Y90 SIRT Therapy Dosimetric Aspects

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1 Y90 SIRT Therapy Dosimetric Aspects David Chee-Eng Ng MBBS, BSc, MSc, MRCP, FAMS, FRCP (Edin) Head and Senior Consultant, Department of Nuclear Medicine and PET Singapore General Hospital Adjunct Assistant Professor, Duke-NUS Graduate Medical School Senior Clinical Lecturer, Yong Loo Lin School of Medicine, National University of Singapore

2 Y-90 microspheres Resin microspheres 50 Bq/sphere million spheres per treatment Glass microspheres 2,500 Bq/sphere 1-2 million spheres per treatment μm diameter (average diameter 40 μm) trapped by small capillary vessels. Half-life 64.1 hrs (2.67 days) Y90 mean beta energy average penetration maximum range MeV 2.5 mm (in tissues) 11.0 mm (in tissues) Targetted delivery of radiation. Delivers most of its energy in 2 weeks (5 half lives).

3 Hepatic tumour response depends on radiation dose delivered

4 Radiation delivery and treatment success depends on flow distribution of microspheres: Size, shape and physical characteristics of particles Hepatic vascular anatomy, leading to tumour sites differential blood flow in hepatic arterial branches to tumour vs non-tumour vessels. intra-hepatic arterio-portal shunting and abnormal channels leading to other organs. Radioactive properties of the particles Clinical functional status and tumour biology and radiobiological considerations

5 Microsphere flow dynamics Computational hydrodynamics simulations suggests that vessel geometry and curvature and initial injection conditions may have effect on ultimate particle trajectories. Basciano et al. J Nucl Med Radiat Ther 2011, 2:1

6 MAA mapping study Macro-Aggregated Albumin (MAA) particles are used as a surrogate of Y90 microspheres to capture the end-state of the in-vivo distribution of particles. Planar or SPECT/CT imaging To quantify liver-to-lung shunting (%) tumor-to-normal liver ratio (TNR) To determine presence of extra-hepatic activity (gallbladder, pancreas, stomach, bowel, etc)

7 Question How to determine the actual activity ( dose ) of radioactive particles to be given individualized for every patient such that: the radiation dose to the tumour is maximized? Subject to the constraints that: the dose to the normal organs are kept as low as possible? Mathematically, this is called an optimization problem.

8 Empirical dose calculation Simple. Based on % lung shunting and % tumour involvement. Body surface area (BSA) Partition model Y-90 activity calculation Semi-empirical. Widely popular method. Clinically validated. Based on Body Surface Area and estimation of tumour fraction Easy to use. The partition model is a validated and scientifically sound (MIRD) method of radionuclide internal dosimetry for Y-90 microspheres. In the standard model: there are 3 partitions: tumour, normal liver, lung.

9 Empirical activity calculation

10 Body Surface Area Method Volumetric fraction of tumour

11 Partition model Partition model takes into account partition of radioactivity between the tumour, normal liver and lung compartments

12 Distribution of microsphere particles 3 major compartments in the typical situation of Y90 microspheres distribution in the body: 1. lung 2. normal liver 3. tumour (exclude extrahepatic non-lung compartment eg: stomach)

13 Partition Model 3 unknown variables 3 equations A A A A total lung tumour liver...(1) LungShunt A A tumour lung A liver...(2) TNR A tumour A liver / / M M tumour liver...(3) 1 Gbq( Activity) 50Gy 50 J / kg

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15 Partition Model: radiation dose estimated by partition model compared against intraoperative beta-probing. coefficients of correlation for linear regression performed on the two independent sets of data were for the tumours and for the normal liver compartments (P < 0.001)

16 Partition Model: Target dose was 100 Gy to tumour Median dose delivered to the tumour was 104 Gy ( Gy) 11 patients received > 100 Gy, 5 received Gy and 4 received < 80 Gy

17 new paradigm selective administration of Y90 microspheres with arteryspecific multi-sub-partitions model. instead of lung-liver-tumour compartment, we have lung-multiple liver segment-multiple-tumour compartments model, depending on vascular territory, mapped by hepatic angiography (using CT hepatic angiography). partition modelling applied to each arterial vascular territory.

