Radiopharmaceutical Therapy Part I: Safety Aspects for Dispensing Alpha and Beta Radioisotopes

Transcription

1 Radiopharmaceutical Therapy Part I: Safety Aspects for Dispensing Alpha and Beta Radioisotopes William D. Erwin, MS, DABSNM Senior Medical Physicist The University of Texas M.D. Anderson Cancer Center Houston, TX

2 Disclosures William Erwin discloses research support from FUJIFILM Radiopharmaceuticals U.S.A., Inc., Alfasigma S.p.A. and OncoSil Medical, Ltd The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

3 Target Audience: Pharmacists ACPE#: L05-P Activity Type: Knowledge-based

4 Learning Objectives 1. Describe the difference between particulate and gamma decay in nuclear medicine (NM) therapy radionuclides 2. Provide an understanding of radiation monitoring when using particulate emitters 3. Describe methods of accurate dose calibration during dispensing

5 1. Assessment Question The greatest concern related to exposure to alpha radiation is: A. Dose from internalization B. External skin dose C. Lens dose D. External deep dose

6 2. Assessment Question The best material for shielding beta radiation is: A. Air B. Acrylic C. Steel D. Lead

7 3. Assessment Question Which type of therapy radionuclide is most likely to not decay immediately to a stable daughter nuclide? A. Positron emitter B. Beta emitter that also emits gammas C. Pure beta emitter D. Alpha emitter

8 4. Assessment Question The variation in dose calibrator setting based on source volume, geometry and material composition is greatest for which type of therapy radionuclide? A. Gamma emitter B. Positron emitter C. Pure beta emitter D. Alpha emitter

9 Categories of NM Therapy Radionuclides Beta-Emitting Therapeutic With Gamma Emissions: 131 I, 153 Sm, 177 Lu (these are imageable) Pure Beta Emitters: 89 Sr, 90 Y, 32 P Alpha-Emitting Therapeutic 223 Ra on the radar : 225 Ac, 211 At (and others are in the pipeline )

10 NM γ emitters decay to a stable daughter (isomeric transition) 99 Tc (β - ) half life = 211,100 years (effectively stable)

11 NM β + emitters decay to a stable daughter β + Intensity < 100% means the rest of the decays are the alternative, electron capture +

12 NM β - emitters decay to a stable daughter (+ a plethora of variable-energy and small-yield secondary Auger and internal conversion e - s)

13 NM β - emitters decay to a stable daughter

14 Whereas, NM α emitters DO NOT!

15 Whereas, NM α emitters DO NOT! Significant γ s Radionuclide kev Yield 221 Fr % 213 Bi %

16 Whereas, NM α emitters DO NOT! Significant X-ray s ( 211 At EC) X-Ray kev Yield kα % kα % kβ % kβ % kβ %

17 Nudat ( An excellent resource for radionuclide decay characteristics ( free, U.S. Dept. of Energy-sponsored web site)

18 Radiation Penetration in Tissue 0.1 mm ~1 cm γ β β - + α + +

19 Therapy β - Emitter Properties Radionuclide T 1/2 Max. (mean) E β [MeV] Mean./Max. range in Tissue [mm] 32 P 14.3 d (0.695) 3.3/ Sr 50.5 d (0.585) 2.9/ Y 2.67 d (0.934) 4.0/ I 8.03 d 0.606, 0.334, (0.182) 1.1/ Sm 1.94 d 0.704, 0.635, (0.223) 1.3/ Lu 6.65 d 0.498, 0.177, (0.134) 0.8/1.8

20 Therapy β - Emitters Energy Spectra Unique 131 I mean MeV max MeV 90 Y mean MeV max 2.28 MeV

21 Therapy α Emitter Properties Radionuclide T 1/2 Significant a energies (MeV) Range in Tissue (mm) 223 Ra ( 219 Rn) ( 215 Po) ( 211 Bi) 225 Ac ( 221 Fr) ( 217 At) ( 213 Po) 211 At ( 211 Po) 11.4 d 3.96 s 1.78 ms 2.14 m 10.0 d (4.8 m) (32 ms) (4.2 μs) 7.21 h (0.5 s) 5.716,5.607,5.747,5.540 [95%] (6.819,6.553,6.425 [99.8%]) (7.386 [99.9%]) (6.623,6.279 [99.7%]) 5.830,5.794,5.792,5.732 [87%] (6.341,6.126 [98%]) (7.069 [100%]) (8.377 [100%]) (42%) [58% EC] (7.450 [0.58x99%])

22 Pure β - Emitter Shielding Primary The source itself (usually water) (i.e., most β radiation is self-absorbed) Secondary Container Glass or Plastic (vial source) Plastic (syringe) Tertiary Acrylic

