1. Internal Radiation Dosimetry J.D. Kalen, Ph.D.

2. Radiation Dose (Quantities and Units) Radiation Dose (D)Radiation Dose (D) The quantity of radiation energy deposited in an absorber/gm of absorber materialThe quantity of radiation energy deposited in an absorber/gm of absorber material Units: rad; radiation absorbed doseUnits: rad; radiation absorbed dose 1 rad = 100 ergs deposited/gm of absorber1 rad = 100 ergs deposited/gm of absorber SI units: gray (Gy): 1 Gy = 1 joule/kg absorberSI units: gray (Gy): 1 Gy = 1 joule/kg absorber note: 1 joule = 10 7 ergs 1Gy = 100 radsnote: 1 joule = 10 7 ergs 1Gy = 100 rads

3. Calculation of Radiation Dose (Absorbed Fraction Method) 3 Step Process: 1) Amount of activity and time within the source organ within the source organ 2) Amount of radiation emitted from the source organ; from the source organ; energy and emission frequency dependent 3) Fraction of energy absorbed by the target organ; dependent on target organ; dependent on a) characteristics of organ (tissue) b) positional relationship of source to target.

4. Calculation of Radiation Dose Cumulative Activity (A) ~ Cumulative Activity: The amount of radiation delivered to the organ and the length of time the activity is present within the organ. Units:(  Ci-hr) Activity (  Ci) time (hr) A(t) A =  A(t) dt 0  ~ time activity curve

5. Cumulative Activity (A)~ Four situations Four situations Instantaneous uptake with physical decayInstantaneous uptake with physical decay 90 Y Microspheres (Unresectable Hepatocellular Carcinoma) 90 Y Microspheres (Unresectable Hepatocellular Carcinoma) Instantaneous uptake with clearance by biologic excretion.Instantaneous uptake with clearance by biologic excretion. Radionuclide T 1/2 >> Biologic T 1/2Radionuclide T 1/2 >> Biologic T 1/2 Instantaneous uptake with clearance by biologic excretion and physical decay.Instantaneous uptake with clearance by biologic excretion and physical decay. 131 I (Hyperthyroidism and Thyroid Cancer) 131 I (Hyperthyroidism and Thyroid Cancer) 90 Y (Zevalin) and 131 I (Bexxar) radioimmunotherapy 90 Y (Zevalin) and 131 I (Bexxar) radioimmunotherapy Non-instantaneous uptake with clearance by biologic excretion and physical decay.Non-instantaneous uptake with clearance by biologic excretion and physical decay.

6. Cumulative Activity (A) ~ Situation 1: Instantaneous uptake; no biologic excretion ( (Unresectable Hepatocellular Carcinoma) i.e.: 90 Y Microspheres MicroSphere Properties: Glass sphere diameter: 20-30  mGlass sphere diameter: 20-30  m Trapped in the vasculatureTrapped in the vasculature 1 mg contains  22,000 – 73,000 spheres1 mg contains  22,000 – 73,000 spheres 90 Y Properties: Pure β - emitterPure β - emitter Decays to 90 ZrDecays to 90 Zr T 1/2 (hr): 64.1T 1/2 (hr): 64.1 E β ave (MeV): 0.9348; Range (mm): 4E β ave (MeV): 0.9348; Range (mm): 4

7. Cumulative Activity (A) ~ Situation 1: Instantaneous uptake; no biologic excretion A(t) = A 0 exp (-0.693*t/Tp) T p = physical half-life of radionuclide A 0 = initial activity present in organ A =A 0 exp (-0.693*t/Tp ) dt ~ A = T p A 0 = 1.44(A 0 T p ) 0.693 0.693 Activity (  Ci) time (hr)  0 8 Semi-log Activity (  Ci)

8. Cumulative Activity Trap vs Shunt to Lungs inject 4 mCi of 99m Tc MAA Shunt (F) = [Lungs / (Lungs + Liver)] x 100% =10% =10%