18 Three different hepatic arterial territories Give rise to different tumour uptake of particles relative to the rest of the vascular territory Tumours may also be supplied by various extrahepatic blood supply

19 Multi-subpartitions model for more precise targetted radiation delivery to tumour Different TNRs and different internal doses Instead of giving a single delivery at the proper hepatic artery to treat the whole liver, we can choose to be more selective or super-selective. E.g. deliver the microspheres at more distal branch arteries or selectively choose to treat only 1 lobe of the liver or different segments of the liver as close to the tumours while sparing as much normal liver parenchyma as possible and avoiding arteries that carry microspheres flow to other extrahepatic sites. Further, more selective delivery is important because different multifocal tumours in different parts of the liver may have different flow dynamics and different TNRs, hence to optimise the uptake (or TNR) for different tumours separately. Additionally, we have seen cases where different parts of the same tumour can have different vascular supply and different uptakes of microspheres (or TNRs).

20 Artery-Specific Multi-subpartitions model (Y90 activity calculation) Hepatic multi-subpartitions model for pre-therapy dose estimation (artery-based on MAA study) together with selective infusion of microspheres into different vascular territories, allows for more targetted delivery of Y90 radioembolization - optimize radioactivity delivery to tumours in different vascular territories while reducing radiation dose to normal liver and lung.

21 Right hepatic artery injection Left hepatic artery injection

22 Single tumour supplied by 3 vascular territories Right hepatic artery injection Middle hepatic artery injection Left hepatic artery injection

23 3-subpartitions to obtain more accurate tumour-liver ratios

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25 Subpartitions volume and counts

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27 Artery-specific SPECT/CT subpartitions modelling Results Clinical success was achieved in 7 of 8 patients, including 2 by sub-lesional dosimetry, in 1 of whom there was radioembolization lobectomy intent. Median predicted mean radiation absorbed doses were: 106 Gy (95% CI, Gy) to tumour 27 Gy (95% CI, Gy) to non-tumorous liver 2 Gy (95% CI, Gy) to lungs Across all patients, the predicted mean doses were: > 91 Gy to tumour < 51 Gy to non-tumorous liver < 16 Gy to lungs Kao YH et al. J Nucl Med 2012; 53:1 8 27

28 Artery-specific SPECT/CT subpartitions modelling Results 100% tumor response rate could be achieved when the predicted mean tumor radiation absorbed dose was >91 Gy to a target volume. There were no significant toxicities. Median time to progression and overall survival were not reached. SPECT/CT-derived mean tumour to normal liver ratios varied widely across all planning target volumes (median, 5.4; 95% CI, ), even within the same patient. Kao YH et al. J Nucl Med 2012; 53:1 8 28

29 Example: right and left hepatic treatments PLANNING TARGET VOLUME 1 (Tri-compartmental MIRD): Left hepatic artery Mass of implanted non-tumorous liver: gm Mass of implanted tumor: 12.8 gm Mean Tumor-to-normal liver ratio by mean SPECT/CT count density: 3.5 Desired mean radiation dose to implanted, non-tumorous liver: 30 Gy Predicted mean radiation dose to implanted tumor: Gy Predicted mean radiation dose to lungs: 2.4 Gy Injected yttrium-90 activity for this planning target volume: 0.5 GBq PLANNING TARGET VOLUME 2 (Tri-compartmental MIRD): Right hepatic artery Mass of implanted non-tumorous liver: gm Mass of implanted tumor: 99.7 gm Mean Tumor-to-normal liver ratio by mean SPECT/CT count density: 9.3 Desired mean radiation dose to implanted, non-tumorous liver: 20.5 Gy Predicted mean radiation dose to implanted tumor: Gy Predicted mean radiation dose to lungs: 3.4 Gy Injected yttrium-90 activity for this planning target volume: 0.7 GBq

30 Other pre-therapy dosimetry methods Using voxel based S values Using Monte Carlo methods to calculate personalized voxelbased dose Using dual-tracer for liver-tumour segmentation Post-Y90 therapy dosimetry Y90 PET radioconcentration/activity Y90 PET convolution with voxel dose kernel

31 Voxel S values (VSVs) in VOXELDOSE software (derived from Monte Carol simulation) is convolved with Tc99m MAA SPECTCT time-integrated activity map to give the dose map

32 MAA results are extracted on a voxel level and Monte Carlo methods used to calculate absorbed doses

33 25 patients with colorectal carcinoma liver metastases had Tc99m MAA and Tc99m sulphur colloid SPECTCT coregistration imaging to provide contrast. To allow for dualtracer segmentation of metastases vs normal liver tissue.

34 Y90 PET voxel dosimetry was performed based on voxel mean radioconcentration derived from phantom studies. Kao et al, EJNMMI research 2013; 3: 57

35 Y90 PET images were convolved with a Monte Carlo generated voxel dose kernel to obtain the dose to tumour and nontumour tissues in 5 patients.

36 Thank you for your attention