTH Pre-clinical radionuclide therapy dosimetry in several pediatric cancer xenografts Ian R. Marsh A. Besemer MS B. Bednarz PhD Department of Medical Physics Wisconsin Institutes for Medical Research University of Wisconsin Madison NCCAAPM Spring Meeting April 15, 216

2 Targeted Radionuclide Therapy Neuroblastoma 2 nd most extracranial malignant solid tumor of childhood High mortality rate in advanced stages mibg Established diagnostic ( 123 I or 124 I) and therapeutic agent ( 131 I) for NB treatment 9% of NB is mibg avid since mibg has a similar transport mechanism to norepinephrine mibg TRT has become a standard treatment technique for recurrent or refractory cases of NB with response rates ranging from 2-37% (a.) 1.5 hr, (b.) 19.5 h (c.) 43.5 h, (d.) 115 h 4/15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh Huang et al. (215) 2

3 Targeted Radionuclide Therapy CLR144 Cancer-targeted diagnostic and therapeutic agent Phospholipid ether analog with selective uptake in vitro and in vivo Promising initial in vitro data in a variety of different pediatric cell lines. Prostate (PC-3) Glioma 4/15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh 3

4 Radiopharmaceutical Development Discovery and Development Pre-clinical Trials Clinical Trials (Phase 1-4) Clinical Implementation Identify dose limiting organs Determine maximum tolerated doses Evaluate dose toxicity relationships Evaluate tumor dose response relationships Patient-specific treatment planning Determine appropriate dose prescriptions 4/15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh 4

5 Dosimetry Limitations of standard OLINDA/EXM method Assumes homogeneous: Organ/Tumor composition Radionuclide uptake Dose deposition Phantom organs do not accurately represent individual patient s organ shapes and relative spatial distribution Dose errors of ± 2-6% have been reported 1 RAPID Robust Monte Carlo internal dosimetry platform Developed at UW - Madison Reported MC doses 6-23% larger than OLINDA 4/15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh [1] Divoli et al 29 5

6 Pre-treatment Image Acquisition CT/PET Fusion ROI Contouring Simulation Output AD BED EQD2 EUD ROI Dose Statistics and DVHs Serial PET/CT or SPECT/CT images Courtesy of Abby Besemer Monte Carlo Simulation Geant4 PET/SPECT Pre-processing At each time pt CT Radiobiological Modeling,,, BED, EQD2, EUD E, NTCP, TCP Volume (%) Tumor DVH Dose (Gy/MBq) Dose (Gy/MBq) Structure Min Mean Max Brain Cord Lungs Heart Testes Tumor D Dose Distribution Absorbed Dose Rate Coregistration Kinetic Modeling Total Absorbed Dose Integration 1

7 Pre-treatment Image Acquisition CT/PET Fusion ROI Contouring Simulation Output AD BED EQD2 EUD ROI Dose Statistics and DVHs Serial PET/CT or SPECT/CT images Courtesy of Abby Besemer Monte Carlo Simulation Geant4 PET/SPECT Pre-processing At each time pt CT Radiobiological Modeling,,, BED, EQD2, EUD E, NTCP, TCP Volume (%) Tumor DVH Dose (Gy/MBq) Dose (Gy/MBq) Structure Min Mean Max Brain Cord Lungs Heart Testes Tumor D Dose Distribution Absorbed Dose Rate Coregistration Kinetic Modeling Total Absorbed Dose Integration 1

8 Pre-treatment Image Acquisition CT/PET Fusion ROI Contouring Simulation Output AD BED EQD2 EUD ROI Dose Statistics and DVHs Serial PET/CT or SPECT/CT images Courtesy of Abby Besemer Monte Carlo Simulation Geant4 PET/SPECT Pre-processing At each time pt CT Radiobiological Modeling,,, BED, EQD2, EUD E, NTCP, TCP Volume (%) Tumor DVH Dose (Gy/MBq) Dose (Gy/MBq) Structure Min Mean Max Brain Cord Lungs Heart Testes Tumor D Dose Distribution Absorbed Dose Rate Coregistration Kinetic Modeling Total Absorbed Dose Integration 1

9 Pre-treatment Image Acquisition CT/PET Fusion ROI Contouring Simulation Output AD BED EQD2 EUD ROI Dose Statistics and DVHs Serial PET/CT or SPECT/CT images Courtesy of Abby Besemer Monte Carlo Simulation Geant4 PET/SPECT Pre-processing At each time pt CT Radiobiological Modeling,,, BED, EQD2, EUD E, NTCP, TCP Volume (%) Tumor DVH Dose (Gy/MBq) Dose (Gy/MBq) Structure Min Mean Max Brain Cord Lungs Heart Testes Tumor D Dose Distribution Absorbed Dose Rate Coregistration Kinetic Modeling Total Absorbed Dose Integration 1

10 Pre-treatment Image Acquisition CT/PET Fusion ROI Contouring Simulation Output AD BED EQD2 EUD ROI Dose Statistics and DVHs Serial PET/CT or SPECT/CT images Courtesy of Abby Besemer Monte Carlo Simulation Geant4 PET/SPECT Pre-processing At each time pt CT Radiobiological Modeling,,, BED, EQD2, EUD E, NTCP, TCP Volume (%) Tumor DVH Dose (Gy/MBq) Dose (Gy/MBq) Structure Min Mean Max Brain Cord Lungs Heart Testes Tumor D Dose Distribution Absorbed Dose Rate Coregistration Kinetic Modeling Total Absorbed Dose Integration 1