9. Cumulative Activity (A) ~ Situation 1: Example ( 90 Y: Unresectable Hepatocellular Carcinoma) 90% retention in Liver (1-F) 10% shunting to the Lung (F) A(Liver) = 1.44(T p )(1-F)(A 0 ) A(Liver) = 1.44(T p )(1-F)(A 0 ) = 1.44(64.16 hr)(0.9)[A 0 (  Ci)] = 1.44(64.16 hr)(0.9)[A 0 (  Ci)] ~ A(Lung) = 1.44(T p )(F)(A 0 ) A(Lung) = 1.44(T p )(F)(A 0 ) = 1.44(64.16 hr)(0.1)[A 0 (  Ci)] = 1.44(64.16 hr)(0.1)[A 0 (  Ci)] ~

10. Cumulative Activity Situation 2: Instantaneous uptake; biologic excretion no physical decay, or T p (1/2) >> biologic excretion i.e. 131 I (8.04 days) >> T b ( few hrs); Decay fraction: ( > T b ( few hrs); Decay fraction: (< 5%) Activity time T b1 T b2 T b3 f2f2f2f2 f1f1f1f1 f3f3f3f3 A = 1.44 T b1 f 1 A 0 + 1.44 T b2 f 2 A 0 + 1.44 T b3 f 3 A 0 ~ Semi-log

11. Cumulative Activity Situation 3: Instantaneous uptake Clearance by biologic and Physical decay Determine effective T 1/2 Effective T 1/2 = T e T e = T p T b T p + T b A = 1.44(T e )(A 0 ) ~ note: T e is always shorter than T p and T b T e T p T b 1 1 + 1 =

12. Cumulative Activity Situation 3: Instantaneous uptake 131 I (Hyperthyroidism) T e = T p T b T p + T b A = 1.44(T e )(A 0 ) ~ 131 I T p (days): 8.04 T b (days): 13.22 T b (days): 13.22 = 5 days

13. Cumulative Activity Situation 3: Uptake is NOT Instantaneous significant amount of physical decay occurs during uptake process. Activity time A(t) = A 0 (1-e -0.693t/T(u,e) ) A = 1.44 A o T e T ue TuTuTuTu ~ T ue = effective uptake T u = uptake half-life T e = effective excretion

14. Equilibrium Absorbed Dose Constant  Step 2: Determine amount of radiation emitted by source organ *  i = 2.13 N i E i g-rad g-rad  Ci-hr E i = ave. energy (MeV) of the i th emission N i = # emitted per disintegration  total =  i  i =    +    + … +  n  total is obtained from tables * the energy emitted per nuclear disintegration: 1 MeV/dis = 2.13 g-rad/(  Ci-hr) 1 MeV/dis = 2.13 g-rad/(  Ci-hr)

15. Equilibrium Absorbed Dose Constant  Step 2: Example ( 90 Y) 90 Y emits  particles: 100% of its disintegrations with E  ave  = 0.9348 MeV. with E  ave  = 0.9348 MeV.  i = 2.13 N i E i  total =   = 2.13 (1.0) 0.9348 = 1.99  Ci-hr g-rad  total =  i  i =  β

16. Equilibrium Absorbed Dose Constant  Step 2: Example ( 131 I) 131 I emits  particles  i = 2.13 N i E i   1 = 2.13 (0.0213) 0.069 = 0.003   4 = 2.13 (0.894) 0.192 = 0.365   14 = 2.13 (0.812) 0.364 = 0.629   7 = 2.13 (0.0606) 0.284 = 0.036   = 2.13 (0.0727) 0.637 = 0.098  Ci-hr g-rad  total =  i  i =  β1 +  β2 + …+  βn +   1 +   2 + …+   n Emission E ave (MeV) Emission Rate β1β1β1β10.0692.13% β4β4β4β40.19289.4%  14 0.36481.2% 77770.2846.06%  17 0.6377.27% = 1.133

17. Equilibrium Absorbed Dose Constant   total g-rad A is the cumulated activity (  Ci-hr)  Ci-hr ~  is the total energy emitted per  Ci-hr A x  = total energy emitted (g-rad) or (ergs) 1 g-rad = 1 erg ~ Step 2: Example

