Radioimmunotherapy Dosimetry. William D. Erwin, M.S. Department of Imaging Physics UT M. D. Anderson Cancer Center

Transcription

1 Radioimmunotherapy Dosimetry William D. Erwin, M.S. Department of Imaging Physics UT M. D. Anderson Cancer Center

2 Radioimmunotherapy Localized internal radiation therapy of cancer using radiolabeled antibodies targeted to specific antigen binding sites on tumor cells

3 90 90 Y (pure β - emitter, more ideal for therapy) - Bremsstrahlung imaging possible, but non-quantifiable, so In used as a surrogate for imaging 131 imageable 172, 247 kev γ s + similar T 1/2 (67 hr vs. 90 Y 64 hr) 131 I (β( - + imageable 364 kev γ,, but also higher kev γ s) 67 Radioimmunotherapy: Radionuclides of Interest 67 Cu (β( - + imageable 184 kev γ) Miscellaneous other β - emitters (e.g., 186 Future: emitters for α therapy ( At, Re, 177 Lu) 212 Bi, 213 Bi)?

4 Radioimmunotherapy: Routes of Administration Intravenous (most common) Intratumoral Intra-arterial arterial Intraperitoneal

5 Radioimmunotherapy: Current Applications Non-Hodgkin s B-Cell B Lymphoma 90 Y-Zevalin (IDEC) FDA approved 2/02 (anti-cd20) 131 I-BEXXAR (Corixa)) FDA approval 6/03 (anti-cd20) antibodies targeted to other expressed antigens Other cancers under investigation Other Lymphomas, Leukemias Colorectal, Breast, Liver, Prostate, Renal, misc. GI Gliomas, Astrocytomas (intra-tumoral tumoral infusion)

6 Radioimmunotherapy Dosimetry: Regulatory Requirements Radiopharmaceutical Clinical Trials Primarily Safety-Related: critical organ MTD (rad( rad,cgy), and thus maximum tolerated administered activity (mci( mci,mbq) Efficacy: absorbed dose in tumors (dose-response) Approved Therapeutic Agents (package inserts): Zevalin: BEXXAR: organ radiation abs. dose estimates (mean, range)

7 Radioimmunotherapy Dosimetry: Organs of Interest Whole Body (estimate of average dose over entire body) Red Marrow - radiosensitive - dose from radioactivity in blood (esp. IV administrations) Lungs (radiosensitive) Liver, Kidneys (and secondarily, GI tract, Bladder) - antibody clearance organs Spleen Thyroid (e.g., free 131 I)

8 Medical Internal Radiation Dosimetry: Model-Based Approach Energy (E) Deposition vs. Radiation Type/Energy non-penetrating penetrating: β +/- s, e - s < 4 MeV; γ s < 10 kev Penetrating: γ s > 10 kev Anthropomorphic Computer Phantoms (10) Adult M/F; 3/6/9 mo. pregnant; newborn; 1/5/10/15 yo Standard (average) organs - modeled density, volume, shape, location - 28 Source organs, 27 Target organs Dynamic Models: GI and Urinary Tracts

9 MIRD Source-Target Radiation Dose Model np = non-penetrating radiation p = penetrating radiation Source s np + p (s s S factor = S np + S p ) (s s self Dose) p (γ s( > 10 kev) (t s S factor = S p ) (t s Dose) Target t

10 MIRD Absorbed Dose S Factor S(t s) = radiation absorbed dose in t per unit cumulated activity in s Units: rad/µci Ci-hr (traditional) mgy/bq Bq-sec (S. I.) radionuclide and source-target specific

11 MIRD Absorbed Dose S Factor S np (t s) = 1/m Σ i i φ np (t s); S p (t s) = 1/m Σ j j φ p (t s) S(t s) = S np (t s) + S p (t s) m = reference phantom target organ mass Traditional units: i = 2.13n i E i g-rad/µci-h; E i MeV S.I. units: i = n i E i kg-gy Gy/Bq-s; E i Joule n i = probability of emission i φ(t s) = energy absorbed in t energy emitted in s np: = 1 (t = s), 0 (t s) = ½ (contents wall): heart, stomach, GI tract, bladder p: < 1 (dependent on: radionuclide, phantom, source, target)

