UNIVERSITY OF WISCONSIN SCHOOL OF MEDICINE AND PUBLIC...

Pre-clinical radionuclide therapy dosimetry in several pediatric cancer xenografts

NCCAAPM Spring MeetingApril 15, 2016

Ian R. Marsh A. Besemer MSB. Bednarz PhD

Department of Medical PhysicsWisconsin Institutes for Medical Research

University of Wisconsin – Madison

DEPARTMENT OF

Medical PhysicsUNIVERSITY OF WISCONSIN SCHOOL OF MEDICINE AND PUBLIC HEALTH

Targeted Radionuclide Therapy

0 0

Neuroblastoma 2nd most extracranial malignant solid

tumor of childhood High mortality rate in advanced stages

mIBG Established diagnostic (123I or 124I) and

therapeutic agent (131I) for NB treatment 90% 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 20-37%

24/15/2016 | NCCAAPM Spring Meeting, La Crosse WI | Ian Marsh

(a.) 1.5 hr, (b.) 19.5 h (c.) 43.5 h, (d.) 115 h

Huang et al. (2015)


0 0 34/15/2016 | NCCAAPM Spring Meeting, La Crosse WI | Ian Marsh

CLR1404 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

Radiopharmaceutical Development


• Patient-specific treatment planning

• Evaluate dose toxicity relationships

• Evaluate tumor dose response relationships

• Determine appropriate dose prescriptions

• Identify dose limiting organs

• Determine maximum tolerated doses

Discovery and Development

Pre-clinical Trials

Clinical Trials (Phase 1-4)

Clinical Implementation

Dosimetry

0 0

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 ± 20-60% have been reported1

RAPID Robust Monte Carlo internal dosimetry platform Developed at UW - Madison Reported MC doses 6-23% larger than OLINDA

54/15/2016 | NCCAAPM Spring Meeting, La Crosse WI | Ian Marsh [1] Divoli et al 2009

1

CT/PET Fusion

ROI Contouring

Monte Carlo Simulation

Geant4

At each time pt

PET/SPECT Pre-processing

CT

Radiobiological Modeling

Coregistration Kinetic Modeling

Total Absorbed Dose Integration

Dose (Gy/MBq)Structure Min Mean Max Brain 0.24 0.78 0.85Cord 0.11 0.21 0.58Lungs 0.20 0.69 0.82Heart 0.15 0.30 0.68Testes 0.09 0.18 0.36Tumor 0.23 0.90 1.51

DVH

ROI Dose Statistics and DVHs

Simulation Output

, , ,

Absorbed Dose Rate

020406080

100

0.0 0.3 0.5 0.8 1.0 1.3 1.5

Vol

ume

(%)

Dose (Gy/MBq)

Tumor

BED EQD2 EUD

3D Dose Distribution

AD

BED, EQD2, EUDE, NTCP, TCP

Pre-treatment Image Acquisition

Serial PET/CT or SPECT/CT imagesCourtesy of Abby Besemer

Monte Carlo


CT → Geometry

Material Composition27 Major groups1

1 for air 1 for lung tissue 9 for soft tissues 15 for bone/skeletal

tissues 1 for high Z

[1] Schneider et al 2000 Phys. Med. Biol. 45 459–78[2] Tuli 2010

Monte Carlo


CT → Geometry

Material Composition27 Major groups1

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 database2

Source Position Location of decay is

uniformly sampled within each voxel

PET → Source

[1] Schneider et al 2000 Phys. Med. Biol. 45 459–78[2] Tuli 2010

Monte Carlo

0 0

Computer Clusters UW Center for High Throughput Computing (CHTC) cluster

25,000 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


Experiments


Cell Line

Mouse ID No. of Imaging Time Points [hrs]

Initial Body Weight [g]

Injected Activity [μCi]

Activity/BW [μCi/g]

CHLA20

1 1, 24, 48, 72, 96 and 144 22.8 273 12.0

2 1, 24, 48, 72, 96 and 144 23 265 11.5

3 1, 24, 48, 72, and 96 23.3 271 11.6

4 1, 24, 48, 72, and 96 24.4 273 11.2

NB1691

1 1, 24, 48, 72, 96 and 144 22.7 274 12.1

2 1, 24, 48, 72, 96 and 144 31 272 8.8

3 1, 24, 48, 72, and 96 20.5 268 13.14 1, 24, and 48** 32.6 274 8.4

Tc71

1 1, 24, 48, 72, and 170 27.9 230 8.2

2 1, 24, 48, 72, and 170 24.1 227 9.4

3 1, 24, 48, 72, and 170 26.5 229 8.6

4 1, 24, 48, 72, and 170 20.4 232 11.4

Rh30

1 1, 24, 48, 72, and 170 23.5 230 9.8

2 1, 24, 48, 72, and 170 20.7 232 11.2

3 1, 24, 48, 72, and 170 20.2 231 11.4

4 1, 24, 48, 72, and 170 25.5 228 8.9


ROI Activity

CHLA20-2

NB1691-2

TC71-2

Absorbed Dose Rate Distribution


3 hr

CHLA20-2

24 hrs 45 hrs 70 hrs 96 hrs 141 hrs

10-8

0

131I Absorbed Dose Rate ((Gy/s)/MBq)



4 hr 25 hrs 46 hrs

NB1691-2

72 hrs 98 hrs 141 hrs


10-8

0




10-8

0

1 hr 25 hrs 48 hrs 72 hrs 170 hrs

TC71-2

ROI Dose Stats


Comparison to mIBG


CH

LA20-2

mIBG

NB

1691-2

Seo, Youngho et al. (2016)

CLR1404CLR1404N

B1691

Conclusions

0 0 224/15/2016 | NCCAAPM Spring Meeting, La Crosse WI | Ian Marsh Seo, Youngho et al. (2016)

Summary Preliminary results show significant uptake and retention in

one NB cancer cell line (CHLA20) Similarities between pharmacokinetics between mIBG and

CLR1404 Initial characterization of pharmacokinetics of CLR1404 in

previously uninvestigated TC71

Future Work Complete dosimetry for remaining CHLA20, NB1691, TC71,

and Rh30 mice Comprehensive analysis of all dosimetry to draw conclusions

about uptake, retention, and dose limiting organs

Acknowledgements

0 0

Research Advisor Bryan Bednarz, PhD

UW RED Group Members Abby Besemer, MS Charlie Matrosic Andrew Shepard

Collaborators Mario Otto, MD Dana Baiu, PhD


10 0 1

Thank You!

C&

N P

hoto

grap

hy

Thank You!


Questions

TC71 Activity Distribution

TC71_11 at 72 hrs5.0E+054.0E+04 124I Activity (Bq/cc)


0 0

MIBG Established diagnostic and

therapeutic agent for NB treatment Specifically targets NB cancer cells Diapeutic agent


124I/ 123I

131I/125I

Diagnostic

Therapeutic

CLR1404 Cancer-targeted diapeutic agent Demonstrated selective uptake in

vitro and in vivo in rodent xenograft models of NB

Potentially target other cancers

131I/125I

124I/ 123I

Title

0 0

asdf


Results


UNIVERSITY OF WISCONSIN SCHOOL OF MEDICINE AND PUBLIC...

Documents

Transcript of UNIVERSITY OF WISCONSIN SCHOOL OF MEDICINE AND PUBLIC...