23 Pure β - Emitter Shielding: What about Lead (Pb)? Bremsstrahlung (German for braking radiation ) When a β - particle passes near a + charge nucleus, it is attracted, and thus slows down and loses energy. Lost energy carried away by a secondary x-ray. Likelihood of passing near nucleus is low, thus % yield of bremsstrahlung is small. But, % yield increases with element mass # (Z) (Thus the preference of acrylic over lead for tertiary)

24 Pure β - Emitter Shielding: What about Lead (Pb)? Bremsstrahlung e.g MeV ( 90 Y) Energy E βmax acrylic (β shielding) Pb (brem shielding)

25 Example Syringe Shield for Pure β - Emitters* *Useful for α emitters 223 Ra and 225 Ac also (β - emissions in decay chain)

26 Shielding of β - Emitters with Substantial γ Emissions Primary, Secondary and Tertiary Pb, Pb and Pb Dominant exposure is from the γ s Pb thickness needed depends on: Radionuclide Activity* Target transmitted exposure rate *Therapeutic activities of α emitters << those of β - emitters, so minimal Pb shielding is needed (i.e., equivalent to that used for 99m Tc patient doses is adequate).

27 Shielding of β - Emitters with Substantial γ Emissions Primary γ Radionuclide Emission (kev) % Yield 131 I Sm Lu 208/ / Ho /81/ /6.6/ Secondary, 166 Er k-shell x-rays most prominent (0.92%)

28 Shielding of β - Emitters with Substantial γ Emissions Gamma Constant 1 Pb Atten. Coeff. Radionuclide Γ (R-cm 2 /mci-h) μ (mm -1 ) 131 I Sm Lu Ho (bremsstrahlung: 90 Y: , 32 P: ) 2 1 Smith DS, Stabin MG. Health Phys 2012;102(3): Zanzonico PB, Binkert BL, Goldsmith SJ. J NucI Med 1999;40:

29 Shielding of β - Emitters with Substantial γ Emissions Target R/h (T) = Γ mci e -μx / d(cm distance) 2 x (mm Pb) = ln(γ mci/ [T d 2 ]) / μ Example: T < (2 30 cm (public limit) 200 mci 131 I 153 Sm 177 Lu 166 Ho x(mm Pb) 22 mm 0.6 mm 2.5 mm 36 mm mci 131 I x(mm Pb) 20 mm 26 mm 29 mm

30 NM γ and β Emitter Primary External Exposure Hazards Gamma radiation Deep tissue dose Beta radiation Shallow tissue dose Skin Extremities (e.g., hand) Lens of the eye

31 Special Case: 131 I NaI in Solution (Internal β - Hazard)* radioiodine Tx (mci) Thyroid Ca (30 to 100 s); Hyperthyroidism (< 30) Risk of inhalation (iodine vaporization) Thyroid Relatively high radiosensitivity ~30% nominal normal uptake Bioassay after handling required (ALI only 50 μci) *Not a problem for bound 131 I (e.g., antibodies, mibg)

32 α Particle Primary Radiation Exposure Hazard External exposure to alpha particles is NOT a hazard α particles barely penetrate beyond ~70 um epidermis dead skin layer On the other hand internal exposure definitely IS Accidental inhalation, ingestion or injection Relative risk (probability of future cancer induction) ~20x that for γ, β* NRC α annual limit on intake ~1/100 th of that for β and ~1/10,000 th for γ: 223 Ra 90 Y 99m Tc *multiple progeny α s per decay of parent therapy emitter!!!

33 Example Radiopharmacy α Emitter Safety Controls

34 Dose Calibrator Setting for Activity Assay γ, β +, β - with significant γ s and α emitters Single setting generally adequate May be separate settings for vial vs. syringe Volume/geometry corrections needed for: γ emitters with abundant daughter x-rays (e.g., 123 I and 111 In) Pure β - emitters are a different story No one and only cal # (e.g., for 90 Y)

35 Tales of NM β - and α Therapy Radionuclide Dose Calibrator Calibration

36 131 I Dose Calibrator Setting We have found that factory default works for: NaI (both liquid in glass vial and capsule form) Azedra mibg (Dx: 6 mci, Tx: 8 mci/kg 500 mci) Dx: variable volume in 10-ml B-D syringe Tx: variable volume in 30-ml and 50-ml glass vials (Recall the 364 kev primary γ emission)