12 Cumulated Activity Total number of decays in a given region (µci-hr, Bq-sec), from a given amount of internally administered radioactivity, A inj (0): Quantitative Imaging!!! phys t dt à = A 0 bio (t) e -λphys t dt, t = time Residence Time = à A inj (0) (hr, sec) = f 0 bio (t) e -λphys t dt, f bio (t) = A bio (t) A inj (0) f(t) = fraction of injected activity

13 MIRD Radiation Absorbed Dose Total Dose: D t = Σ s à s S(t s) Units: rad, Gy FYI: Dose Rate, dd t /dt = Σ s A sbio (t) e -λphys t phys t S(t S(t s) Unit Dose: d t = Σ s Tres s S(t s) Units: rad/mci mci, mgy/mbq

14 Previous murine (mouse) or human biodistribution data Pharmacokinetic or compartmental models Both poor predictors of variable biodistribution in individual patients, so Radioimmunotherapy: Absorbed Dose Estimates

15 Radioimmunotherapy: Individualized Dose Estimates Measurement of absolute uptake vs. time of radiolabeled compound in the patient Input data (A( bio (t) e -λphys t ) to patient-specific MIRD dose estimation for: organ safety/toxicity limits tumor therapeutic efficacy treatment planning

16 Radioimmunotherapy: Dose Estimate Mass Correction Stabin MG, SNM 1998 D t = D np + D p = Σ s à s S np (t s) + Σ s à s S p (t s) = à s /m ref Σ i i φ np (t s) + à s /m ref Σ j j φ p (t s) m ref = reference phantom organ mass Correction for Patient Organ Mass: D t = D np [m ref / m patient ] + D p [m ref / m patient patient ] 1/3 Pure β - emitter: D t D self = D np (t t) t) [m ref / m patient patient ]

17 Radioimmunotherapy: Dose Estimate Mass Correction Organ Mass Estimation 1. Estimate organ volume V (cc) from CT, MR or SPECT 2. Calculate organ mass m patient = V ρ ρ 1.0 g/cc (soft-tissue) tissue) ρ 0.3 g/cc (lung) ρ 1.5 g/cc (bone)

18 Radioimmunotherapy: Tracer Principle Assumption: A small (tracer) diagnostic amount of radiolabeled compound can be used to predict the biodistribution of the therapeutic administration (i.e., does not perturb the response of the biological system) A BioTher (t) = A BioDiag (t) x [ A InjTher / A InjDiag ]

19 Radioimmunotherapy Planning: Radioactivity Prescription A Therapy (0) = D Therapy / d Diagnostic D Therapy = tumor or organ prescribed total radiation absorbed dose d Diagnostic = tumor or dose-limiting organ unit radiation absorbed dose estimate from diagnostic tracer procedure

20 Planar Quantitative Imaging 1. [Optional] Transmission Scans (w/o [blank] & w/ patient) - attenuation correction for geometric mean (GM) quant. - not required if whole body at t = 0 is employed as standard for camera sensitivity calibration (see 3 below) 2. Serial, Anterior and Posterior (A/P) images - immediate (0 hr), then up to 4 12 days (out to at least 2 T ½effMax = [T ½bioMax T ½phys ] / [T ½bioMax + T ½phys ]) 3. Camera Sensitivity Calibration, S: cps / µci, cps / kbq - activity standard (reference source) in field-of of-view OR - whole body region GM cps at t = 0 A inj (0) 4. [Optional] Image Scatter Subtraction

21 Planar Quantitative Imaging 5. Region-of of-interest (ROI) counts per sec (cps) vs. time, C(t) GM: [ [ C A (t) - Bkgd A (t) ] [ C P (t) - Bkgd P (t) ] (A & P) Effective Point Source (EPS): C(t) - Bkgd(t) (A or P only) C(t) = total cps in organ/tumor ROI Bkgd(t) = estimated background cps in organ/tumor ROI = background ROI cps (Area ot Area bkgd ) Area ot = no. of pixels in organ/tumor ROI Area bkgd = no. of pixels in background ROI C(t) - Bkgd(t) = net cps in organ/tumor

22 Planar Quantitative Imaging 6. Conversion to absolute activity: µci, kbq - A(t) = (C(t) - A(t) = (C(t) (C(t) ACF) ACF) / S ; ACF = e µ thickness / 2 (GM), e µ depth (EPS) (C(t) Ainj(0)) / Cwb(0) (0) (whole body as std. GM method) 7. Decay Correction: A(t) A bio (t), f bio (t) - e λ imaging t, λ imaging = imaging isotope decay constant - mathematical model function fit to biologic component 8. Cumulated activity Ã, residence time Tres à = A bio (t)e -λ therapy t dt Tres = f bio (t)e (t)e -λ therapy 9. Target(s) Radiation Absorbed Dose Estimation D t = Σ Ã i S[t s i ] i dt therapy t dt d t = Σ Tres i S[t s i ] i