18. Absorbed Fraction (  ) Step 3: Determine the fraction of radiation emitted by the source organ that is absorbed by the target organ. Absorbed Fraction  is dependent on: 1) type and energy of the emission 2) anatomical relationship of target-source pair Total energy absorbed (g-rad) = A  i  i  i ~ Average absorbed Dose (rad) = A  i  i  i ~ mtmtmtmt

19. Average Absorbed Dose (D) Average absorbed Dose (rad) = A  i  i  i mtmtmtmt ~ m t : organ mass “average female/male”  i : fraction of energy delivered to target organ  i : fraction of energy delivered to target organ from all source organs from all source organs  i : amount of energy emitted from source organ  is complicated for energies > 10 keV (penetrating;  -rays)  < 10 keV (non-penetrating radiation; , x-rays)

20. Average Absorbed Dose (D)  = 0 for (penetrating radiation)  = 1 for (non-penetrating radiation): source and target organs are the same source and target organs are the same radiation is locally absorbed within the source organ radiation is locally absorbed within the source organ  nergies < 10 keV (non-penetrating radiation) Average absorbed Dose (rad) = A  i  i  i mtmtmtmt ~  = 1 (rad) = A  i  np (rad) = A  i  np mtmtmtmt ~

21. Average Absorbed Dose (D) Example: (non-penetrating radiation) Compute absorbed dose delivered to the Liver.  i = 2.13 N i E i  total =   = 2.13 (1.0) 0.9348 = 1.99  Ci-hr g-rad  total =  i  i =  β =  np 90 Y emits  particles: 100% of its disintegrations with E  ave = 0.9348 MeV. with E  ave = 0.9348 MeV.  total =   =1.6x10 -13 N i E i Bq-Sec kg-Gy =1.49x10 -13

22. Average Absorbed Dose (D) Example: (non-penetrating radiation): 90 Y Compute absorbed dose delivered to the Liver.

23. Average Absorbed Dose (D) Example: (non-penetrating radiation): 90 Y Compute Activity to be delivered based on Dose to the Organ.

24. Average Absorbed Dose (D) Example: (non-penetrating radiation) 131 I 131 I Emission E ave (MeV) Emission Rate β1β1β1β10.0692.13% β4β4β4β40.19289.4%  14 0.36481.2% 77770.2846.06%  17 0.6377.27%  i = 2.13 N i E i   1 = 2.13 (0.0213) 0.069 = 0.003   4 = 2.13 (0.894) 0.192 = 0.365   14 = 2.13 (0.812) 0.364 = 0.629   7 = 2.13 (0.0606) 0.284 = 0.036   = 2.13 (0.0727) 0.637 = 0.098  Ci-hr g-rad  total =  i  i =  β1 +  β2 + …+  βn +   1 +   2 + …+   n = 1.133 = 0.368 tttt  np

25. Mean Dose per Cumulated Activity (S) [for penetrating radiation:  -rays] Average absorbed Dose (rad) = A  i  i  i ~ mtmtmtmt Non-penetrating radiation:  i =1 Source and target organs: same Source/Target target Penetrating radiation:  i =0 Source and target organs: Different target

26. Mean Dose per Cumulated Activity (S) [for penetrating radiation:  -rays] S = 1  i  i  i mtmtmtmt rad  Ci-hr S =  i  i  i  =  mtmtmtmt specific absorbed fraction

27. Average Dose to an Organ (D) D = A x S ~ _ A : Cumulative Activity (  Ci-hr) (calculate) (calculate) ~ S: Mean dose per cumulated Activity (rad/  Ci-hr) (look-up table) (look-up table) D: Average dose (rad)

28. Mean Dose per Cumulated Activity (S) Source Organs S(rad/  Ci-hr) for I 131 Target Organs

29. 123 I Whole Body Scan Source Target

30. Average Dose to an Organ (D) Example: A patient is to be treated with 131 I for Hyperthyroidism. It is determined by prior studies with a tracer dose of 131 I that the thyroidal uptake is 60%, and the of 131 I that the thyroidal uptake is 60%, and the effective half-life of iodine in the thyroid gland is 5 days. effective half-life of iodine in the thyroid gland is 5 days. Assume instantaneous uptake (T u << T p = 8 days).