37 153 Sm Quadramet Assay Discrepancy circa 2006: Cross-calibration with outside radiopharmacy Syringe (patient dose) 2017: Switched to new outside radiopharmacy First patient dose: Our assay > by 8% (and 12% > prescribed) Per physician request A portion of the dose was emptied from syringe To be within our internal ±10% of prescribed limit Not good clinical practice, however

38 153 Sm Quadramet Dose Calibrator Re-Calibration (no dose calibrator factory setting) 3 rd -party NIST-traceable source requested 153 Sm in solution (3 ml) in 10 ml vial (±1.5% σ uncertainty) Dose calibrator re-calibration Adjusted setting to read correct activity in vial QS ed up to 6 ml, 3 ml withdrawn into 5 ml patient dose syringe Re-assayed vial to compute (by Δ) amount in syringe Adjusted setting to read correct activity in syringe (Outside radiopharmacy did the same)

39 153 Sm Quadramet Dose Calibrator Re-Calibration vial & syringe setting readings differ by > 30%!

40 153 Sm Quadramet Syringe Dose Calibrator Reading Is Volume Correction Needed? NO (only 1.1% total variation)

41 177 Lu (DOTATATE) Dose Calibrator Calibration ( factory setting) For NETTER-1 Clinical Trial 3 rd -party reference source 55 mci in 1.5 ml in vial 11:00) Dose calibrators (4) calibration 13:00) Ref. source assayed: 49.1 mci ( spot on 55 mci decayed!) Dispensed 1 ml into 25 ml dose vial Ref. source re-assayed: 14.5 mci 34.6 mci dispensed 1 ml in 25 ml dose vial assayed: 34.2 mci Difference (assayed calculated): -1.16%

42 177 Lu (DOTATATE) Dose Calibrator Calibration ( factory setting) Dose calibrators (4) calibration 14:00) 1 ml in 25 ml dose vial QS ed up to 21 ml 21 ml in 25 ml assayed: 35.1 mci (34.4 mci expected) Difference (assayed calculated): +2.03% 21 ml in 25 ml dose vial QS ed up to 25 ml 25 ml in 25 ml assayed: 35.1 mci (34.4 mci expected) Difference (assayed calculated): +2.03%

43 177 Lu (DOTATATE) Dose Calibrator Calibration ( factory setting) Assay versus volume of activity (single dose calibrator) 1 ml in 25 ml dose vial assayed 1 ml cold water added and vial re-assayed Repeated up to 20 ml of solution Total variation in reading: 0.8% Minimum: mci (@ 1 ml); Maximum: mci (@ 20 ml) Thus, a single (factory) setting acceptable to Sponsor (Recall the two primary γ emissions: 208 & 113 kev)

44 223 Ra (Xofigo) Dose Calibrator Calibration (no dose calibrator factory setting) 2010: 6 MBq/6 ml in 10-ml glass vial (NIST-traceable) Four CRC-15R cal # s: 268, 268, 269, : 1.25 MBq/2.1 ml in 10-ml syringe (NIST-traceable) Same four CRC-15R cal # s: 264, 264, 264, 262 Difference in vial vs. syringe cal # negligible (< 1%) Thus, a single setting for 223 Ra would be acceptable (Recall all those relatively-high-energy γ emissions)

45 223 Ra (Xofigo) Dose Calibrator Calibration (Syringe Re-calibration) NIST messed up Discovered their original reference calibration was off by -10%!!! Repeated reference material calibration 1,2 2015: 2.72 MBq/5 ml in 10-ml syringe (NIST-traceable) New four CRC-15R cal # s: 238, 237, 237, 238 All patient dose activities now 10% higher 1 J Res NIST 2015; 120: March 18, 2015 letter from Bayer

46 225 Ac Dose Calibrator Calibration (no dose calibrator factory setting) 225 Ac-labeled mab protocol (1.0 to 4.0 μci/kg, escalating) 3 rd -party reference source 1.5 ml in vial (1.031 cal. date/time) Measurements (4 Dose Calibrators) 3, 8, 13, 20, 25, 30 d (same time of day as on cal. date) Sponsor-recommended dose calibrator setting (775 5) % difference (reading 10 d T½ decayed expected value) Adjusted setting at each time point to read expected value

47 225 Ac Dose Calibrator Calibration Results (4 Dose Calibrators)

48 225 Ac Dose Calibrator Calibration (50 ml in 60-ml Syringe) 225 Ac in 100 ml solution in 500 ml plastic bottle (0.995 μci/g 1,2 ) g aliquot added to plastic LSC vial & QS ed to 20 ml μci (dose calibrator assay) 50-ml withdrawn into 60-ml syringe (repeated 5 ) dose calibrator setting for all measurements

49 225 Ac Dose Calibrator Calibration (50 ml in 60-ml Syringe) * i.e., vs μci/g Average Error: 0.55% Thus, a single setting for 225 Ac is acceptable (Recall the two relatively-high-energy γ emissions)

50 225 Ac Dose Calibrator Calibration (Syringe Cross-Calibration with Outside Radiopharmacy)

51 MDACC 90 Y Zevalin Dose Calibrator Settings Qualification by IDEC (12/20/2001) Calibrated 90 Y-chloride source mci/ml 0.80 ml per 40 mci 40 mci diluted to 10 ml in 10 ml Zevalin dose vial Vial and Syringe Dose Calibrator Settings Two Capintec CRC 15R calibrators Assay of 10 ml down to 1 ml of 90 Y in 10 ml vial Assay of 1 ml up to 9 ml of 90 Y in 10 ml syringe (activity drawn from vial in 1 ml increments)

52 MDACC 90 Y Zevalin Dose Calibrator Settings Qualification by IDEC (12/20/2001) CRC 15R Primary CRC 15R Backup

53 MDACC 90 Y Zevalin Dose Calibrator Settings Qualification by IDEC (12/20/2001) Dose Calibrator 90 Y Cal. # vs. Vial Volume y = x R 2 = Cal. # (x 10) y = x R 2 = Primary CRC 15R Backup CRC 15R Linear (Primary CRC 15R) Linear (Backup CRC 15R) Y Volume in 10 ml Vial (cc)

54 MDACC 90 Y Zevalin Dose Calibrator Settings Qualification by IDEC (12/20/2001) Dose Calibrator 90 Y Cal. # vs. Syringe Volume Cal. # (x 10) Primary CRC 15R Backup CRC 15R Primary 3-9 cc avg Backup 3-9 cc avg Y Volume in 10 cc BD Syringe (cc)

55 Dose Calibrator Setting for 90 Y Zevalin Patient Dose in Syringe Siegel JA et al, JNM 2003;44:317P [abstr] 30 dose calibrators, 5 facilities 3-9 ml 90 Y (Zevalin, saline) in 10 ml syringe Mean Calibration Settings Atomlab (n=15): 375 ( ) Capintec (n=11): (47-60) Nuclear Associates (n=3): ( ) abs. vol. corr. factors: % / cc (6 cc ref.) Conclusion: single setting acceptable

56 Dose Calibrator Setting for 90 Y Zevalin Patient Dose in Syringe SIM.SY2 90 Sr/ 90 Y Transfer Standard (AEA Technology QSA) NIST-traceable calibration source k=2σ (95% confidence interval) Each to a certain amount of 90 Y radioactivity (4 ml Zevalin in 10 ml B-D syringe) (e.g., 20 mci 90 Sr- 90 Y mci 90 Y) Decays with T½ of 90 Sr (28.79 y) Determine/periodically check calibrator preset Optional multipliers for other volumes (±1.7% max.)

57 Dose Calibrator Setting for 90 Y Zevalin Cross-Calibration with Outside Radiopharmacy Both sites purchased a transfer standard (independent calibration) Outside radiopharmacy created a mock patient dose 4 ml 90 Y solution in 10-ml B-D syringe Assayed with their calibrator setting and shipped it to us We assayed it with our dose calibrator setting Result: 2.3% difference (corrected for decay) (acceptable given the transfer standard s ±4.7% 2σ)

58 90 Y Microspheres Dose Vials SIR-Spheres vs. TheraSphere 81 mci (3GBq) ± 10% in 5 18:00 ET ml to withdraw per prescribed mci (GBq) Pt. dose vial mci (GBq) for Gy prescription Pt. dose vial cal. date = day of Tx (or day after) cal. time/date = 12:00 ET Sun. the week of or week before day of Tx

59 90 Y Microspheres Dose Calibrator Calibration Must Cross-Calibrate with Manufacturer* SIR-Spheres TheraSphere Repeat for at least the first three doses and average *No transfer standards exist for these products

60 90 Y Microspheres Dose Calibrator Cross-Calibration SIR-Spheres Dose Vial with Outside Radiopharmacy Step 1: μ, ±σ/±2σ & min/max setting for assay agreement (20 vials) ±5.25% σ Step 2: Mean Min. Max. -σ +σ -2σ +2σ Setting (x 10) Assay using μ, ±σ/±2σ & min/max (20 vials) Least squares fit of percent difference Final setting = intercept (63 10) (overall ~±4% σ & ±10% max/min agreement)

61 90 Y Microspheres Dose Calibrator Calibration Example Periodic Cross-Calibration Check: TheraSphere

62 90 Y Dose Calibrator Settings Our Capintec CRC-15/25 cal # s Zevalin in 1-9 ml 10 ml B-D syringe 1 : TheraSphere dose vial 2 : SIR-Spheres shipping vial 2 : SIR-Spheres dose vial 3 : NIST-traceable transfer standard for calibration 2. Cross-calibrated with manufacturer (no NIST-traceable absolute calibration) 3. Cross-calibrated with outside radiopharmacy What if SIR-Spheres was accidentally assayed w/ TheraSphere setting? 25.9 mci (47 10) vs mci (63 10) or ~12% over-estimate! Note: Mfr. has an Estimation use only setting (48 10)

63 Dose Calibrator Setting for 90 Y SIR-Spheres form factor dependency Capintec CRC-15/25 ~10% variation in response

64 90 Y SIR-Spheres Dose Dispensing Worksheet Note the use of a variable dose calibrator setting based on volume remaining in shipping vial

65 90 Y Microspheres % of Dose Delivered SIR-Spheres and TheraSphere mr/h assay of vial pre-tx and waste jar post-tx (ion chamber survey meter and fixed geometry)* % delivered = 100 (mr/h vial mr/h jar ) / mr/h vial *Decayed to time of infusion. (This is a crucial measurement!)

66 General Purpose α, β - or γ Detection A standard Geiger-Müller detector works just fine (protective cover must be removed for α and β - detection) Anecdote: I easily detected ~0.25 μci residual in a Xofigo patient dose syringe with a pancake G-M survey meter.

67 β - Detection (e.g, in the presence of γ s) very-thin plastic scintillator + PMT detector (i.e., air-equivalent density cover)

68 α or β - Detection (e.g, in the presence of γ s) layered very-thin scintillators + PMT detector

69 α detection (e.g, in the presence of γ s) very-thin scintillator + PMT detector (i.e., < air density cover)

70 Dose Calibrator High Activity Linearity Verification High activity 131 I mab clinical trial: is dose calibrator linear up to ~1 Ci?* Dose calibrator 99m Tc response = 0.7 that of 131 I Test: decay method w/ 1.4 Ci 99m Tc ( 1.0 Ci 131 I) Measurements Relative Activity [#] Accuracy Date Time [h:m] Activity [mci] Measured Expected [%] 8/14/ : /14/ : /14/ : /14/ : /15/2017 8: /15/2017 9: /15/ : /15/ : /15/ : /15/ : /16/2017 8: /16/ : /16/ : *Mfr. claims ±2% accuracy/ linearity for up to 6 Ci 99m Tc

71 Example Radionuclide Spill Identification Contamination of Biosafety Cabinet well counter wipe count 1. Spectrum indicates β - emitter No γ emission peaks Characteristic of bremsstrahlung 2. Estimated T½ indicates 89 Sr

72 Localized Spills/Contaminations that don t come clean Pure β - Emitter Covering with 5 10 cm of acrylic generally adequate (small-yield bremsstrahlung typically not a concern) Everything Else Covering with Pb necessary Pb thickness will depend on Radionuclide (i.e., γ emissions, yields, energies) (e.g., thickness needed for 131 I >> that for 153 Sm) Activity Target exposure rate (e.g., 2 30 cm)

73 Some Take-Home Points 1. α and β primary radiation risks differ from that from γ - γ: deep tissue dose; β: skin/lens/extremity dose, α: internal dose dose - Special case: 131 I NaI in solution (thyroid tissue β dose) - Primary shielding: Pb (γ), acrylic/plastic (β), the source itself (α) 2. Dose calibrator calibration for therapy radionuclides essentially no different than that for γ emitters (exc. pure β - ) - Most have substantial γ emissions that dose calibrators are sensitive to - Pure β - dependencies: composition and geometry (bremsstrahlung) 3. Conventional G-M survey meters suffice for therapy radionuclide radiation monitoring (cover off for pure β - )

74 1. Assessment Question The greatest concern related to exposure to alpha radiation is: A. Dose from internalization B. External skin dose C. Lens dose D. External deep dose

75 2. Assessment Question The best material for shielding beta radiation is: A. Air B. Acrylic C. Steel D. Lead

76 3. Assessment Question Which type of therapy radionuclide is most likely to not decay immediately to a stable daughter nuclide? A. Positron emitter B. Beta emitter that also emits gammas C. Pure beta emitter D. Alpha emitter

77 4. Assessment Question The variation in dose calibrator setting based on source volume, geometry and material composition is greatest for which type of therapy radionuclide? A. Gamma emitter B. Positron emitter C. Pure beta emitter D. Alpha emitter