Clinical and dosimetric considerations for Y90: recommendations from an international multidisciplinary working group.

The TheraSphere Global Dosimetry Steering Committee was formed in 2017 by BTG International to review existing data and address gaps in knowledge related to dosimetry. This committee is comprised of health care providers with diverse areas of expertise and perspectives on radiation dosimetry. The goal of these recommendations is to optimize glass microspheres radiation therapy for hepatocellular carcinoma while accounting for variables including disease presentation, tumour vascularity, liver function, and curative/palliative intent. The recommendations aim to unify glass microsphere users behind standardized dosimetry methodology that is simple, reproducible and supported by clinical data, with the overarching goal of improving clinical outcomes and advancing the knowledge of dosimetry.

Comparison of (90)Y activity measurements in nuclear medicine in Germany.

In 2014, PTB and the company Eckert & Ziegler organized a national comparison exercise to determine the activity of a (90)Y solution. One aim of the comparison was to assess the measurement capability of hospitals and medical practices in Germany. P6-type vials were filled with aliquots of a radioactive (90)Y solution and then sent to 19 participants who were asked to measure the activity in the ampoules as well as in their own standard geometry using syringes. Most of the submitted results have a deviation of less than ±10% from the PTB reference activity when measured in the P6-type vials. The spread is somewhat larger when measured in a syringe geometry. The comparison revealed that some participants have difficulties in applying decay corrections and only a few participants were capable of estimating realistic measurement uncertainties.

Standardisation of (90)Y and determination of calibration factors for (90)Y microspheres (resin) for the NPL secondary ionisation chamber and a Capintec CRC-25R.

The use of (90)Y resin microspheres (SIR-Spheres® microspheres) in Nuclear Medicine has dramatically increased in recent years due to its favourable outcome in the treatment of liver cancer and liver metastases (Rajekar et al., 2011). The measurement of administered activity before and residual activity after treatment in radionuclide calibrators is required to determine total activity delivered to the patient. In comparison with External Beam Radiotherapy (EBRT) where administered doses are often know to within ±5%, the actual administered activity in nuclear medicine procedures may only be known to within ±20% and subsequent dose calculations can result in even larger uncertainties (Fenwick et al., 2009). It is a well-recognised issue that ion chambers are instruments that are sensitive to the measurement geometry and matrix of a source, in particular for pure beta or low energy (<100keV) x-ray emitters (Gadd et al., 2006). This paper presents new calibration factors for NPL secondary standard ionisation chamber system (Vinten 671) and a Capintec CRC-25R radionuclide calibrator along with a discussion of the measurement problems associated with this radionuclide and matrix. Calibration of the NPL secondary standard system for this measurement matrix will enable NPL to provide standards for the Nuclear Medicine community and consequently increase the measurement capability.

Production and quality control of radioactive yttrium microspheres for medical applications.

In this paper, a method for production of yttrium silicate microspheres is reported. Yttrium silicate microspheres with approximate sizes of 20-50µm were obtained when an aqueous solution of Y(NO3)3 was added to tetraethyl orthosilicate (TEOS) and was pumped into silicone oil under constant stirring. The shapes of the particles produced by the proposed method were regular and nearly spherical. The spherical shapes, composition and element distribution were investigated by scanning electron microscopy (SEM), carbon/sulfur analysis and SEM/EDS mapping analysis. Paper chromatography was used to identify radiochemical impurities in the radioactive microspheres. The radionuclide purity was determined using a gamma spectrometry system and an ultra-low-level liquid scintillation spectrometer. The results indicated that the proposed silicone oil spheroidization method is suitable for the production of yttrium silicate microspheres.

Comparison of 9°Y and ¹77Lu measurement capability in UK and European hospitals.