31. Average Dose to an Organ (D) T e = T p T b T p + T b A = 1.44(T e )(A 0 ) ~ T e = 5 days = 120 hrs A = 1.44(120 hr)(0.6)(1,000  Ci) ~ = 103,680  Ci-hr/mCi administered

32. Average Dose to an Organ (D) S(Thy Thy) = 2.2 x 10 -2 rad/(  Ci-hr) D = A x S ~ _ D = 103,680  Ci-hr/mCi admin. x 2.2 x 10 -2 rad/(  Ci-hr) = 2,280 rad/mCi administered = 2,280 rad/mCi administered Note: Inspection of the S table for 131 I reveals that in comparison to the Thyroid as the source organ, all other organs produce a much smaller S value. S-factor assumes 20 gm

33. Thyroid Mass Collimator: Pinhole Matrix: 128 x 128 Calibrate Pixel: 0.06 cm 2 /pixel ROI: 405 pixels Mass: [(# pixels)(Pixel Cal) 1.26 ](0.86) Mass: 48 g

34. Internal Dosimetry MIRD D = A x S A = 1.44 x A g (  Ci) x T 1/2 (hr) S = (1/m norm )  i  I (g-rad /  Ci-hr) M norm = 20 g Isotope: 131 I Thyroid Uptake: 60% A 0 = 1,000  Ci T 1/2 eff = 5 days Thyroid Mass = 48 g

35. Internal Dosimetry MIRDMIRD D = A x SD = A x S A = 1.44 x A g (  Ci) x T 1/2 (hr)A = 1.44 x A g (  Ci) x T 1/2 (hr) A = 103,680 (  Ci-hr)A = 103,680 (  Ci-hr) S = (1/m norm )   i  I (g-rad/  Ci-hr)S = (1/m norm )   i  I (g-rad/  Ci-hr) S = 0.022 g-rad/  Ci-hrS = 0.022 g-rad/  Ci-hr D = 2,280.9 rad (M norm = 20 g)D = 2,280.9 rad (M norm = 20 g) D = A x S x (20/48)D = A x S x (20/48) D = 950 rad/  Ci administeredD = 950 rad/  Ci administered note 1 rad = 1 rem in tissuenote 1 rad = 1 rem in tissue D = 950 rem/  Ci administeredD = 950 rem/  Ci administered Isotope: 131 I Thyroid Uptake: 60% A 0 = 1,000  Ci T 1/2 eff = 5 days Thyroid Mass = 48 g Dose (rem) = Dose (rad) x RBE RBE = relative biologic effectiveness ; effect of different radiation on biologic material. RBE ( , , x-ray) = 1 ; RBE (  ) = 20

36. Internal Dosimetry MIRDMIRD D = A x SD = A x S A = 1.44 x A g (  Ci) x T 1/2 (hr)A = 1.44 x A g (  Ci) x T 1/2 (hr) S = (1/m norm )   i  I (g-rad/  Ci-hr)S = (1/m norm )   i  I (g-rad/  Ci-hr) S = 0.022 g-rad/  Ci-hrS = 0.022 g-rad/  Ci-hr D = A x S x (20/Measured Thyroid Mass)D = A x S x (20/Measured Thyroid Mass)

37. Internal Dosimetry MIRDMIRD D = A x SD = A x S S = 0.022 g-rad/  Ci-hrS = 0.022 g-rad/  Ci-hr D = (A 0 )(1.44)(% Uptake)(T eff )(S)(20g/Measured Thyroid Mass)D = (A 0 )(1.44)(% Uptake)(T eff )(S)(20g/Measured Thyroid Mass) Uptake Probe Image: Pinhole

38. Internal Dosimetry Dose: Diffuse Goiter:10,000 rad Uni-nodular Goiter:25,000 rad Multi-nodular Goiter:15,000 rad Ablate:30,000 rad A 0 (  Ci) = (D rads)(Measured Thyroid Mass/20g) (1.44)(% Uptake)(T eff hrs)(0.022 g-rad/  Ci-hr) (1.44)(% Uptake)(T eff hrs)(0.022 g-rad/  Ci-hr)