23 Whole Body/Planar Transmission Scans Administer Radiopharmaceutical Standard Source Images Planar Emission Images Whole Body Emission Images Repeat up to N days post-injection Source Organ/Tumor ROI cps vs. Time Camera Sensitivity (cps/µci) Absolute Uptake TAC (µci) Attenuation Correction Factors Fit TAC/Integrate for Tres (hours) Radiation Absorbed Dose Estimates: Unit (rad/mci,mgy/mbq) or Total (rad,gy)

24 Quantitative Radionuclide Imaging Serial Whole Body Emission Imaging: patient + reference (standard) source of radioactivity

25 Quantitative Radionuclide Imaging Serial Spot View Imaging: - separate images (patient, std) - transmission images

26 Scatter Correction - Radionuclide-Dependent (no.( of γ s, γ energies) - Object and Imaging System-Dependent Object: patient (unique scatter medium) System: spatial/energy resolution; crystal thickness; collimation on - Goal: Scatter Free Imaging Pure photopeak images Pure attenuation (can use published µ (cm - 1 ) values) - Energy Window Weighted Image Subtraction Dual (DEW) (scatter window below photopeak) Triple (TEW) (scatter windows above/below photopeak) Quadruple (QEW) (dual photopeak radionuclides,, e.g., 111 In)

27 Image Scatter: Photopeak Contamination Emission Spectrum Spectra for I-131 Emission Spectrum for In-111 Compton Scatter Window kev Photopeaks Upper Scatter: Collimator septal penetration of high energy γ s Compton scatter in crystal Lower Scatter: Compton scatter in patient

28 131 I TEW Scatter Correction Macey,, et al, Med Phys 22:1637, 1995 GM PP A PP P US A US P LS A LS P PP US LS GMPP GMUS GMLS GMUS PUS LSUS P PUS LSUS

29 Organ CtsO ia CtsB ia Background Quantitative Imaging: ROIs Organ CtsO ip CtsB ip ip Background Anterior Standard CtsS ia Posterior Standard CtsS ip

30 GM ACF from Transmission Scanning Cts p Cts p Lungs Liver Cts 0 Cts 0 ACF GM = e µ Thickness / 2 = [Cts 0 / Cts p ] 1/2 (Cts p = Cts 0 e-µ Thickness )

31 GM ACF from Transmission Scanning: Differing Transmission and Emission Imaging Radionuclides (e.g., 57 Co, 131 I) ACF Trans = e µ T Thickness / 2 = Cts 0 / Cts p µ T = Transmission radionuclide attenuation coefficient ) Thickness / 2 ACF Emission = e µ T (µ E µ T ) Thickness / 2 ACF Emission = (Cts 0 / Cts p ) f, f = (µ( E µ T ) µ E = Emission radionuclide attenuation coefficient

32 Planar ACF from Lateral View Right Lateral t pixels (GM thickness) Left Lateral d pixels (EPS depth, e.g., Post) Distance Calibration Sources p pixels, L cm ACF GM = e µ (t L / p) / 2 (e.g., for A/P Liver) ACF EPS = e µ (d L / p) (e.g., for posterior Spleen) (µ,, L / p known or measured)

33 Planar ACF from Tomograms CT Liver Spleen CT NM SPECT T avg T avg T right T left D avg ACF GM = e µ Tavg for Ant/Post Liver, Spleen Tavg / 2 ACF EPS = e µ Davg for Posterior Lumbar Spine T avg avg = (T( right right +T left left ) / 2 ACF GM = e µ Tavg for Ant/Post Kidneys Tavg / 2

34 Whole Body as Standard GM Method van Reenen,, et al, Eur J Nucl Med 1984 Assumption: : Geometric mean (GM) of t = 0 whole body ROI cps 100% of injected activity, [e -µt/2 (average GM attenuation factor over whole body) /2 ] avg Camera sensitivity: S WB = C(0) A inj (0) = k A inj (0) [e -µt/2 ] avg A inj (0) = k [e -µt/2 ] avg Regional GM activity: A ROI (t) = C ROI (t) S WB = C ROI (t) [e[ µt/2 ] avg k Partial attenuation correction!!!

