Recent Primary Standardisations and Traceability in Nuclear Medicine. Lena Johansson, NPL Radioactivity Group

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1 Recent Primary Standardisations and Traceability in Nuclear Medicine Lena Johansson, NPL Radioactivity Group

2 Outline Primary standards Introduction to primary standards of radioactivity and traceability A few examples of recent standardisations and transfer to secondary standards Quantitative Imaging Calibration and validation of SPECT/CT cameras Dose planning for Molecular Radiotherapy from an NMI point of view

3 Primary standardisations why? The CIPM Mutual Recognition Arrangement responds to the need for an open, transparent and comprehensive scheme to give users reliable quantitative information on the comparability of national metrology services and to provide the technical basis for wider agreements negotiated for international trade, commerce and regulatory affairs. The CIPM MRA has been signed by the representatives of 96 institutes from 53 Member States, 39 Associates of the CGPM, and 4 international organizations and covers a further 153 institutes designated by the signatory bodies.

4 Basics of the 4pb-g coincidence method Count Rates N b = N N g = N o o b g b N c= N o b g g Efficiencies: b c/n g /N g c b Activity : N o = NN b N c g

5 Response /arbitrary scale Ionisation chamber response modelling Secondary Standards 30 Empirical model of ionisation chamber response to photons and electrons developed by NPL for the BIPM SIR ionisation chamber Same model applied to NPL chambers; generally predicts factors to within few % of true value, dependent on the emissions; most accurate for strong gamma emissions between 200 kev and 2 MeV This model was used to e.g. predict calibration factors for 223 Ra and decay progeny in equilibrium, based upon 30+ years of ion chamber calibration data and the nuclear decay data Energy /kev

6 Primary standards medical nuclides Recent standardisations include Ra-223 Y-90 microspheres BIPM/SIR Transfer Instrument (for short-lived radionuclides) Submission for Tc-99 m (2008), F-18 (2003 and 2014) and trials for C-11 (2014) On-going Ge-68 (pilot laboratory is NIST) Th-227

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8 SIR Transfer Instrument Carine Michotte from the BIPM came to do measurements at NPL in September 2014 Results (F-18) have been submitted as a paper to ICRM 2015

9 223 RaCl 2 (Xofigo) is the first a-emitting radioactive palliative therapeutic agent to be approved by the FDA following successful clinical trails (ALSYMPCA) for patients with castration-resistant prostate cancer and symptomatic bone metastases. The EC granted a marketing authorisation valid throughout the European Union for Xofigo on 13 November Presently used in over 1000 clinics worldwide To be launched in 20 further countries in 2014 Bayer bought Algeta for USD $2.9 billion

10 Scope of NPL work Primary standardisation of radioactivity of 223 Ra in equilibrium with its progeny and a submission to the International Reference System. Instigation of a new service for NPL to provide traceability to NPL primary standards. Publication of calibration factors for radionuclide calibrators used in nuclear medicine clinics, enabling accurate assay of administered activities Publication of new nuclear decay data (g-emission intensities, half lives )

11 223 Ra lies in the decay series of 235 U New nuclear data determined in this work: g-photon emission probabilities half-lives benefits many other sectors, not just the nuclear medicine community.

12 Activity Measurement Regime ( 223 Ra + progeny) Primary method 4p(LS)-g coincidence counting Pseudo-Primary methods CIEMAT/NIST LS efficiency tracing relies on nuclear and atomic data as inputs Confirmatory Methods 4p(PC)a-g coincidence counting 4p(PC)(a+b)-g coincidence counting High resolution gamma spectrometry Ionisation chamber response modelling

13 Multiple Dimensional Extrapolations ( 223 Ra) 1 [0.993, 0.983] 2 [0.922,0.771]

14 Ionisation chamber response modelling Chamber & container Modelled factor pa MBq -1 Measured factor pa MBq -1 Vinten 5 ml ISO ampoule 3.16 ± ± 0.02 NPL is working closely with: BIPM, NIST, PTB and CCRI(II) to harmonise international efforts in provision of international standard for 223 Ra and is also working closely with manufacturers. Continuation of project to include similar studies for 227 Th (parent of 223 Ra) starting clinical trials in 2015.

15 Y-90 SIR-Spheres used for Liver Cancer Treatments. SIR-Spheres microspheres are a medical device used in Selective Internal Radiation Therapy (SIRT) for liver tumours. In the treatment, the biocompatible resin microspheres lodge in the liver and deliver a therapeutic dose from a betaemitting radionuclide, yttrium-90 (half-life of 64.1 hours). The treatment is targeted as the spheres lodge preferentially in the microvasculature surrounding the tumour and the maximum range of the beta particles in tissue is 11mm with a mean of 2.5mm. Following administration, 94% of the radiation is delivered in 11 days.

16 90 Y microspheres standardisation Primary std of 90 Y solution relatively straight forward, ~100% Liquid scintillation and 4p proportional counter 90 Y microspheres challenge in IC measurements due to measurement geometry and settling effects (response goes up as spheres settle)

17 90 Y microspheres vials 80 Sirtex vials were weighed and divided into two batches (heavy and light) 6 vials were selected from the heavy batch

18 Quantitative Imaging

19 COUNCIL DIRECTIVE 2013/59/EURATOM of 5 December 2013 Article 56 Optimisation 1. Member States shall ensure that all doses due to medical exposure for radiodiagnostic, interventional radiology, planning, guiding and verification purposes are kept as low as reasonably achievable consistent with obtaining the required medical information, taking into account economic and societal factors. For all medical exposure of patients for radiotherapeutic purposes, exposures of target volumes shall be individually planned and their delivery appropriately verified taking into account that doses to non-target volumes and tissues shall be as low as reasonably achievable and consistent with the intended radiotherapeutic purpose of the exposure. (81) "radiotherapeutic" means pertaining to radiotherapy, including nuclear medicine for therapeutic purposes; Wednesday, 14 January

20 CHAPTER X FINAL PROVISIONS Article 106 Transposition Member States shall bring into force the laws, regulations and administrative provisions necessary to comply with this Directive by 6 February Wednesday, 14 January

21 The measurements 1. Activity administered: measured in a calibrated well-chamber (less residual) 2. Quantitative imaging: a measurement of activity within a defined volume that can be calibrated 3. Calculation of dose from cumulative activity: can be validated against calibrated measurements of absorbed dose possibly a primary standard of absorbed dose from unsealed radionuclides? Traceable? Traceable? 21

22 Activity measurement Development of the TDCR- Cerenkov technique for direct standardisation of radiopharmaceuticals Development of standardisation and transfer methods for 90 Y microsphere samples Determination of beta spectra (not NPL) 22

23 Quantitative imaging - calibration Investigation of methods calibrating a QI measurement with traceability to an activity standard Y-90, I-131, Lu-177 Reference phantom: Elliptical Jaszczak phantom, 33mm dia. fillable sphere Reference conditions: In air on axis In water on axis In water off axis Which gives the calibration factor? 23

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26 Wednesday, 14 January Full report at EANM conference 2014 Jill Merrett et al. and Andrew Fenwick et al.

27 Investigation of the accuracy of different approaches to integrating the activity-time curve How many time points? What times? What type of curve to be fitted? Double exponential? A priory knowledge of biokinetics? Straight lines? What difference does it make?? Wednesday, 14 January 2015

28 Other things to consider Biological effect Combined treatments Dose planning software International and National Guidelines

29 MetroMRT 3 rd Workshop: Clinical implementation of dosimetry for molecular radiotherapy National Physical Laboratory, Teddington, UK April 2015

30 Title of Presentation Name of Speaker Date The National Measurement System delivers world-class measurement science & technology through these organisations The National Measurement System is the UK s national infrastructure of measurement Laboratories, which deliver world-class measurement science and technology through four National Measurement Institutes (NMIs): LGC, NPL the National Physical Laboratory, TUV NEL The former National Engineering Laboratory, and the National Measurement Office (NMO).