39. Average Dose to an Organ (D) Example: Calculate the radiation dose to the Liver for an injection of 3 mCi of 99m Tc sulfur colloid. Assume injection of 3 mCi of 99m Tc sulfur colloid. Assume 60% of the activity is trapped by the liver, 30% by 60% of the activity is trapped by the liver, 30% by the spleen, and 10% by the red bone marrow, with the spleen, and 10% by the red bone marrow, with instantaneous uptake and no biologic excretion. instantaneous uptake and no biologic excretion. A = 1.44(T p )(A 0 ) ~ A LIVER = 1.44 (6 hr)(0.6)(3,000  Ci) = 15,600  Ci-hr A spleen = 1.44 (6 hr)(0.3)(3,000  Ci) = 7,780  Ci-hr A rbm = 1.44 (6 hr)(0.1)(3,000  Ci) = 2,590  Ci-hr ~ ~ ~

40. Average Dose to an Organ (D) S Values: S(Liver Liver) = 4.6 x 10 -5 rad/  Ci-hr S(Liver Spleen) = 9.8 x 10 -7 rad/  Ci-hr S(Liver Spleen) = 9.8 x 10 -7 rad/  Ci-hr S(Liver RBM) = 9.2 x 10 -7 rad/  Ci-hr S(Liver RBM) = 9.2 x 10 -7 rad/  Ci-hr D = A x S ~ D(Liver Liver) = (15,600  Ci-hr) x (4.6 x 10 -5 rad/  Ci-hr) D(Liver Spleen) = (7,780  Ci-hr) x (9.8 x 10 -7 rad/  Ci-hr) D(Liver RBM) = (2,590  Ci-hr) x (9.2 x 10 -7 rad/  Ci-hr) D(total) = 0.718 + 0.0076 + 0.0024 = 0.728 rad = 0.728 rad

41. Comparisons Tc 99m Inject: 5,000 uCi T 1/2 : 6.03 hr A = 1.44 A 0 T p = 43,416 uCi-hr = 43,416 uCi-hr I 131 Inject: 100 uCi T 1/2 : 8 days A = 1.44 A 0 T p = 27,648 uCi-hr = 27,648 uCi-hr Activity (uCi) Time (hr) I 123 Inject: 300 uCi T 1/2 : 13.2 hr A = 1.44 A 0 T p = 5,702 uCi-hr = 5,702 uCi-hr

42. Comparisons Source Organs Target Organs Tc 99m I 131

43. Comparisons Radionuclide Tc 99m l 131 l 123 Injection (mCi) 50.10.3 Physical Half-life (hr) 6.0319213.2 E  (keV) 140364159 Cumulative Activity (  Ci-hr) 43,41627,6485,702 S-Factor (rad/  Ci-hr) 2.3 x 10 -3 2.2 x 10 -2 3.86 x 10 -3 Dose (rad) = A x S 10060822

44. Cumulative Activity: Comparison A = 1.44 A o T e T ue = 1.44 A o T e T u T p = 1.44 A o T e T p T u (T u +T p ) T ue = effective uptake T u = uptake half-life T e = effective excretion T ue = T u T p T u + T p ~ TuTuTuTu (T u +T p ) Activity time

45. Cumulative Activity Example: A radioactive (10 mCi) gas T p(1/2) (20 sec) is injected in an intravenous solution. The lung uptake is is injected in an intravenous solution. The lung uptake is T u (30 sec) and is excreted (by exhalation) with a T u (30 sec) and is excreted (by exhalation) with a biologic T b(1/2) (10 sec). biologic T b(1/2) (10 sec). Effective Uptake =T ue = T u T p = 30(20) = 12 sec. Effective Uptake =T ue = T u T p = 30(20) = 12 sec. T u + T p 30 + 20 Effective Excretion =T e = T e T p = 10(20) = 6.7 sec. T e + T p 10 + 20

46. Cumulative Activity Situation 3: Example T e = 6.7 sec T ue = 12 sec T u = 30 sec A = 1.44 A o T e T ue ~ TuTuTuTu = 1.44 (10 mCi) 6.7 sec (12 sec) 30 sec = 38.6 mCi-sec = 10.7  Ci-hr = 26.8  Ci-hr (Instantaneous Uptake)