Comparison exercises involving (90)Y and (177)Lu were performed during 2009 and 2012, respectively, to assess the measurement capability of hospitals in the UK and Europe. The results from the measurement of a typical liquid solution of (90)Y show that only 40% of participants could measure the solution to within 5% of the certificated value and that a significant -6% bias was present due to the use of non-standard geometries for the calibration of equipment. The results from the measurement of a standard liquid solution of (177)Lu show that 81% of participants could measure to within 5% of the certificated value and in fact 65% of these results were within 2% of the certificated value, showing administered activities can be far more accurately measured for (177)Lu than for (90)Y and that (177)Lu has a far smaller geometry dependence. These studies were performed to identify specific measurement issues in the user community and to identify areas where future research should be focused. In addition to this the work allows the participants to adjust measurement practice and identify key measurement issues.

Proficiency test of 9°Y and 89Sr activity measurements in Polish hospitals.

The Radioisotope Centre POLATOM organized a proficiency test of activity measurements of (90)Y and (89)Sr with nuclear medicine departments in Polish hospitals. Radioactive solutions used in this exercise were standardized by the TDCR method using the measurement systems of the National Standard of Radionuclides Activity in Poland. Results were analysed in compliance with ISO/IEC 17043:2010 (ISO, 2010) by calculating z scores and ζ (zeta) scores. The overall performance of the participants varied significantly. The sources of errors appeared to be the values of the calibration factor used during activity assay and the underestimation of uncertainties by the participants.

Calibration of the 90Sr+90Y ophthalmic and dermatological applicators with an extrapolation ionization minichamber.

(90)Sr+(90)Y clinical applicators are used for brachytherapy in Brazilian clinics even though they are not manufactured anymore. Such sources must be calibrated periodically, and one of the calibration methods in use is ionometry with extrapolation ionization chambers. (90)Sr+(90)Y clinical applicators were calibrated using an extrapolation minichamber developed at the Calibration Laboratory at IPEN. The obtained results agree satisfactorily with the data provided in calibration certificates of the sources.

(Depth-dose curves of the beta reference fields (147)Pm, (85)Kr and (90)Sr/(90)Y produced by the beta secondary standard BSS2.

The most common reference fields in beta dosimetry are the ISO 6980 series 1 radiation fields produced by the beta secondary standard BSS2 and its predecessor BSS. These reference fields require sealed beta radiation sources ((147)Pm, (85)Kr or (90)Sr/(90)Y) in combination with a source-specific beam-flattening filter, and are defined only at a given distance from the source. Every radiation sources shipped with the BSS2 is sold with a calibration certificate of the Physikalisch-Technische Bundesanstalt. The calibration workflow also comprises regular depth-dose measurements. This work publishes complete depth-dose curves of the series 1 sources (147)Pm, (85)Kr and (90)Sr/(90)Y in ICRU tissue up to a depth of 11 mm,when all electrons are stopped. For this purpose, the individual depth-dose curves of all BSS2 sources calibrated so far have been determined, i.e. the complete datasets of all BSS2 beta sources have been re-evaluated. It includes 191 depth-dose curves of 116 different sources comprising more than 2200 data points in total. Appropriate analytical representations of the nuclide-specific depth-dose curves are provided for the first time.

Comparison of calibration results for an extrapolation chamber obtained with different 90Sr+90Y secondary standard sources.

Two secondary standard systems of beta radiation were used to calibrate a PTW extrapolation chamber Model 23391. Three (90)Sr+(90)Y sources of different activities were used in this calibration procedure. Medium-term stability of the response of the chamber was also studied. The calibration was performed with and without field-flattening filters. The relative standard deviation of the obtained calibration factors was 8.3% for the aluminum collecting electrode and 4.1% for the graphite collecting electrode.

Recommendations of the American Association of Physicists in Medicine on dosimetry, imaging, and quality assurance procedures for 90Y microsphere brachytherapy in the treatment of hepatic malignancies.

Yttrium-90 microsphere brachytherapy of the liver exploits the distinctive features of the liver anatomy to treat liver malignancies with beta radiation and is gaining more wide spread clinical use. This report provides a general overview of microsphere liver brachytherapy and assists the treatment team in creating local treatment practices to provide safe and efficient patient treatment. Suggestions for future improvements are incorporated with the basic rationale for the therapy and currently used procedures. Imaging modalities utilized and their respective quality assurance are discussed. General as well as vendor specific delivery procedures are reviewed. The current dosimetry models are reviewed and suggestions for dosimetry advancement are made. Beta activity standards are reviewed and vendor implementation strategies are discussed. Radioactive material licensing and radiation safety are discussed given the unique requirements of microsphere brachytherapy. A general, team-based quality assurance program is reviewed to provide guidance for the creation of the local procedures. Finally, recommendations are given on how to deliver the current state of the art treatments and directions for future improvements in the therapy.

Activity measurements of 18F and 90Y with commercial radionuclide calibrators for nuclear medicine in Switzerland.

The activity of radiopharmaceuticals in nuclear medicine is measured before patient injection with radionuclide calibrators. In Switzerland, the general requirements for quality controls are defined in a federal ordinance and a directive of the Federal Office of Metrology (METAS) which require each instrument to be verified. A set of three gamma sources (Co-57, Cs-137 and Co-60) is used to verify the response of radionuclide calibrators in the gamma energy range of their use. A beta source, a mixture of (90)Sr and (90)Y in secular equilibrium, is used as well. Manufacturers are responsible for the calibration factors. The main goal of the study was to monitor the validity of the calibration factors by using two sources: a (90)Sr/(90)Y source and a (18)F source. The three types of commercial radionuclide calibrators tested do not have a calibration factor for the mixture but only for (90)Y. Activity measurements of a (90)Sr/(90)Y source with the (90)Y calibration factor are performed in order to correct for the extra-contribution of (90)Sr. The value of the correction factor was found to be 1.113 whereas Monte Carlo simulations of the radionuclide calibrators estimate the correction factor to be 1.117. Measurements with (18)F sources in a specific geometry are also performed. Since this radionuclide is widely used in Swiss hospitals equipped with PET and PET-CT, the metrology of the (18)F is very important. The (18)F response normalized to the (137)Cs response shows that the difference with a reference value does not exceed 3% for the three types of radionuclide calibrators.

Quality assurance issues for therapeutic application of radioactive microspheres.

The use of radioactive microspheres for the treatment of hepatic cancer is a procedure that raises unique quality assurance (QA) concerns. The greatest of these concerns is the coordination of the responsibilities among the medical team members from interventional radiology, radiation oncology, nuclear medicine, and medical physics. A single QA practice and procedure guidance document does not currently exist that addresses the range of issues of concern for radioactive microspheres. A small sampling of QA issues of concern include imaging QA, procedure-specific imaging protocols, detector calibration, activity measurement, radiation safety, patient dose calculations, and patient-specific QA. Some of the items listed have historically been the responsibility of a single team member, and other items have been concerns for all. A procedural overview of the therapeutic application of radioactive microspheres is presented to illustrate the broad, team-based QA approach necessary to safely and effectively deliver this type of treatment. From this overview, the reader will be able to customize the local QA protocol to meet the local division of responsibilities.

A performance evaluation of 90Y dose-calibrator measurements in nuclear pharmacies and clinics in the United States.

A blind performance test was conducted to evaluate dose-calibrator measurements at nuclear pharmacies in the United States (US). Two test-sample geometries were chosen to represent those used for measurements of 90Y-ibritumomab tiuxetan (ZEVALIN). The radioactivity concentration of test-samples was verified by the US National Institute of Standards and Technology. Forty-five results were reported by 10 participants. Eighty percent of reported values were within the US Pharmacopoeia content standard (+/-10%) for 90Y-ZEVALIN. All results were within US Nuclear Regulatory Commission conformance limits (+/-20%) for defining therapeutic misadministrations.

Resin 90Y microsphere activity measurements for liver brachytherapy.

The measurement of the radioactivity administered to the patient is one of the major components of 90Y microsphere liver brachytherapy. The activity of 90Y microspheres in a glass delivery vial was measured in a dose calibrator. The calibration value to use for 90Y in the dose calibrator was verified using an activity calibration standard provided by the microsphere manufacturer. This method allowed for the determination of a consistent, reproducible local activity standard. Additional measurements were made to determine some of the factors that could affect activity measurement. The axial response of the dose calibrator was determined by the ratio of activity measurements at the bottom and center of the dose calibrator. The axial response was 0.964 for a glass shipping vial, 1.001 for a glass V-vial, and 0.988 for a polycarbonate V-vial. Comparisons between activity measurements in the dose calibrator and those using a radiation survey meter were found to agree within 10%. It was determined that the dose calibrator method was superior to the survey meter method because the former allowed better defined measurement geometry and traceability of the activity standard back to the manufacturer. Part of the preparation of resin 9()Y microspheres for patient delivery is to draw out a predetermined activity from a shipping vial and place it into a V-vial for delivery to the patient. If the drawn activity was placed in a glass V-vial, the activity measured in the dose calibrator with a glass V-vial was 4% higher than the drawn activity from the shipping vial standard. If the drawn activity was placed in a polycarbonate V-vial, the activity measured in the dose calibrator with a polycarbonate V-vial activity was 20% higher than the drawn activity from the shipping vial standard. Careful characterization of the local activity measurement standard is recommended instead of simply accepting the calibration value of the dose calibrator manufacturer.

Half-life evaluations for 3H, 90Sr, and 90Y.

A recent paper has reviewed methods for the evaluation of discrepant sets of data and demonstrated the results of applying these methods to the published half-life data of 90Sr and 137Cs [MacMahon, T.D., Pearce, A., Harris, P., 2004. Convergence of techniques for the evaluation of discrepant data. Appl. Radiat. Isot. 60, 275-281]. The half-life data for 3H has been subject to a comprehensive review and critical evaluation by Lucas and Unterweger [2000. Comprehensive review and critical evaluation of the half-life of tritium. J. Res. Natl. Inst. Stand. Technol. 105, 541-549]. The current paper reports the results of applying the various evaluation procedures of MacMahon et al. Convergence of techniques for the evaluation of discrepant data. Appl. Radiat. Isot. 60, 275-281] to the data of Lucas and Unterweger [Comprehensive review and critical evaluation of the half-life of tritium. J. Res. Natl. Inst. Stand. Technol. 105, 541-549], resulting in a recommended half-life of 4497(4) days. MacMahon et al. [Convergence of techniques for the evaluation of discrepant data. Appl. Radiat. Isot. 60, 275-281] highlighted problems in the evaluation of the discrepant half-life data of 90Sr, in particular the worrying upward trend in the data, where the weighted mean of all the measurements increases, on average, by 35 days each time a new measurement result is added. The current paper reports on further analyses of these data. New measurements of the half-life of 90Y have been reported by Kossert and Schrader [2004. Standardization by liquid scintillation counting and half-life measurements of 90Y. Appl. Radiat. Isot. 60, 741]. This has prompted a new evaluation of all available published 90Y half-life data. The data are fairly consistent, and a value of 64.063(16) h is recommended.

Monte Carlo modeling of the response of NRC's 90Sr/90Y primary beta standard.

The BEAMnrc/EGSnrc Monte Carlo code system is employed to develop a model of the National Research Council of Canada primary standard of absorbed dose to tissue in a beta radiation field, comprising an extrapolation chamber and 90Sr/90Y beta source. We benchmark the model against the measured response of the chamber in terms of absorbed dose to air, for three different experimental setups when irradiated by the 90Sr/90Y source. For the first setup, the chamber cavity depth is fixed at 0.2 cm and the source-to-chamber distance varied between 11 and 60 cm. In the other two cases, the source-to-chamber distance is fixed at 30 cm. In one case the response for different chamber depths is studied, while in the other case the chamber depth is fixed at 0.2 cm as different thicknesses of Mylar are added to the front surface of the extrapolation chamber. The agreement as a function of distance between the calculated and measured responses is within 0.37% for a variation in response of a factor of 29. In the case of dose versus chamber depth, the agreement is within 0.4% for the ISO-recommended nominal depths of 0.025-0.25 cm. Agreement between calculated and measured responses is very good (between 0.02% and 0.2%) for added Mylar foils of thicknesses up to 10.8 mg cm(-2). For larger Mylar thicknesses, deviations of 0.6%-1.2% are observed, which are possibly due to the systematic uncertainties associated with the restricted collisional stopping powers of air or Mylar used in the calculations. We conclude that our simulation model represents the extrapolation chamber and 90Sr/90Y source with adequate accuracy to calculate correction factors for accurate realization of dose rate to tissue at a depth of 7 mg cm(-2) in an ICRU tissue phantom, despite the fact that the uncertainties in the physical characteristics of the source leave some uncertainty in certain calculated quantities.

