Radium-223 Therapy: Handling & Radiation Safety Issues

Transcription

1 Nuclear Physics Enterprises Radium-223 Therapy: Handling & Radiation Safety Issues Jeffry A. Siegel, Ph.D. President & CEO 2014 Meeting Mid-Atlantic States Radiation Control Programs Malvern, PA

2 NRC s Licensing Decision on 223 Ra Dichloride January 10, 2013 (FSME ) NRC staff carefully reviewed radiation safety aspects of medical use of 223 Ra dichloride to determine if radiopharmaceutical should be licensed under 10 CFR Part 35, Subpart E ( ) or 10 CFR Part 35, Subpart K ( ) ACMUI evaluated medical use & submitted report recommending regulation under NRC staff agreed with ACMUI recommendation licensing under appropriate because medical use similar to other commonly used beta and photonemitting therapeutic radiopharmaceuticals In addition, physicians who are approved for use of any beta emitter or any photon-emitting radionuclide with a photon energy < 150 kev under or can be authorized for the medical use of 223 Ra dichloride NOTES: Depending on type of license (broad or limited scope) and location (NRC or Agreement State), many licensees may need to apply for and receive a license amendment (e.g., Ra has Z=88) before being able to use Ra-223 dichloride NRC does not require use of dose calibrator for medical use of radium-223 dichloride as it is licensed under However, some Agreement States and importantly, FDA prescribing information do require dose calibrator measurement

3 NRC Regulations & Agreement State Compatibility 10 CFR Use of unsealed byproduct material for which a written directive is required Compatibility Category Health and Safety (H&S) designation Not required for compatibility; has particular health and safety significance 10 CFR Training for use of unsealed byproduct material for which a written directive is required 10 CFR Training for the parenteral administration of unsealed byproduct material requiring a written directive and carry Compatibility Category B designation Must be adopted as written; if not, significant transboundary implications 10 CFR Other medical uses of byproduct material or radiation from byproduct material Licensing new medical use/emerging technology Some confusion & compatibility concerns unintended regulatory hole NRC licenses under 300, can Agreement State license under 1000?

4 Xofigo Treatment Regimen Administered on a patient-specific basis Treatment activity is based on patient body weight 1.35 Ci/kg (50 kbq/kg) 70-kg patient would receive 95 Ci (3.5 MBq) Supplied as unit dosage in syringe (contamination and activity intake highly unlikely for members of public and radiation workers) Ra-223 mimics Ca selectively targets bone, specifically areas of bone mets by forming complexes with the bone mineral hydroxyapatite Ra & Ca in same column of periodic table Group 2 (II A) Treatment given every 4 weeks for 6 cycles (6 total administrations)

5 Common Radionuclide Therapy Procedures (licensed under ) Radionuclide Agent Indication AA (MBq) 32 P Phosphate Polycythemia Vera 148 Chromic Phosphate Neoplastic Effusions and Radiation Synovectomy Sr Chloride Bone pain Y Ibritumomab Tiuxetan NHL 1184(max) 131 I Sodium iodide Hyperthyroidism Sodium iodide Thyroid Cancer Tositumomab NHL 3108(av) 153 Sm EDTMP Bone pain Ra Xofigo Bone mets 3.5 (av)

6 Radium-223: Decay Properties 4 particles emitted per decay 223 Ra dichloride is a radiopharmaceutical; t ½ = 11.4 days 1 Total decay energy is 28 MeV 2 Of the total energy emitted during decay of 223 Ra and its progeny % emitted as particles 3.7% emitted as particles 1.1% emitted as γ or X-rays Principal photon emissions (>5%): X: 81 kev, 84 kev γ: 154 kev, 269 kev, 271 kev, 351 kev, 402 kev 223 Ra d α 219 Rn 3.96 s α 215 Po 1.78 ms α 211 Pb 36.1 m Radium-223 decay chain 1 β Decays via a series of α-, β-, and γ-emitting daughters 211 Bi 2.17 m α 207 TI 4.77 m β β 211 Po 516 ms α 207 Pb stable References: 1. Henriksen G, et al. Can Res. 2002;62: ENSDF decay data in the MIRD format for 223 Ra, 219 Rn, 215 Po, 211 Pb, 211 Bi, 207 Tl and 211 Po. 6