47. Cumulative Activity: Comparison A = = 1.44 A o T e T p ~ (T u +T p ) Activity time 10.7  Ci-hr 26.8  Ci-hr: D(rad)= 2.5 x D(non-instantaneous uptake)

48. Medical Internal Radiation Dose MIRD LimitationsMIRD Limitations Activity is uniformly distributed within a standard size organActivity is uniformly distributed within a standard size organ Absorbed Fraction  is based on standard models of human anatomy.Absorbed Fraction  is based on standard models of human anatomy. Calculation of Cumulated activity.Calculation of Cumulated activity. First based on animal studiesFirst based on animal studies Different between disease states; uptake and decayDifferent between disease states; uptake and decay

49. Medical Internal Radiation Dose MIRDMIRD New techniques are developedNew techniques are developed Actual distribution of activity is becoming availableActual distribution of activity is becoming available Easy to implementEasy to implement

50. MIRD-Summary Organ-specific Length of time and the amount of the radiopharmaceutical is within the organ. Obtained using Nuclear Medicine Techniques.

51. Radioimmunotherapy J.D. Kalen, Ph.D.

54. Non-Hodgkin's Lymphoma Systemic Radiation TreatmentSystemic Radiation Treatment Monoclonal Antibodies (MAb)Monoclonal Antibodies (MAb) Located on the surface of malignant and normal B lymphocytes is the antigen CD20.Located on the surface of malignant and normal B lymphocytes is the antigen CD20. Develop an antibody that binds with high affinity and specificity to the CD20 antigen.Develop an antibody that binds with high affinity and specificity to the CD20 antigen. Bind a radionuclide (beta emitter) to the MAb.Bind a radionuclide (beta emitter) to the MAb.

55. Non-Hodgkin's Lymphoma Radionuclide SelectionRadionuclide Selection Physical and Chemical propertiesPhysical and Chemical properties Production methodsProduction methods High specific activityHigh specific activity Biological behaviorBiological behavior Disassociation of radionuclide from MAbDisassociation of radionuclide from MAb

56. Radiopharmaceutical Selection Match the T b of the radiopharmaceutical with T p of the radionuclide maximizes the benefit of RadioimmunotherapyMatch the T b of the radiopharmaceutical with T p of the radionuclide maximizes the benefit of Radioimmunotherapy Long T b require long lived radionuclidesLong T b require long lived radionuclides Short T b require short lived radionuclidesShort T b require short lived radionuclides Activity Time (hr) TpTp TbTb

57. Non-Hodgkin's Lymphoma Radionuclide SelectionRadionuclide Selection 131 I-Tositumomab; Bexxar (GlaxoSmithKline) 131 I-Tositumomab; Bexxar (GlaxoSmithKline) Direct coupling to the MAb-iodinationDirect coupling to the MAb-iodination 90 Y-Ibritumomab Tiuxetan; Zevalin (Biogen Idec, Inc.) 90 Y-Ibritumomab Tiuxetan; Zevalin (Biogen Idec, Inc.) Indirect coupling to the MAb: chelator (Tiuxetan)Indirect coupling to the MAb: chelator (Tiuxetan) Antibody: IbritumomabAntibody: Ibritumomab

59. Beta-Particle Emitters 192 h

61. 131 I-Tositumomab (Bexxar) Whole-Body Dosimetry: AssumptionsWhole-Body Dosimetry: Assumptions Hematologic toxicity limits the amount of radioactivity that may be administered.Hematologic toxicity limits the amount of radioactivity that may be administered. Red marrow absorbed doseRed marrow absorbed dose Difficult to measure:Difficult to measure: Requires repeated blood sampling over timeRequires repeated blood sampling over time Can be determined from scans, but difficult to accurately measure.Can be determined from scans, but difficult to accurately measure.

62. Dosimetry

63. 131 I Tositumomab (Bexxar) Whole-Body DosimetryWhole-Body Dosimetry S ↔ Gender & Mass → Activity-Hours: Look-up tableS ↔ Gender & Mass → Activity-Hours: Look-up table Total Body Residence Time: Determined by ImagingTotal Body Residence Time: Determined by Imaging Platelet counts- Determined in Phase I studiesPlatelet counts- Determined in Phase I studies 65 cGy (100,000 to < 150,000 platelets/mm 3 )65 cGy (100,000 to < 150,000 platelets/mm 3 ) 75 cGy (≥ 150,000 platelets/mm 3 )75 cGy (≥ 150,000 platelets/mm 3 )

64. WB Cumulative Activity (Act-Hr) Cumulative Activity: The amount of radiation and the length of time the activity is present within the whole body. Units:(mCi-hr) Assume: 1. Uniform homogenous distribution 2. Patient can be modeled as an ellipsoid 3. Determine S values for various masses

65. Total Body Residence Time (TBRT) TBRT is directly correlated with the effective T 1/2 (clearance rate) of 131 I-Tositumomab within the WHOLE-BODY.TBRT is directly correlated with the effective T 1/2 (clearance rate) of 131 I-Tositumomab within the WHOLE-BODY. Treatment Dose (mCi) time (hr) 75 cGy Treatment Dose (mCi) time (hr) 75 cGy

66. Day 0 Residence Time Day 0 Dose Patient: 5 mCi 131 I-Tositumomab Perform WB scan Obtain Ant and Post WB counts Geometric Mean and subtract background! 100% Calculate % Injected Activity:

67. Day 3 Residence Time Day 3 Perform WB scan Obtain Ant and Post WB counts Remember to subtract background! 71.1% Calculate % Injected Activity:

68. Day 6 Residence Time Day 6 Perform WB scan Obtain Ant and Post WB counts Remember to subtract background! 20.7% Calculate % Injected Activity:

69. Day 0 Day 3 Day 6 Diagnostic Dose Therapeutic Dose 131 I Bexxar- Tositumomab

70. Residence Time (Hr)

71. Total Body Residence Time (Hr)

72. 131 I-Tositumomab (Bexxar) DosimetryDosimetry Based on WB scans Look-up table: Gender/weight Based on Platelets

73. Non-Hodgkin Lymphoma 131 I-Tositumomab; Bexxar 131 I-Tositumomab; Bexxar Multiple Dx scans: To determine Whole-Body Residence TimeMultiple Dx scans: To determine Whole-Body Residence Time β -,  emitterβ -,  emitter Must block thyroid uptakeMust block thyroid uptake Need to reduce radiation to the publicNeed to reduce radiation to the public 90 Y-Ibritumomab Tiuxetan; Zevalin 90 Y-Ibritumomab Tiuxetan; Zevalin One Dx scan: 111 In-Ibritumomab Tiuxetan scan to determine distributionOne Dx scan: 111 In-Ibritumomab Tiuxetan scan to determine distribution Pure β - emitterPure β - emitter 90 Y uptake into bone: difficult to block 90 Y uptake into bone: difficult to block Low or no radiation to the publicLow or no radiation to the public

74. Radionuclide T p (1/2) (days) A (Bq-hr) (per  kBq admin)  (np) (g Gy Bq -1 Hr -1 ) D (Gy) (per gm) 131 I 810,229,7600.109 1.12x10 6 90 Y 2.73,452,5440.539 1.86x10 6 Radionuclide Comparison

75. D (rad) = A x S ~

78. The curability of tumours of differing size by targeted radiotherapy using 131 I or 90 Y T. E. Wheldon, J. A. O'Donoghue, A. Barrette and A. S. Michalowski Radiotherapy and Oncology Volume 21, Issue 2Radiotherapy and Oncology Volume 21, Issue 2, June 1991, Pages 91-99 Abstract: The analysis implies that an advantage might result from the use of a panel of several radionuclides (including short-range emitters) or from combining targeted radiotherapy using long-range-emitters with external beam irradiation or some other modality to which microscopic tumours are preferentially vulnerable.

79. Bexxar or Zevalin?

80. It DEPENDS!

81. Radioimmunotherapy MAb IssuesMAb Issues RadiolysisRadiolysis Nuclide cleaves off of the MAbNuclide cleaves off of the MAb Radionuclide distribution different than MAbRadionuclide distribution different than MAb

82. 3 Future: Nano-Platforms