Radiation protection considerations with [⁸⁹Zr]Zr-girentuximab PET and surgery

Abstract

^Background

⁸⁹Zr is emerging as a popular positron-emitting radionuclide for imaging; however, its 909 keV gamma emission presents shielding challenges, and radiation exposure safety guidelines for healthcare professionals working with the radionuclide have not been well-established. To guide assessment of the radiation risk and necessary safety guidelines, we present laboratory dose rate measurements of ⁸⁹Zr syringes and vials, and dose rates measurements made during the ZIRCON clinical trial ([⁸⁹Zr]Zr-girentuximab) to evaluate healthcare provider exposure during administration, imaging, and surgical procedures.

Results

The maximum dose rate from a vial with no shielding was 0.334 µSv/h/MBq, and the minimum dose rate with 66 mm lead shielding was 0.004 µSv/h/MBq. The controlled spill measured 0.52 µSv/h/MBq. Dose rates 1 m from patients who received [⁸⁹Zr]Zr-girentuximab had an average of 3.90 µSv/h at imaging. During surgery, waste measured below background levels, and a bed assistant 0.8 m from the patient received a 5 µSv/h whole-body dose rate. The excised kidney measured 6 µSv/h at 5 cm.

Conclusions

Our results demonstrate low radiation exposure levels associated with ⁸⁹Zr handling and exposure to the patient. With potential integration of ⁸⁹Zr into clinical practice, appropriate radiation safety guidelines are needed. Dose rate measurements can help guide development of best practices and site-specific protocols.

Clinical trial number: not applicable for this study; ZIRCON trial number NCT03849118, registered on 19 February 2019.

Background

Zirconium-89 (⁸⁹Zr), a positron-emitting radionuclide, is increasingly utilized in the field of nuclear medicine for diagnostic imaging and theranostic agents with monoclonal antibodies (mAb). This radionuclide’s favourable 78.4-h half-life aligns well with the biological half-lives of mAbs, allowing for effective imaging over extended periods. Additionally, ⁸⁹Zr demonstrates stable labelling with chelators such as desferoxamine (DFO) and exhibits minimal in vivo de-chelation, enhancing its suitability for clinical applications [1, 2].

Despite the growing application of ⁸⁹Zr, no radiopharmaceuticals labelled with this radionuclide have received regulatory approval for commercial use, and consequently, specific guidelines for safe handling are not yet established. The rise in ⁸⁹Zr use parallels the overall increased popularity of positron emission tomography (PET) imaging, leading to heightened radiation exposure risks for healthcare staff. ⁸⁹Zr is notably dose-intensive compared to other commonly used radionuclides, such as fluorine-18 (¹⁸F), necessitating stringent radiation protection measures. Comparisons of nuclear decay data of common PET and immuno-PET radionuclides can be seen in Table 1. Effective strategies to mitigate staff exposure include enhanced shielding, optimized handling protocols, and minimized activity usage.

Table 1.

Comparison of the main nuclear decay properties of ⁶⁸ Ga, ¹⁸F, ⁶⁴Cu and ⁸⁹Zr

	68 Ga	18F	64Cu	89Zr
T1/2 (h)	1.13	1.83	12.70	78.4
β+ branching ratio (% emission)	88.9	96.7	17.5	22.7
Eβ+mean (keV)	830	250	278	396
Eβ+max (keV)	1899	633	653	902
Main γ rays E (keV) [Iγ (%)]	1077 [3.22]	–	–	909 [99.0]

Obtained from NuDat 3.0 [14]

⁸⁹Zr exhibits radiation shielding and exposure challenges due to its 909 keV gamma ray that is emitted with 99% abundance. This highly penetrating emission makes it somewhat unique amongst commonly used positron-emitters, requiring additional attention to shielding and radiation worker exposure over and above what is typically encountered with PET radiopharmaceuticals.

Some work has been previously performed characterizing ⁸⁹Zr dose rates from phantoms to inform safety procedures [3, 4] but to date there appear to be no published actual ⁸⁹Zr dose rate measurements from patients, nor have there been published exposure rates from vials and syringes in geometries that might inform radiation safety procedures. Further, published exposure rate constants for ⁸⁹Zr, typically used to estimate radiation exposures in the absence of experimental data, are discordant by close to 50% [5, 6], making theoretical dose rate calculations problematic. However, no recommendations for working with radiopharmaceuticals labelled with ⁸⁹Zr, have been proposed.