[Radioimmunotherapy with yttrium-90 ibritumomab tiuxetan. Clinical considerations, radiopharmacy, radiation protection, perspectives]. / Radioimmuntherapie mit 90Y-markiertem Ibritumomab-Tiuxetan: Klinik, Radiopharmazie, Strahlenschutz, Perspektiven.

90Y-ibritumomab tiuxetan (Zevalin) is currently approved for radioimmunotherapy of patients with relapsed or refractory follicular non-Hodgkin's lymphoma pretreated with rituximab. Future directions are the combined use of 90Y-ibritumomab tiuxetan as part of the initial treatment and as first-line multi-agent therapy of relapsed disease. Current studies investigate patients with other than follicular indolent histologies, e. g. diffuse large cell lymphoma. Labelling of 90Y ibritumomab tiuxetan is a safe procedure, the radiochemical purity is not disturbed by a higher room temperature or by metallic impurity. Quality control is recommended by thin layer chromatography (TLC), strips >15 cm are favourable. TLC cannot distinguish between the correctly radiolabelled antibodies and radiocolloid impurity. If necessary, additional HPLC should be performed. Radiocolloid impurities are absorbed to the solid phase and do not reach the eluate. If the radiochemical purity test is insufficient (<95%), the additional cleaning using EconoPac 10 DG columns (Biorad, Hercules, CA, USA) is a reliable procedure to reduce the percentage of free radionuclide. However, this procedure is not part of the approval.

Development of activity standard for 90 Y microspheres.

(90)Y microspheres are important therapeutic radiopharmaceuticals used in the treatment of liver cancer through a process known as selective internal radiation therapy. SIR-spheres is a radiopharmaceutical product that is comprised of (90)Y microspheres suspended in sterile, pyrogen-free water for injection into patients. It is necessary to establish for the SIR-spheres production the capability of accurately measuring the activity of this product to a traceable national measurement standard. An activity standard for SIR-spheres was developed from a standard for (90)Y solution, employing a highly quantifiable chemical digestion process. Calibration factors for the manufacturer's ionisation chambers were determined for 1 and 5 ml of the SIR-spheres product placed in Wheaton vials, for both 34% and 44% of (90)Y microsphere concentration.

Half-life determination of 88Y and 89Sr.

Half-life measurements have been carried out at LNHB for 88Y using a 4pi gamma-ionisation chamber and for 89Sr using a proportional counter. The determined half-life values and associated standard uncertainties are 106.63 +/- 0.05 d for 88Y and 50.65 +/- 0.05 d for 89Sr, being consistent with relevant values reported in literature. Based on the present results and relevant literature values revised recommended half-life values and associated standard uncertainties are proposed, viz. 106.626 +/- 0.021 d for 88Y and 50.57 +/- 0.03 d for 89Sr.

Activity standardization by liquid scintillation counting and half-life measurements of 90Y.

Radioactive 90Y was standardized by means of 4piBeta liquid scintillation efficiency tracing with a two-phototube counting system. The efficiencies of 90Y and the tracer 3H are related by the CIEMAT/NIST method. The dependence of the calculated efficiency on various shape factors and the importance of accurately measuring the radionuclide impurity of 90Sr are discussed. The half-life of 90Y was measured with improved accuracy by means of a liquid scintillation counting and a 4pi ionization chamber measuring system, and an average value T1/2 = 64.053(20) h was found.