35 Radionuclide Conversion Necessary when imaging and therapy radionuclides differ (e.g., 111 In/ 90 Y labeled antibody): imaging t A imaging (t) = A bio (t) e -λimaging t imaging t A bio (t) = A imaging (t) e λimaging t therapy t A therapy (t) = A bio (t) e -λtherapy t

36 Radioimmunotherapy: Blood-Based Based Marrow Dosimetry Blood Activity vs. each of N time points t i : 1. Draw whole blood (b) sample (X ml) from patient 2. Measure background cpm in well counter 3. Measure C b (t i ) bkgd = cpm/ml for 1 or 2 Y ml subsamples 4. Measure sensitivity from 1 or 2 Y ml decaying standard(s): S(t i ) = (C s (t i ) bkgd) ) / [A[ std (0) e -λ physti] ] (cpm( cpm/µci, cpm/mbq MBq) 5. Calculate biologic activity/ml: A ml (t i )=C b (t i )e λ physti/[ /[S avg (t i ) Y Y ml] Alternatively, at time t end : 1. Measure sensitivity S(t end ) (step 4) 2. Measure all C b (t i ) subsamples and simply correct to t = 0 ( ( e λ phystend end), as they are already effectively decay corrected

37 Radioimmunotherapy: Blood-Based Based Marrow Dosimetry Calculate whole blood Tres b /ml: therapyti/a inj Fit A ml (t i ) e -λ therapy inj (0) to model (e.g., bi-exponential) e.g., bi-exponential Tres b /ml = [f (0)T 1 1/2eff + f (0)T 1 2 (0)T 1/2eff Calculate Red Marrow Tres rm from model formula: (0)T 1/2eff 2 ] - Tres b /ml Mass rm.19 / (1-h) (Sgouros( Sgouros, J Nucl Med 1993) e.g., MIRD adult Mass rm = 1120 g (M), 1050 g (F) h = hematocrit - Tres b /ml Mass rm.25 (DeNardo( DeNardo,, et al, Nucl Med Comm 1993) Dose rm rm = Tres rm A therapy (0) S rm rm rm

38 Radioimmunotherapy: Image-Based Marrow Dosimetry Posterior View DeNardo,, et al, Clin Nucl Med cm wide L2-L4 L4 region (L) Counts/pixel in 1 cm wide background region counts/sec-to to-total total marrow activity: cps = [L counts (bkgd L pixels)] / t A[t] = cps[t] S e µ d.046 S = camera sensitivity calibration µ = linear attenuation coefficient d = average L2-L4 L4 depth (e.g., from CT).046 = 4.6 % of total marrow in L2-L4 L4 Dose rm rm = Tres rm rm A therapy (0) (0) S rm rm rm

39 Planar Imaging & MIRD Dosimetry: Deficiencies Overlapping structures in planar images (e.g., Liver/R Kidney, Tumor/Organ) 2-D D estimates of 3-D 3 D activity, scatter, attenuation Average dose over organ/region calculated (uniform activity distribution is assumed) Crude estimate of radiation absorbed dose (calculated on a MIRD phantom, NOT the patient!)

40 Future: 3-D 3 D Imaging & Dosimetry Quantitative SPECT-CT Removal of overlap of activity (tomographic( tomographic) Quantitative Iterative SPECT reconstruction: Resolution recovery Attenuation correction: registered CT µ maps Scatter compensation Absolute µci, MBq in 3-D 3 D (NM s holy grail )

41 Future: 3-D 3 D Imaging & Dosimetry SPECT: Cumulated Activity (Sources) Registered CT: Radiation Absorption (Targets) Patient-Specific 3-D 3 D (voxel( voxel-level) level) Dosimetry Radiation Transport Code (MCNP, EGS4), Dose Point Kernels, or Voxel S values Answer local dosimetry questions, such as organ, tumor dose-volume histograms spinal cord adjacent to treated tumor

42 3-D D Imaging & Dosimetry: CT-based SPECT Attenuation Map CT (70-80 kev eff.) SPECT µ map SPECT-CT Image Registration (software or SPECT-CT device) CT-to to-spect µ map conversion

43 3-D D Imaging & Dosimetry: Quantitative SPECT SPECT Projections SPECT µ map Iterative Recon µci/cc, µci