11 Monte Carlo CT Geometry Material Composition 27 Major groups 1 1 for air 1 for lung tissue 9 for soft tissues 15 for bone/skeletal tissues 1 for high Z [1] Schneider et al 2 Phys. Med. Biol /15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh [2] Tuli 21 11

12 Monte Carlo CT Geometry PET Source Material Composition 27 Major groups 1 1 for air 1 for lung tissue 9 for soft tissues 15 for bone/skeletal tissues 1 for high Z Radionuclide Decay G4RadioactiveDecay module Nuclear structure and decay information from ENSDF database 2 Source Position Location of decay is uniformly sampled within each voxel [1] Schneider et al 2 Phys. Med. Biol /15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh [2] Tuli 21 12

13 Monte Carlo Computer Clusters UW Center for High Throughput Computing (CHTC) cluster 25, CPU cores available Slices of the source distribution are simulated in parallel RED lab KING cluster 64 CPU cores available Entire source distribution simulated in each job. Output at Each Time Point Simulated until <1% relative error is achieved for the voxel mean dose 3D voxelized absorbed dose rate distribution 3D voxeleized relative error distribution 4/15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh 13

14 Experiments Cell Line CHLA2 NB1691 Tc71 Rh3 Mouse ID No. of Imaging Time Points [hrs] Initial Body Weight [g] Injected Activity [μci] Activity/BW [μci/g] 1 1, 24, 48, 72, 96 and , 24, 48, 72, 96 and , 24, 48, 72, and , 24, 48, 72, and , 24, 48, 72, 96 and , 24, 48, 72, 96 and , 24, 48, 72, and , 24, and 48** , 24, 48, 72, and , 24, 48, 72, and , 24, 48, 72, and , 24, 48, 72, and , 24, 48, 72, and , 24, 48, 72, and , 24, 48, 72, and , 24, 48, 72, and /15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh 14

15 Experiments Cell Line CHLA2 NB1691 Tc71 Rh3 Mouse ID No. of Imaging Time Points [hrs] Initial Body Weight [g] Injected Activity [μci] Activity/BW [μci/g] 1 1, 24, 48, 72, 96 and , 24, 48, 72, 96 and , 24, 48, 72, and , 24, 48, 72, and , 24, 48, 72, 96 and , 24, 48, 72, 96 and , 24, 48, 72, and , 24, and 48** , 24, 48, 72, and , 24, 48, 72, and , 24, 48, 72, and , 24, 48, 72, and , 24, 48, 72, and , 24, 48, 72, and , 24, 48, 72, and , 24, 48, 72, and /15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh 15

16 ROI Activity CHLA2-2 TC71-2 NB /15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh 16

17 Absorbed Dose Rate Distribution 131 I Absorbed Dose Rate ((Gy/s)/MBq) 1-8 CHLA2-2 3 hr 24 hrs 45 hrs 7 hrs 96 hrs 141 hrs 4/15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh 17

18 Absorbed Dose Rate Distribution 131 I Absorbed Dose Rate ((Gy/s)/MBq) 1-8 NB hr 25 hrs 46 hrs 72 hrs 98 hrs 141 hrs 4/15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh 18

19 Absorbed Dose Rate Distribution 131 I Absorbed Dose Rate ((Gy/s)/MBq) 1-8 TC71-2 1hr 25 hrs 48 hrs 72 hrs 17 hrs 4/15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh 19

20 ROI Dose Stats 4/15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh 2

21 Comparison to mibg mibg NB1691 CLR144 CLR144 NB CHLA2-2 4/15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh Seo, Youngho et al. (216) 21

22 Conclusions Summary Preliminary results show significant uptake and retention in one NB cancer cell line (CHLA2) Similarities between pharmacokinetics between mibg and CLR144 Initial characterization of pharmacokinetics of CLR144 in previously uninvestigated TC71 Future Work Complete dosimetry for remaining CHLA2, NB1691, TC71, and Rh3 mice Comprehensive analysis of all dosimetry to draw conclusions about uptake, retention, and dose limiting organs 4/15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh Seo, Youngho et al. (216) 22

23 Acknowledgements Research Advisor Bryan Bednarz, PhD UW RED Group Members Abby Besemer, MS Charlie Matrosic Andrew Shepard Collaborators Mario Otto, MD Dana Baiu, PhD 4/15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh 23

24 Questions Thank You! Thank You! 4/15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh C&N Photography 24 1

25 TC71 Activity Distribution TC71_11 at 72 hrs 4.E I Activity (Bq/cc) 5.E+5

26 Targeted Radionuclide Therapy MIBG Established diagnostic and therapeutic agent for NB treatment Specifically targets NB cancer cells Diapeutic agent CLR144 Cancer-targeted diapeutic agent Demonstrated selective uptake in vitro and in vivo in rodent xenograft models of NB Potentially target other cancers 124 I/ 123 I Diagnostic 124 I/ 123 I 131 I/ 125 I Therapeutic 131 I/ 125 I 4/15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh 26

27 Title asdf 4/15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh 27

28 Results 4/15/216 NCCAAPM Spring Meeting, La Crosse WI Ian Marsh 28