For safe deployment of ⁸⁹Zr for future imaging applications, dosimetric measurement studies and radiation guidance are imperative to enable assessment of the radiation exposure and protection considerations for healthcare professionals. Based on these, standardized safety protocols for those with occupational exposure to ⁸⁹Zr-based tracers can be developed.

In many regions around the world, including France, the United Kingdom, and Australia, the annual radiation exposure limits for healthcare staff are set at 20 mSv for whole-body exposure, 500 mSv for extremities, and 20 mSv for the eyes. In contrast, the United States imposes higher annual limits, with thresholds of 50 mSv for whole-body exposure, 500 mSv for extremities, and 150 mSv for the lens of the eyes. Our study provides critical data from measurements involving ⁸⁹Zr-containing vials and syringes, as well as dose rates from patients administered with [⁸⁹Zr]Zr-girentuximab. This information is essential for individual sites to assess and manage the radiation risks faced by technologists and healthcare professionals during patient interactions. To support sites in evaluating these risks, we offer a comparative analysis of the primary nuclear decay properties of commonly used clinical radioisotopes, including gallium-68 (⁶⁸ Ga), ¹⁸F, copper-64 (⁶⁴Cu), and ⁸⁹Zr, as shown in Table 1.

We present carefully controlled laboratory-based dose rate measurements using known activities of ⁸⁹Zr in both syringe and vial geometries as well as measurements taken at three sites during a clinical trial utilizing a ⁸⁹Zr-labelled mAb, girentuximab (phase 3 ZIRCON trial) [7], in accordance with their institutional requirements and independent from the clinical trial procedures. These reported results are a summary from radiation exposure data gained during the trial to inform safe usage of ⁸⁹Zr and [⁸⁹Zr]Zr-girentuximab in the clinic, generally, and to specifically report on radiation safety aspects of clinical usage of [⁸⁹Zr]Zr-girentuximab, including receiving, handling, infusing, imaging, and patient handling to assist with risk assessment.

Methods

To assess the safety and risks associated with radiation exposure from ⁸⁹Zr, we measured radiation dose rates from vials, syringes, controlled spills, and patients. These measurements were conducted in the context of the Phase 3 ZIRCON clinical trial (NCT03849118), which evaluated the diagnostic performance of PET imaging with ⁸⁹Zr-labeled girentuximab ([⁸⁹Zr]Zr-girentuximab). This monoclonal antibody targets the tumor-associated antigen carbonic anhydrase IX (CAIX) and aims to detect, differentiate, and characterize clear cell renal carcinoma (ccRCC) from other renal and extrarenal lesions.

Dose rate measurements during ⁸⁹Zr and [⁸⁹Zr]Zr-girentuximab vial handling

To help estimate radiation dose rates to a radiation worker handling ⁸⁹Zr, multiple dose rate measurements were acquired from vials containing ⁸⁹Zr aqueous solution. At Site 1 (Royal Free London in London, UK). Dose rates were acquired from a 21 MBq [⁸⁹Zr]Zr-girentuximab in 12 mL in the trial vial with no shielding at 0.05, 0.5, and 1 m using a Fluke Victoreen 451P with a detection range for gamma rays > 25 keV and beta particles > 1 MeV and a calibration factor of 0.2 μSv/h/MBq at 1 m.

Site 2 (University Hospital of Bordeaux in Bordeaux, France) measured radiation dose rates from a [⁸⁹Zr]Zr-girentuximab vial with and without 10 mm tungsten shielding using a Berthold LB123 ion chamber survey meter with an energy range of 30 keV–1.3 MeV and calibration factor of 0.214 µSv/h per cps.

To determine the radiation dose rates that a radiation worker may be exposed to while handling ⁸⁹Zr in a vial, we conducted a series of measurements. Measurements in these shielded experiments were conducted using two calibrated ion chamber survey metres: The Fluke Model 491-30 and the Ludlum Model 9DP. These instruments were chosen for their accuracy and reliability in detecting radiation dose rates, ensuring precise and consistent data collection throughout the study. As the Ludlum 9DP is more stable at lower exposure rates, data from this ion chamber is presented herein; however, averaged data from the two survey meters generated functionally concordant results.