44 3-D D Imaging & Dosimetry: Dose Calculation Sources (SPECT) Ã(x,y,z) [uci[ uci-hr, hr,bq-s]* Targets (CT) radiation absorption media 3-D D Dose Calculation: 1. Monte Carlo (MCNP, EGS4) 2. Dose Point Kernels 3. Voxel S Values 3-D D Dose Distribution Maps Define 3-D 3 Sources/Targets (volumes of interest) * Ã(x,y,z) computed from either: Dose Volume Histograms 1. A combination of a single-point quantitative SPECT volume and source activity vs. time from m planar imaging 2. Voxel-by by-voxel activity vs. time from spatially registered, serial quantitative e SPECT volumes

45 Quantitative Radionuclide Imaging & Dosimetry: : Examples 111 In imaging/ 90 Y dosimetry/therapy Y MAb tumor dosimetry BEXXAR treatment planning Simple methodology based on Zevalin approved radioimmunotherapy regimen images

46 MAb: 111 In imaging/ 90 Y dosimetry/therapy Dual-head, A/P GM whole body imaging Blank/transmission scans ( 57 Co sheet source on lower head) In In MAb (5 mci) ) emission images (0, 4, 24, 72, 144 hr) Photopeak (172/15%, 247/15%) and Scatter (130/34%) images Photopeak (0.4 Scatter) image subtraction GM ROI organ quantification method (lungs, liver, kidneys) Transmission attenuation correction Reference source ( µci) ) camera sensitivity calibration Model function fit of f bio (t) Tres (= f bio (t) 90 Y e -λt dt) 90 Y organ unit dose, d Diag (= Tres t S t t [m ref m patient (from CT)] A Ther = D Ther / d Diag based on prescribed organ dose (e.g., 500 cgy)

47 MAb: 111 In imaging/ 90 Y dosimetry/therapy Transmission Imaging Emission Imaging In 111 In A/P 5 Immed 4 hr 24 hr 72 hr 144 hr 57 Co Blank 57 Co Patient Photopeak Scatter

48 111 In Scatter Correction: Energy Windows based on Gilland,, et al, IEEE Trans Nucl Sci 38:761, 1991 Compton Scatter Window kev Photopeaks

49 MAb: 111 In imaging/ 90 Y dosimetry/therapy: 111 In Scatter Subtraction = Photopeak Scatter Corrected

50 MAb: 111 In imaging/ 90 Y dosimetry/therapy: Kidney ROIs 111 In GM Emission ROIs 57 Co Transmission ROIs reference source ROIs Kidney background ROI Immediate: Ant Post Patient Blank

51 MAb: 111 In imaging/ 90 Y dosimetry/therapy FIA bio (t) = C A (t) C P (t) e µ In Thickness/2 e λ In t S Ref e µ In Thickness/2 : [C ROIblank C ROItrans ] f e f µ Co Thickness f = µ In µ Co =

52 MAb: 111 In imaging/ 90 Y dosimetry/therapy 90 Y β - MIRD organ (self-)dose scaling: MIRD ref. mass pat. mass N slices Mass = V (cc) ρ (g/cc) ρ =.9869 (soft-tissue)* tissue)* ρ =.2958 (lung)* Kidney volume from CT Σ ROIpixels i pixel area [cm 2 ] slice thickness [cm] i=1 * from MIRD Pamphlet No. 5, Revised 1978

53 90 Y MAb Tumor Dosimetry Dual-head, A/P GM whole body imaging Blank/transmission scans ( 57 Co sheet source on lower head) 111 In MAb (5 mci) ) emission images (4,24,72,144 hr) Photopeak (172/15%, 247/15%) and Scatter (130/34%) images Photopeak (0.4 Scatter) image subtraction GM ROI tumor quantification method Transmission attenuation correction Reference source ( µci) ) camera sensitivity calibration Biologic fraction of inj.. activity vs. time ( 111 In decay corr.) Model function fit of f bio (t) Tres (= f bio (t) 90 Y e -λt dt) Active tumor mass estimation (CT volume 1 g/cc) MIRDOSE v 3.1 Nodule Module S value for tumor (rad( rad/µci-hr) 90 Y MIRD β - self-dose (rad( rad) ) = Tres S 1000 A ther (mci)