7 223 Ra Production 223 Ra occurs naturally 235 U But insufficient quantity for medical use 223 Ra for medical use is byproduct material 226 Ra irradiated by neutrons in reactor 227 Ac 227 Ac 227 Th 223 Ra 227 Ac: ; t½ = 22 y 227 Th: ; t½ = 18.7 d

8 Range of α-emitting Radiopharmaceuticals Compared to β-emitters Short range of α-particles reduces bone marrow exposure 1 Range of α-particle (short range 2 to 10 cell diameters 2 ) Bone Optimize radiation dose to bone mets; minimize dose to bone marrow (minimize toxicity) Bone marrow Tumor Range of β-particle (long range 10 to 1000 cell diameters 2 ) Radionuclide Bone Mineral (Hydroxyapatite) References: 1. Henriksen G, et al. Cancer Res. 2002;62: Brechbiel MW. Dalton Trans. 2007;43:

9 Xofigo: External Radiation Exposure Associated with Handling is Low Dose rates as calculated values * (All data presented are unshielded values) µsv/h per MBq Distance from vial Ra-223 Tc-99m Ra MBq (95µCi) µsv/h per patient dose Tc-99m 740 MBq (20000µCi) one meter one centimeter ~27* 2652* * Estimated finger dose per minute, assuming handling of unshielded source *Exposure rate constants published by David S. Smith & Michael G. Stabin (Health Physics 2012; 102: ). Value for 223 Ra represents derived value for 223 Ra + all its radioactive progeny in equilibrium. 9

10 Xofigo Pharmacokinetics Distribution After iv injection, rapidly cleared from blood and incorporated primarily into bone/bone mets or is excreted into the intestine Elimination Organ activity uptake: At 10 minutes post injection, activity uptake observed in bone and intestine. At 4 h, 44-77% of administered activity in bone. No significant uptake in other organs at 4 h Blood: At 15 minutes post injection, 20% of administered activity remains in blood, decreasing to 4% at 4 h and <1% at 24 h Fecal excretion is major route of elimination from body, 5% excreted in urine (no evidence of hepato-biliary excretion). A median of 76% of administered activity excreted from the body at 7 days Median biological half-time in body 3.5 days (t eff 2.7 days)

11 Measurement of Radium-223 Radium-223 primarily emitter, but s & photons also emitted during decay of 223 Ra and its radioactive progeny enabling detection with conventional routinely available instrumentation: Standard dose calibrators for determining patient dosages Survey meters for external radiation level surveys (e.g., routine area surveys, material receipt, after spills & monitoring of waste held for decay-in-storage prior to disposal) Due to short physical half-life of 223 Ra, disposable as non-radioactive waste after appropriate amount of time (decay-in-storage) pursuant to 10 CFR (radioactive progeny have much shorter half-lives ranging from 1.8 msec to 36 min) Well counters for removable contamination (wipe) surveys

12 NIST and Measurement Accuracy of Dose Calibrator for Ra-223 NIST * performed activity measurements in variety of dose calibrators for Ra-223 in various dose vials and syringes containing range of volumes and activities Single calibrated dial setting found to result in accurate measurements Dose calibrator measurement accuracies for Ra-223 were shown to be within +/-5% for all geometries * Bergeron DE, Zimmerman BE, Cessna JT. Development of secondary standards for 223 Ra. Appl Radiat Isot 2010; 68:

13 Dose Calibrator Measurements of Ra-223 activity Licensees to calibrate their own dose calibrator with NIST traceable 223 Ra standard Capintec CRC-25R used; calibrated using NIST traceable activity source - dial setting determined to be 264. Each syringe contained 2 MBq in 3.5 cc volume Elapsed Expected Activity Measured Activity % Deviation Time (days) 10 cc 5 cc 10 cc 5 cc 10 cc 5 cc MBq 2.08 MBq 2.14 MBq 2.08 MBq 0% 0% MBq 1.36 MBq 1.39 MBq 1.35 MBq -0.6% -0.4% MBq 0.89 MBq 0.90 MBq 0.89 MBq -1.5% 0.2% MBq 0.58 MBq 0.60 MBq 0.59 MBq 0.2% 1.6% MBq 0.38 MBq 0.39 MBq 0.38 MBq -0.8% 1.3% MBq 0.25 MBq 0.26 MBq 0.25 MBq 0% 1.7% MBq 0.16 MBq 0.17 MBq 0.16 MBq 0% 0.6% MBq 0.11 MBq 0.11 MBq 0.11 MBq 0.9% 0.3% MBq MBq MBq MBq 1.3% 1.3% MBq MBq MBq MBq -6.5% -4.4% MBq MBq MBq MBq -1.3% 1.7% MBq MBq MBq MBq 1.0% -3.2%

14 Xofigo: Radiation Surveys Associated with Medical Use Measurements made at two separate locations using 4 different GM survey meters, which all consisted of Ludlum Model 14C ratemeters connected to Model 44-9 GM pancake probes Activity present in one drop of Ra-223 dichloride solution, a volume corresponding to 0.05 ml, 50 kbq. Ra-223 activities from 50 kbq down to 0.3 kbq were prepared. The survey meters, all placed at a distance of 2 cm from the activity, indicated that all radium-223 activities were distinguishable from background and could be detected; the MDA was estimated to be at least 5 Bq for all 4 survey meters studied. Conventional pancake detector can easily measure presence of radium- 223 dichloride, if a spill or contamination event should occur, or as necessary for permissible waste disposal after on-site decay-instorage.

15 Survey meter exposure and count rate measurements of Ra-223 activity Syringe/Volume Activity Ludlum mr/h Ludlum cpm Background (cpm) bkg bkg cc syringe + 50 kbq 50 / K cc (1.35 Ci) 0.3 cc syringe kbq 20 / , cc (0.77 Ci) 0.3cc syringe kbq 20 / /.05 50,000 80, cc (0.72 Ci) 3 cc syringe + 1 cc 5.98 kbq 2.5 / /.05 8,000 10, (0.16 Ci) 3 cc syringe kbq 2.0 / /.05 6, cc (0.15 Ci) 0.3 cc syringe kbq 0.6 / / cc (0.016 Ci) 0.3 cc syringe kbq 0.7 / / cc (0.015 Ci) 0.3 cc syringe kbq 0.3 / / cc ( Ci) 0.3 cc syringe kbq 0.4 / / cc ( Ci)

16 Patient Release: Xofigo is an Outpatient Treatment Xofigo treatment involves low administered activity 95 µci / 3.5 MBq for a 70 kg patient Estimated maximum likely external dose to others, D( ) = 34.6 Q 0 T p (0.25) = 34.6 x ( μsv/mbq h) x (3.5 MBq) x (11.4 d) x (0.25) = 16 μsv = 1.6 mrem (= dose to total decay; conservative by factor 8) Specific gamma ray constant of (at 1 m) is for 223 Ra + all its progeny in radioactive equilibrium (Smith & Stabin. Health Phys 2012; 102: ) Xofigo patients immediately releasable pursuant to 10 CFR Negligible external radiation dose & risk to others (activity intake/internal radiation dose highly unlikely). 5 msv 1081 MBq (av = 3.5 MBq) 1.6 mrem equivalent to exposure to 2 days of background radiation ( 300 mrem/y or 0.8 mrem/day) or 1/5 that received from a chest x-ray (10 mrem). Given most conservative LNT risk model, fatal cancer risk %. Given that normal incidence of cancer in US 40%, the additional risk due to this exposure is a factor of 500K less