Initially, an aqueous solution of 5 mL of ⁸⁹ZrCl₄ in aqueous solution was placed in a 10 mL vial, and the dose rates was measured at a distance of 1 m unshielded. Subsequently, the vial was placed in an 8.16 mm lead pot, and additional lead shielding was incrementally added. Dose rate measurements were taken at 1 m with the following lead thicknesses: 16.4, 23.6, 24.0, 42.2, and 66.7 mm (Fig. 1A).

Fig. 1.

Experimental setup measuring ⁸⁹ZrCl₄ radiation dose rates. A 10 mL vial containing 5 mL in a lead pot with lead sheets place sequentially in front of the syringe. B 50 mL vial containing 30 mL in a lead pot with lead sheets place sequentially in front of the syringe. C 10 mL syringe in a lead syringe shield. D 10 mL syringe in a tungsten syringe shield

Similarly, in a second geometry, an unshielded 30 mL of aqueous ⁸⁹ZrCl₄ in a 50 mL vial were measured at 1 m. Measurements were taken both in air and with a 23.6 mm lead pot. The lead thicknesses for these measurements were 23.6, 42.2, and 66.7 mm (Fig. 1B).

From these two shielded vial experiments, dose rates measured at 1 m were generated and extrapolated to other distances using a simple 1/R² correction. Half-value layer (HVL) estimates for ⁸⁹Zr shielded in lead pots was also calculated. All results were normalized to express the percentage of gamma radiation not attenuated by the lead shielding.

Dose rate measurements during handling of ⁸⁹Zr and [⁸⁹Zr]Zr-girentuximab syringe

To measure radiation rates associated with anticipated syringe handling with commercially available syringe shields, dose rate measurements were performed in two different configurations.

In the first configuration, a 10 mL syringe was placed in a syringe shield with 6 mm lead thickness (Cardinal Health) and a 41 mm diameter (Fig. 1C). In the second configuration, the 10 mL syringe was placed in a tungsten syringe shield with an 8.5 mm thick wall and a 36.6 mm diameter (Fig. 1D).

This setup was designed to generate safety data to inform measured HVL thickness for ⁸⁹Zr in tungsten in a syringe geometry.

In both configurations, dose rates from syringe shields were measured at 1 m and corrected for distance (1/R²) to obtain a surface reading to inform dose handling. Measurements were taken with 2 calibrated ion chamber survey meters, which were the same devices used for the syringe experiments as for the vial measurements.

Dose rate measurements from a controlled spill of [⁸⁹Zr]Zr-girentuximab

To inform risk assessments regarding foreseeable incidents involving ⁸⁹Zr, it was necessary to determine the dose rate from a radioactive spill. For this purpose, a controlled spill of ⁸⁹Zr was conducted. Specifically, 1 MBq of ⁸⁹Zr was spilled onto an absorbent surface with an area of 10 × 10 cm. Radiation dose rate measurements were then taken at a distance of 1 m from the spill.

These measurements were carried out using a Fluke Victoreen 451P ion chamber survey meter with a detection range for gamma rays > 25 keV and beta particles > 1 MeV and a calibration factor of 0.2 μSv/h/MBq at 1 m. The data obtained from this controlled spill experiment provide critical insights into the potential exposure risks for healthcare personnel in the event of a similar incident.

Clinical trial radiation dose rate measurements

To assess radiation dose rates experienced from patients following infusion of 37 MBq (± 10%) [⁸⁹Zr]Zr-girentuximab, dose rate measurements were performed during various phases of a clinical trial at each of three sites.

• Site 1: Nuclear Medicine, Royal Free Hospital, London, United Kingdom.

• Site 2: University Hospital of Bordeaux, Bordeaux, France.

• Site 3: Department of Molecular Imaging and Therapy, Austin Health, University of Melbourne.

Each of the 3 sites performed their measurements independently and according to their local protocol.

Site 1

Dose rates from one patient who had undergone infusion of [⁸⁹Zr]Zr-girentuximab were measured at 0.05, 1 m and 2 m, anteriorly and posteriorly using Fluke Victoreen 451P with a detection range for gamma rays > 25 keV and beta particles > 1 MeV and a calibration factor of 0.2 μSv/h/MBq at 1 m. These measurements were performed immediately post infusion (p.i), at 1 h p.i, 2 h p.i, and on the day of the PET/CT scan (day 3).

The research nurse responsible for monitoring the patient during infusion and 2 h post infusion was equipped with an electronic personal dosimeter (EPD) (ThermoScientific EPD TruDose BG; detection range for gamma rays 16 keV–10 MeV and for beta particles 200 keV–1.5 MeV) and positioned 3 m from the patient. The total radiation dose was recorded.

On day 4 the patient went to surgery, dose rates were obtained at anterior at 1 m due to the patient being on the hospital bed. Dose rates were taken before and after surgery. A ThermoScientific EPD TruDose BG with a detection range for gamma rays 16 keV–10 MeV and for beta particles 200 keV–1.5 MeV was worn by the assistant closest to the patient during surgery. The radiation dose rates from surgical equipment and waste were measured with a Thermo Fisher Scientific mini 900 scintillation monitor with a 44a probe (energy range 15–250 keV; calibration factor 41 cps/MBq at 1 m). Surgery lasted 2hs.

Site 2

Dose rates were taken from 28 patients who had all undergone infusion of [⁸⁹Zr]Zr-girentuximab. Measurements were taken immediately p.i., at 1h p.i., 2h p.i., and on the day of the PET/CT scan (mean 5 ± 1days). Measurements were acquired at the liver and at 1m from the liver. Measurements were acquired with a LB123 dose rate monitor with an energy range of 30 keV–1.3 MeV and calibration factor of 0.214 µSv/h per cps. Personnel monitoring was performed for hands, eyes, and whole body using thermoluminescent dosimeters. Dose rates during surgery were performed using a Thermo Fisher Scientific RadEye B20 meter.

Site 3

Radiation exposure measurements were taken 10 cm from a patient who was IV infused with [⁸⁹Zr]Zr-girentuximab, using a Polimaster PM1610B X-ray and Gamma Radiation Personal Dosimeter. The dose rates recorded by the PM1610B were consistent with those measured using a Berthold LB134 with a LB1236 H10 probe.

Excised tissue dose rate measurements

Site 1 surgically excised a kidney on Day 4 from a patient who had received 37 MBq [⁸⁹Zr]Zr-girentuximab, and radiation dose rates were measured 5 cm from the excised kidney with a Thermo Fisher Scientific mini 900 scintillation monitor with a 44a probe (energy range 15–250 keV; calibration factor 41 cps/MBq at 1 m).

Results

Dose rate measurements during ⁸⁹Zr and [⁸⁹Zr]Zr-girentuximab vial handling

Unshielded dose rate measurements for ⁸⁹Zr vial are found Table 2. For 30 mL ⁸⁹Zr in a 50 mL vial, the dose rate with no shielding was 0.164 µSv/h/MBq.

Table 2.

Radiation dose rates of a [⁸⁹Zr]Zr-girentuximab drug vial from sites 1 and 2

Distance (m)	Dose rate (µSv/h/MBq)
Site 1 (unshielded)
0.05  0.5  1	31.4
	0.78
	0.20
Site 2 (unshielded)
0	15.6
1	0.32
Site 2 (10 mm tungsten shielding)
0	4.2
1	0.05

Shielded dose rate measurements can be seen in Fig. 2 and Table 2. Measured dose rates for various lead thicknesses between 0–66.7 mm in front of 5 mL ⁸⁹Zr in a 10 mL are shown in Fig. 2A. For 30 mL ⁸⁹Zr in a 50 mL vial, with 66.7 mm shielding was 0.002 µSv/h/MBq (Fig. 2B). Transmission factors by lead thickness are shown in Table 3.

Fig. 2.

Radiation dose rates from vials in lead pots with increasing lead thickness in front of the vial and pot. Dose rates measured at 1 m. A 5 mL ⁸⁹Zr in 10 mL vial in 8.16 mm lead pot. B 30 mL ⁸⁹Zr in 50 mL vial in 23.6 mm lead pot

Table 3.

Measured transmission factors for thicknesses of lead shielding

Sample geometry	Lead thickness (mm)	Transmission factor
5 mL in 10 mL vial	0	1.000
	8.1	0.611
	16.4	0.287
	24	0.158
	23.6	0.174
	42.2	0.052
	66.7	0.012
30 mL in 50 mL vial	0	1.000
	23.6	0.171
	42.2	0.041
	66.7	0.010

Measured dose rates at 1 m for Sites 1 and 2, and laboratory measurements at the same distance are plotted in Fig. 3. For this figure, the values at 1.00 m are measured values, all dose rates at distances between 1 and 100 cm are theoretically calculated from 1/R² corrections.

Fig. 3.

Dose rate as a function of distance from unshielded vials measured both under laboratory conditions and at clinical trials site. Theoretical values from Stabin are functionally coincident with the 10 mL vial measurements. All values are back-calculated from actual measurements at 1.00 m using 1/R² corrections

Dose rate measurements during ⁸⁹Zr and [⁸⁹Zr]Zr-girentuximab syringe handling

The dose rates at the surface of the lead and tungsten syringe shields were calculated from the 1-m measurements using the 1/R² law to be approximately 268 µSv/h/MBq, and 221 µSv/h/MBq, respectively. Laboratory measured dose rates at 1 m, calculated dose rates for 30 cm, and shield-surface dose rates are provided in Table 2. [⁸⁹Zr]Zr-girentuximab 20 mL syringe dose rates with and without shielding at Site 2 are provided in Table 4.

Table 4.

Radiation dose rates at the surface of syringe shields containing ⁸⁹Zr estimated from 1 m using the 1/R² law and dose rates of a syringe of [⁸⁹Zr]Zr-girentuximab from site 2

Distance (m)	Dose rate (µSv/h/MBq)
89Zr in 6 mm lead syringe shield
0	268
89Zr in 8.5 mm tungsten syringe shield
0	221
Site 2 (unshielded)
0	111.11
0.3	2.74
Site 2 (10 mm tungsten syringe shield)
0	11.28
0.3	1.79

Dose rate measurements from a controlled spill of [⁸⁹Zr]Zr-girentuximab

In a controlled spill over a 10 × 10 cm area on absorbent material, the dose rate measured at a distance of 1 m was 0.52 µSv/h/MBq and the activity was 1 MBq.

Clinical trial dose rate measurements

Following administration of [⁸⁹Zr]Zr-girentuximab during the clinical trial, a research nurse at Site 1 observed the patient for 2 h immediately following administration to observe for any adverse reactions. The research nurse was 3 m from the patient behind a shield unless needed to provide care to the patient. EPD measurements from the research nurse was 3 µSv.

To assess the dose rates healthcare professionals interacting with patients in the hours and days following administration, such as during PET/CT imaging, three sites took measurements. These measurements can be seen in Table 5. Figure 4 presents the dose rates of a patient enrolled in the ZIRCON trial at Site 3, 1 m from the patient several days following administration of [⁸⁹Zr]Zr-girentuximab.

Table 5.

Measured dose rates from patients receiving [⁸⁹Zr]Zr-girentuximab at sites 1, 2, and 3

Distance (m)	Site 1	Site 2	Site 3
	Dose rate (µSv/h) (anterior, posterior) N = 1	Mean dose rate (SD) (µSv/h), N = 28	Dose rate (µSv/h) N = 1
Day 0
0		109.5 (29.5)
1	4.0, 4.3	11.7 (3.6)	9.9
2	1.5, 1.4
Hour 1
0		98.6 (28.6)
1		10.0 (2.4)
Hour 2
0	55, 68	95.3 (22.7)
1	3.9, 4.3	10.3 (3.4)
2	1.9, 1.9
PET/CT imaging	Day 3	Median day 5	Day 3
0	34, 35	34.5 (11.5)
1	3.1, 2.6	3.9 (1.2)	4.5
2	1.0, 0.9

Day 0 is day of infusion

Fig. 4.

Radiation dose rates 1 m from a patient who received [⁸⁹Zr]Zr-girentuximab and curve fit to indicate estimated dose rates after Day 3

Patients enrolled in the ZIRCON trial were scheduled to undergo surgical procedures to remove lesions. Thus, the radiation risk to surgical staff was also measured at each site.

A radical nephrectomy was performed on Day 4 at Site 1, and EPD measurement from the assistant surgeon/junior doctor sitting 1 m from the patient was 5 µSv. Surgical equipment had a low level of contamination (maximum 50 cps) at the surface but did not measure above background at 1 m, and surgical waste did not measure above background (10–15 cps).

Radiation doses received by a bed assistant at Site 2 located 0.8 m from a patient undergoing surgery was measured at the assistant’s hands, eyes, and whole body, which received 21, 3, and 5 µSv/h, respectively.

Site 3, measurements from a patient were taken during the first 3 days following administration of [⁸⁹Zr]Zr-girentuximab at 0.1 m can be seen in Table 6. Using curve fitting, an estimate of the maximum dose rate surgeons would be exposed to at 0.3 m was calculated, which is the estimated distance of robotic surgery (Fig. 4).

Table 6.

Estimation of maximum dose rates measured at 0.1 and 0.3 m from a patient, cumulative dose a surgeon would receive at 0.3 m during a 2-h surgery, and the maximum number of patients a surgeon would be able to operate upon at 0.3 m based upon an annual dose constraint of 1 mSv/year

Day	Exposure 0.1 m (µSv/h)	Exposure 0.3 m (µSv/h)	Cumulative dose for 2 h surgery at 0.3 m (µSv)	Number of patients allowed for a surgeon at 0.3 m
0	49.20	10.93	22	46
1	41.88	9.31	19	54
2	35.65	7.92	16	63
3	30.35	6.74	13	74
4	25.84	5.74	11	87
5	22.00	4.89	10	102
6	18.72	4.16	8	120
7	15.94	3.54	7	141
8	13.57	3.02	6	166
9	11.55	2.57	5	195
10	9.83	2.19	4	229
11	8.37	1.86	4	269
12	7.13	1.58	3	316
13	6.07	1.35	3	371
14	5.16	1.15	2	436

Day 0 is day of infusion

Excised tissue dose rate measurements

A kidney removed during a radical nephrectomy at Site 1 on Day 4 was measured immediately following excision. Four days following excision (8 days following infusion of [⁸⁹Zr]Zr-girentuximab), the excised kidney was measured again, at which point pathology staff processed the sample for histology (Table 7).

Table 7.

Measured radiation dose rate from excised kidney following radical nephrectomy at site 1

Distance (m)	Dose rate (µSv/h)
Day 4, immediately following excision
0.05	6
Day 8 (4 days following surgery)
0.05	1.5
1	0.18

Day 0 is day of infusion

Discussion

Unlike other commonly used PET radionuclides, ⁸⁹Zr emits a 909 keV gamma ray. This characteristic results in significant radiation safety challenges due to its ability penetrate both biological tissue and standard shielding materials like lead and tungsten more effectively. Our work aims to address these challenges by providing a detailed quantitative analysis of dose rate measurements and extrapolated estimates. To the best of our knowledge, this study is the first to present clinically derived radiation exposure rates of ⁸⁹Zr for healthcare workers. By offering comprehensive data on the dose rates encountered by healthcare professionals under various clinical scenarios, we fulfil a critical need for radiation safety information involving the use of ⁸⁹Zr.

Measurements at Site 1 indicate a relatively high exposure of 31.4 µSv/h/MBq (Table 1) when directly handling an unshielded vial of ⁸⁹Zr-girentuximab at a distance of 5 cm. In contrast, Site 2's measurements, both with and without shielding, demonstrate a substantial reduction in exposure when shielding is employed (Table 2, Figs. 2 and 3). These findings underscore the necessity of using tools such as tongs to maintain distance from unshielded vials, implementing shielding, and practicing efficient handling techniques to minimize exposure time. In addition, these results emphasize that distance corrections, even at small distances, make a difference in dose rate measurements. We recommend specialized training for radiation technicians, particularly those receiving the highest doses, and advise that an experienced technologist, equipped with appropriate radiopharmaceutical PPE, be responsible for minimizing manipulation time.

For context, typical dose rates for ⁶⁸Ga are approximately 0.68 µSv/h/MBq. Although the dose rate with ⁸⁹Zr is 46 times higher, it is important to consider that the activity applied for ⁸⁹Zr (37 MBq) is about five times less than that for ⁶⁸Ga (200 MBq), and that significantly more ⁶⁸Ga procedures are conducted annually. For instance, Site 2 plans to dose 20 patients with ⁸⁹Zr-girentuximab per year, compared to 300 procedures involving ⁶⁸Ga.

Table 3 presents high dose rates for syringes, even when appropriate syringe shields are used. Although the dose rates at the surface appear significantly different between the two tables, this discrepancy arises from the methodologies used. The top half of the table displays theoretical dose rates at the surface, extrapolated from calculations at 1 m and assuming the source is a point source. While this approach is not geometrically accurate, it provides essential information for assumptions used in risk assessments. Conversely, the second half presents actual measurements taken at the surface of the syringe or syringe shield at Site 2, offering a closer approximation to the true dose rate.

The use of a syringe shield while drawing up the solution and positioning an infusion pump behind appropriate shielding is recommended, as demonstrated by our syringe shielding measurements (Table 4). Site 1 implemented several strategies to minimize staff exposure, including preparing as much as possible prior to administering ⁸⁹Zr-girentuximab. Preparatory steps included drawing blood on Day 0, placing ECG leads, and positioning the blood pressure cuff. During the 2-h observation period required for the study of the new 89Zr-girentuximab agent, a nurse was positioned 3 m away from the patient behind a shield, attending to the patient only when necessary. This extended observation period is specific to the clinical study phase and will not generally be required in routine post-approval clinical practice.

Site 3 estimated that for a surgery performed on Day 3, surgeons would be exposed to 30.35 µSv/h at 0.1 m (Table 6). For comparison, during sentinel lymph node removal procedures, surgeons received approximately 32 µSv/h at the same distance, and their yearly dose to hands was estimated at 16 mSv/year with an average of 42 cases per year [8]. The vast majority of partial nephrectomies are now robot-assisted, which also limits radiation exposure to the surgeon. At 0.3 m, Site 3 found an exposure of 6.74 µSv/h on Day 3 (Table 7). At this distance and time, surgeons would be able to operate on over 70 patients without reaching the annual limit of 1 mSv.

Surgical assistants who are closest to the patient should increase distance where possible and limit time near the patient when possible but only when this does not affect patient care. At Site 2, the bed assistant was located at 70–90 cm for 1–4 h, leading to a whole-body dose of a maximum 16 µSv per procedure for the bed assistant. Thus, the measured data are far from the occupational limits imposed, regardless of the country.

Another critical factor to consider is the transportation of blood and tissue samples from patients to pathology departments for processing and analysis. These samples may contain varying levels of radioactivity, necessitating careful measurement to ensure compliance with acceptable standards for routine processing in pathology departments. It is essential to establish effective communication mechanisms between clinical and pathology teams regarding the radioactivity levels of these samples. If samples exceed established limits, dedicated equipment may be required for processing, and additional precautions must be implemented to ensure safe handling.

The kidney removed during surgery at Site 1 registered a dose rate of 6 µSv/h (Table 7), which is significant for personnel who frequently handle such samples. It is advisable that samples be managed by experienced operators. Since most of the radiation dose affects the extremities, which cannot be shielded effectively, consideration should be given to delaying sample processing to allow for additional radioactive decay. Site 1 measured the excised kidney four days after nephrectomy (Table 7) and found the dose rate to be at acceptable levels for safe handling by pathology staff. To ensure safety, we recommend proper storage of samples prior to processing, continuous monitoring of personnel exposure rates using dosimeters, and diligent management of radioactive waste.

According to each site and patient flow, radiation protection officers can determine if additional radiation safety measures are needed based on national regulations. Given the incidence of clear cell renal cell carcinoma in a particular area, it is feasible to estimate the number of doses required per year. However, the incidence of small renal masses is increasing due to the aging population and obesity epidemic, and the overall incidence rate varies globally [9, 10].

When considering ⁸⁹Zr pharmaceuticals, it is important to discuss the normal distribution of the product. As a monoclonal antibody, most of the signal from [⁸⁹Zr]Zr-girentuximab, which is targeted against CAIX, is located in the liver and elimination is through the faeces; unlike other products, urinary contamination is low risk. The direct consequence is a longer retention in the body. It should also be noted that the measurements presented here apply only for this probe and do not necessarily reflect the situation with other ⁸⁹Zr-radiopharmaceuticals. For example, [⁸⁹Zr]Zr-prostate-specific membrane antigen (PSMA) agents are under evaluation (such as [⁸⁹Zr]Zr-PSMA-617) as well as ⁸⁹Zr-labelled leukocytes and platelets, and these are cleared through the kidneys [11–13] with two consequences. First, urinary contamination must be considered, although the collection of urine is dependent on local radiation regulations; for example, for doses used in the ZIRCON trial (and similar imaging studies with ⁸⁹Zr antibodies), it is not required to collect urine in Australia. Second, the elimination of the radiopharmaceutical will be faster, leading to a more rapid reduction in external dose rate.

The utilization of ⁸⁹Zr in PET imaging presents additional radiation protection considerations for healthcare professionals compared with other commonly used radionuclides due to its relatively long half-life and high energy gamma emission alongside the positron decay (Table 1). While ⁸⁹Zr-based radiopharmaceuticals like [⁸⁹Zr]Zr-girentuximab offer significant benefits for diagnostic imaging, they necessitate appropriate safety protocols to minimize radiation exposure to medical staff. The development and adherence to comprehensive radiation safety guidelines, including the use of personal protective equipment, proper handling and disposal of radioactive materials, and regular monitoring of occupational exposure, are paramount. Continuous education and training of safe use of ⁸⁹Zr and other radionuclides in medical applications are crucial for minimizing radiation exposure and safeguarding the health of professionals in this field.

Conclusions

As the use of ⁸⁹Zr continues to grow in clinical settings, the adoption of appropriate safety measures is an important aspect of harnessing the full potential of ⁸⁹Zr in advancing patient care. Our data provides information necessary for individual sites to make appropriate risk assessments for healthcare providers when incorporating ⁸⁹Zr into clinical practice. The use of shielded syringe (at least 6 mm tungsten) is recommended to handle [⁸⁹Zr]Zr-girentuximab. A minimum of 3 days is recommended between imaging and surgery. Dose constraints might also be applied according to local regulations.

Abbreviations

¹⁸F

Fluorine-18

⁶⁴Cu

Copper-64

⁶⁸ Ga

Gallium-68

⁸⁹Zr

Zirconium-89

CAIX

Carbonic anhydrase IX

ccRCC

Clear cell renal cell carcinoma

DFO

Desferoxamine

EPD

Electronic personal dosimeter

HVL

Half-value layer

mAb

Monoclonal antibody

PET

Positron emission tomography

PSMA

Prostate-specific membrane antigen

p.i.

Post-infusion

Author contributions

A.C. and B.F.H. conceived manuscript topic. A.C., S.B., C.M., and C.B. performed field measurements. S.A.G. and J.S. performed vial and syringe measurements. A.C., S.B., C.M., C.B., A.M.S., S.A.G., J.S., and B.F.H contributed to manuscript writing and approved the final version.

Funding

The ZIRCON trial (NCT03849118) was sponsored by Telix Pharmaceuticals.

Availability of data and materials

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

The conduct of the ZIRCON clinical trial met all local, legal, and regulatory requirements. The trial was conducted in accordance with ethical principles originating in the Declaration of Helsinki and the International Conference on Harmonization (ICH) guideline E6: Good Clinical Practice (GCP). Patients provided written informed consent.

Consent for publication

Not applicable.

Competing interests

C.M. received funding from Telix Pharmaceuticals but outside the scope of this study. C.B. has served on an advisory board for Telix Pharmaceuticals. A.M.S. has received funding from Telix Pharmaceuticals for research projects and clinical trials (to Institution), was a site Investigator of the ZIRCON study, and has served on advisory boards for Telix Pharmaceuticals (non-compensated).