54 90 Y MAb Tumor Dosimetry: : Tumor ROIs Emission (140.5 hr) Transmission

55 90 Y MAb Tumor Dosimetry: : Tumor TAC

56 90 Y MAb Tumor Dosimetry: : CT Volume OSIRIS software v Univ. Hosp. of Geneva, Switzerland ( expasy.ch/uin)

57 90 Y MAb Tumor Dosimetry: : CT Volume OSIRIS software v cc = ~99g (ρ ~ 1 g/cc)

58 90 Y MAb Tumor Dosimetry: : S value MIRDOSE v 3.1 Nodule Module Stabin, J Nucl Med 1996; 37: g ~ 100 g (else, must interpolate between nearest sphere mass S-values) S D = ~1600 (1593) rad = 16 Gy (1.79 hr.0185 rad/µci Ci-hr mci)

59 Approved Regimen for BEXXAR: BEXXARAdminProcess.pdf Day 0 Tositumomab (cold antibody) infusion 450 mg 131 I-BEXXAR infusion (5 mci in 35 mg) < 1 hr post-inf., pre-void A/P whole body scan (10-30 cm/min) Day 2, 3 or 4 post-void A/P whole body scan (10-30 cm/min) Day 6 or 7 post-void A/P whole body scan (10-30 cm/min) Day IF normal 131 I-BEXXAR biodistribution (whole body Tres,, visual) Cold antibody infusion (450 mg), then 35 mg 131 I-BEXXAR 131 I mci based on 65 cgy (low platelets) or 75 cgy to total body

60 Approved Regimen for BEXXAR: Whole Body Scanning Background Sensitivity QC Standard Patient 3

61 Approved Regimen for BEXXAR: Total Body Residence Time (t) = [C A (t) - C BA (t)] [C P (t)-c BP (t)] C WB (t) = FIA TB (t) = C WB (t) / C WB (0) Tres TB : T TB1/2eff Ex: hr = 105 hr 37% ln(1.0) (0.693/72.8)t 105

62 Approved Regimen for BEXXAR: Therapeutic Activity Prescription (Wahl, et al, J Nucl Med 1998; 39(Suppl Suppl):14S-20S) à (mci-hr) TBD (cgy( cgy) 131 I (mci( mci) ) = Tres TB (hr) 75 cgy 75 cgy à = mass corrected S(TB TB) TB) (cgy( cgy/mci-hr) TBD = targeted total body dose (65 cgy or 75 cgy)

63 Approved Regimen for Zevalin: Day 0 Rituxan (cold antibody) 250 mg/m In-Zevalin (5 mci in 1.6 mg) 2 24 hr post-infusion A/P whole body scan (10 cm/min) Day 2 or hr post-infusion A/P whole body scan (7 cm/min) [Optional] Day 4 or hr post-infusion A/P whole body scan (5 cm/min) Day 7 IF 111 In-Zevalin biodistribution is visually normal, THEN: Cold antibody (250 mg/m 2 ), then 1.6 mg 90 Y-Zevalin 0.3 (low platelets) or 0.4 mci/kg 90 Y ( ( 32 mci)

64 Approved Regimen for Zevalin: Simple (but coarse) Dose Estimates 2 hr 111 In 47 hr 111 In 93 hr 111 In Camera Sensitivity, S wb (assuming 2 hr is pre-voiding) [CPS wbant (2 hr) CPS wbpost (2 hr)] ½ [A inj (0) e hr/67.9hr ] (Alternative: add a reference source and transmission scans)

65 Approved Regimen for Zevalin: Simple (but coarse) Dose Estimates Ex: Liver estimate based on all 3 pts, limited to mono- exponential model: T effin-111 = 67.4 hr T physin-111 = 67.9 hr T physy-90 = 64.1 hr GM cps(0) = Liver 111 In GM ROI cps vs. Time 294.2e -.693t/ / T effy-90 = [ (1/T effin-111 ) (1/T physin ) ) ] + (1/T physy T resl = GM cps(0) / [S[ wb A In (0)] T effy-90 D L A injy-90 90(0) T resl S Y-90L 90L L opt. [m[ Ref / m patient physy-90 ) patient ]

66 Approved Regimen for Zevalin: 2 Point (2 hr, 48 hr) Dose Estimates? Ex: Liver estimate based on 1 st 2 pts: T effin-111 = 68.2 hr (> T physin ,, which indicates Zevalin is biologically on the increase up to 24 hr!) GM cps(0) = Liver 111 In GM cps vs. Time 293.7e -.693t/68.2 Thus, coarse dose estimates based on just 1 st 2 points and mono-exponential model will suffice?

67 A Word About MIRDOSE v 3.1 ( Oak Ridge Associated Universities) Currently THE accepted standard (e.g., by FDA) for calculating radiation absorbed doses from internally administered radiopharmaceuticals, BUT a) only runs on Windows 95/98 (not NT/2000/XP) and b) is no longer publicly available, so: Use previously procured copy of the software (IF you have one) ELSE, procure S tables from a colleague who has the software ELSE calculate your own S factors!? Use radionuclide decay scheme and S factor formula Practical only for β - self-dose purposes: D t = Ã t S np (t t) t) Best case: pure β - emitter w/ simple decay scheme (e.g. 90 Y) ELSE, see and wait for OLINDA ( next MIRDOSE version, FDA approval pending)

68 References 1. Loevinger R, Budinger TF, Watson EE. MIRD primer for absorbed dose calculations, Revised Ed. New York: The Society of Nuclear Medicine; Siegel JA, Thomas SR, Stubbs JB, et al. MIRD pamphlet no. 16: : techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates. J Nucl Med 1999; 40:37S-61S 3. Macey DJ, Williams LE, Breitz HB, Liu A, Johnson TK, Zanzonico PB. AAPM Report No. 71: A primer for radioimmunotherapy and radionuclide therapy. Madison: Medical Physics Publishing; DeNardo GL, Raventos A, Hines HH, et al. Requirements for a treatment planning system for radioimmunotherapy. Int J Radiat Oncol Biol Phys 1985; 11: Eary JF, Press OW, Badger CC, et al. Imaging and Treatment of B-Cell B Lymphoma. J Nucl Med 1990; 31: Noz ME, Kramer EL, Maguire GQ, et al. An Integrated Approach to Biodistribution Radiation Absorbed Dose Estimates. Eur J Nucl Med 1993; 20:

69 References 7. Sgouros G. Bone marrow dosimetry for radioimmunotherapy: : theoretical considerations. J Nucl Med 1993; 34: Macey DJ, DeNardo SJ, DeNardo GL, et al. Estimation of radiation absorbed doses to the red marrow in radioimmunotherapy. Clin Nucl Med 1995; 20: Wahl RL, Kroll S, Zasadny KR. Patient-Specific Whole-Body Dosimetry: : Principles and a Simplified Method for Clinical Implementation. J Nucl Med 1998; 39(Suppl Suppl):14S-20S 10. Wiseman GA, White CA, Stabin M, et al. Phase I/II 90Y Zevalin (yttrium-90 ibritumomab tiuxetan,, IDEC-Y2B8) radioimmunotherapy dosimetry results in relapsed or refractory non-hodgkin s lymphoma. Eur J Nucl Med 2000; 27: Wiseman GA, White CA, Sparks RB, et al. Biodistribution and dosimetry results from a phase III prospectively randomized controlled trial of ZevalinTM radioimmunotherapy for low-grade, follicular, or transformed B-cell B non-hodgkin s lymphoma. Crit Rev Oncol/Hematol 2001; 39; Voz JM, Wahl RL, Saleh M, et al. Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory relapsed/refractory low-grade and transformed low-grade B-cell B non- Hodgkin's lymphomas. J Clin Oncol ; 18:

70 References 13. Erwin WD, Groch MW. Quantitative radioimmunoimaging for radioimmunotherapy treatment planning: effect of reduction in data sampling on dosimetric estimates. Cancer Biother Radiopharm 2002; 17: Kolbert KS, Sgouros G, Scott AM, et al. Implementation and evaluation of patient- specific three-dimensional internal dosimetry.. J Nucl Med 1997; 38: Bolch WE, Bouchet LG, Robertson JS, et al. MIRD pamphlet no. 17: the dosimetry of nonuniform activity distributions - radionuclide S values at the voxel level. J Nucl Med 1999; 40:11S-36S 16. Yoriyaz H, Stabin MG, dos Santos A. Monte Carlo MCNP-4B 4B-based absorbed dose distribution estimates for patient-specific dosimetry.. J Nucl Med 2001; 42: Ljungberg M, Frey E, Sjögreen K, et al. 3D absorbed dose calculations based on SPECT: evaluation for 111-In/90 In/90-Y Y therapy using Monte Carlo simulations. Cancer Biother Radiopharm 2003; 18: