Quantitative measurement of ²¹⁹Rn radioactivity in exhaled breath from patients with bone metastasis of castration-resistant prostate cancer treated with ²²³RaCl₂

Abstract

Background

The α-emitting radionuclide radium-223 (²²³Ra) is widely used for the treatment of bone metastasis in patients with castration-resistant prostate cancer. However, ²²³Ra decays into radon-219 (²¹⁹Rn) which is a noble-gas isotope, and ²¹⁹Rn may escape from patients treated with ²²³Ra via their respiration. In this study, we quantified the amount of ²¹⁹Rn contained in the breath of patients treated with ²²³Ra to estimate its effect on the internal exposure dose of caregivers.

Methods

A total of 12 breath samples were collected using a breath collection bag from a total of six patients treated with ²²³RaCl₂. Approximately 300 mL of exhaled breath was collected in a breath bag at 1 min and at 5 min after the start of ²²³RaCl₂ administration. The contents of each bag were measured using an HPGe detector, and the amount of ²¹⁹Rn was quantified based on the detection of the γ peak of ²¹¹Bi, which is a descendant nuclide of ²¹⁹Rn, persisting in the breath bag. The effective dose to caregivers arising from the inhalation of ²¹⁹Rn was estimated by referring to the scenario for the calculation of release criteria established for ¹³¹I therapy in Japan.

Results

A small peak for the 351-keV γ ray of ²¹¹Bi originating from the exhalation of ²¹⁹Rn was observed. Using the observed γ peak of ²¹¹Bi, the average amounts of ²¹⁹Rn per unit breath volume at 1 min and 5 min after the start of ²²³RaCl₂ administration were calculated as 90 ± 56 Bq/mL and 28 ± 9 Bq/mL, respectively. The effective dose of ²¹⁹Rn to caregivers was estimated to be 3.5 μSv per injection.

Conclusions

The amount of ²¹⁹Rn in the exhaled breath of patients treated with ²²³RaCl₂ was quantitatively calculated using breath collection bags. The internal radiation exposure of caregivers from ²¹⁹Rn in the exhaled breath of patients treated with ²²³RaCl₂ is relatively small.

Background

Recently, radium-223 (²²³Ra) dichloride (²²³RaCl₂; Xofigo®) has been widely used for the treatment of bone metastases in patients with castration-resistant prostate cancer (CRPC) [1, 2]. This radionuclide emits α-particles within a short range in tissues and with a high linear energy transfer, making it suitable for the treatment of cancer cells with minimal side effects in the surrounding tissues. As shown in the decay chain of ²²³Ra (Fig. 1), some descendant nuclides of ²²³Ra also emit α-particles and contribute to its killing effect on cancer cells. However, ²²³Ra decays into radon-219 (²¹⁹Rn) which is an isotope of a noble-gas element, and this ²¹⁹Rn may escape from patients treated with ²²³Ra. Although the escape of ²¹⁹Rn from patients is probably minor because of the very short half-life of ²¹⁹Rn (3.96 s), the amount of ²¹⁹Rn escaping from patients should be quantified to allow the internal radiation exposure experienced by medical staff and caregivers to be estimated. Yamamoto et al. mentioned that ²¹⁹Rn may escape via the respiration of patients and reported that the concentration of the descendant nuclides of ²¹⁹Rn in a room increased during radionuclide therapy with ²²³Ra, compared with that without the patients [3]. However, the amount of ²¹⁹Rn exhaled through the respiration of patients has not been quantified in a hospital setting. In this study, the breath of patients treated with ²²³Ra was collected using a breath collection bag and the ²¹⁹Rn radioactivity was quantified by measuring the γ rays of ²¹¹Bi, which is a descendant nuclide of ²¹⁹Rn, persisting in the breath bag. The purpose of this study was to evaluate the level of ²¹⁹Rn radioactivity in the exhaled breath of patients treated with ²²³Ra to enable a precise estimation of the internal radiation exposure dose experienced by caregivers.

Fig. 1

Main decay chain of ²²³Ra

Methods

Measurement of expired gas from patients

The study protocol was approved by the institutional review board of Osaka University Hospital. First, we investigated whether the breath of the patients contains radionuclides emitting α-particles using an α survey meter (Hitachi TCS-232b, Tokyo, Japan). A patient (body weight 55.0 kg) received ²²³RaCl₂ of 3.0 MBq (55 kBq/kg) for the treatment of bone metastases from CRPC. After informed consent was obtained from the patient, the α survey meter was placed closely to the mouth of the patient from the start of ²²³RaCl₂ administration, and α-particles in the breath of the patient were directly measured until 3 min after the start of administration. Additionally, the count rate at 5 min after the start of administration was also measured.

Then, a total of 12 breath samples were collected using breath collection bags (Otsuka Pharmaceutical, Tokyo, Japan) from a total of six patients (71.3 ± 5.4 years old, body weight 59.5 ± 11.7 kg) received ²²³RaCl₂ (3.4 ± 0.8 MBq). The administration of ²²³RaCl₂ to the patients was conducted slowly over a period of approximately 1 min. After informed consent was obtained from each patient, approximately 300 mL of exhaled breath was collected into a breath bag at 1 min and at 5 min after the start of ²²³RaCl₂ administration. A breath sampling time of 1 min after the start of administration was selected because the amount of ²¹⁹Rn contained in a patient’s breath is expected to reach a peak value at this time because of the slow administration of ²²³RaCl₂ (see also Fig. 3 which is the result of the direct measurement of the breath of the patient by the α survey meter). A sampling time of 5 min is expected to correspond to the time at which the patient is likely to leave the injection room. After sampling, the breath sample was removed from the bag using a syringe (volume 50 mL, minimum volume scale 1 mL) to enable the bag to be folded into a small, fixed geometric shape (see also Fig. 2) for measurement using a high-purity germanium (HPGe) detector (Canberra BE-2020, Connecticut, USA). The volume of the breath collected in the bag was measured using the volume scale printed on the syringe (the uncertainty for the measured volume of the breath sample was estimated to be several milliliters). Because ²¹⁹Rn and its descendant nuclides may escape from the bag during the use of the syringe, the bag was allowed to stand for more than 80 s until almost all the ²¹⁹Rn atoms in the breath bag had decayed into non-volatile descendant nuclides prior to the removal of the breath sample. Then, the breath sample was removed through a glass-fiber filter (ADVANTEC GB-100R, Tokyo, Japan) attached to the syringe to catch the descendant nuclides of ²¹⁹Rn. After the removal of the breath sample, the breath bag, together with the glass-fiber filter, was subjected to γ-ray spectrometry using an HPGe detector for 1800 s at almost zero distance. The amount of ²¹⁹Rn in the breath sample was estimated as follows. Based on the observed γ peak of ²¹¹Bi (351 keV), the radioactivity of ²¹¹Pb in transient radioactive equilibrium with ²¹¹Bi was calculated [4]. Then, from the ²¹¹Pb radioactivity at the end of the breath collection, the amount of ²¹⁹Rn contained in the breath sample was estimated assuming that the number of ²¹¹Pb atoms at the end of the breath collection would be equivalent to that of ²¹⁹Rn because of the very short half-life of ²¹⁹Rn. The measurement efficiency for the 351-keV γ peak of ²¹¹Bi at the same distance with the measurement of the breath bag was evaluated based on the measurement of a self-produced ²²³Ra point source, the radioactivity of which was determined using a ¹³³Ba standard source. The measurement efficiency was determined to be 2.63 ± 0.13%. The uncertainty for the efficiency is including the uncertainty of the radioactivity of the ¹³³Ba standard source (4.8%) and counting errors for the measurements of the ¹³³Ba standard source and the ²²³Ra point source (less than 1%).

Fig. 2

Photographs of a the breath bag with the glass-fiber filter after the removal of the breath sample and b the folded breath bag for the measurement with an HPGe detector

Estimation of radiation exposure experienced by medical staff

The descendant nuclides of ²¹⁹Rn exhaled through the breath of patients may float through the air by attaching to dust or aerosol particles. These nuclides can contribute to medical staff and caregivers being exposed to radiation internally. Therefore, we also investigated whether the inhalation of descendant nuclides of ²¹⁹Rn can be blocked by the use of a mask. Medical staff wore an N95 mask (3M 1870+, Tokyo, Japan) during the administration of ²²³Ra to the patients. After administration, the outside and inside (face side) of the mask were measured using an α survey meter (Hitachi TCS-232b, Tokyo, Japan). A total of five masks worn by medical staff who stood close to the patients during ²²³RaCl₂ therapy were measured during two injections (three medical staff for one injection [administration dose 3.9 MBq] and two staff for the other [administration dose: 3.0 MBq]). The measurements using the survey meter were conducted while placing the survey meter in close contact with the surface of each mask, and the count rate was recorded at 2 min after the start of measurement with a time constant of 30 s.

Estimation of radiation exposure experienced by caregivers

The radiation exposure experienced by caregivers was calculated based on documentation regarding the calculation of release criteria established for ¹³¹I therapy by the Ministry of Health and Welfare in Japan [5]. The blood concentration of ²²³Ra immediately after injection (C_Ra) was estimated using the following formula:

$$ {C}_{\mathrm{Ra}}=\frac{A_{\mathrm{injection}}}{V_{\mathrm{blood}}}, $$

where A_injection is the injection dose of ²²³Ra and V_blood the blood volume in the human body. In this calculation, we used A_injection = 3.4 × 10³ kBq which is the average injection dose in this study and V_blood = 5.0 × 10³ mL, and C_Ra was estimated to be 0.68 kBq/mL. The area under the curve (AUC) for the blood concentration of ²²³Ra was obtained using the clinical trial data (phase I) for ²²³RaCl₂ published in Japan by the Pharmaceutical and Medical Devices Agency (PMDA) (https://www.pmda.go.jp). Duration (T), which corresponds to the AUC up to 72 h post injection (0.674 kBq·h/mL) with the assumption that the blood concentration level immediately after the injection of ²²³Ra is maintained, was calculated using the following equation:

$$ T=\frac{\mathrm{AUC}}{C_{\mathrm{Ra}}}, $$

and T was estimated to be 0.99 h. The concentration of ²¹⁹Rn in the exhaled breath was assumed to be proportional to the blood concentration of ²²³Ra. The total exhaled amount of ²¹⁹Rn was calculated by multiplying the radioactivity in the exhaled breath immediately after the injection by a factor of 0.99 h, assuming that the respiration rate was 12 breaths per minute and the volume of breath was 500 mL per single respiration. The effective dose coefficient for the inhalation of ²¹⁹Rn was calculated as 7.9 × 10⁻⁹ mSv/Bq, with reference to the ²²²Rn data (6.5 × 10⁻⁶ mSv/Bq) [6] corrected by the effective half-life. Regarding the exposure scenario for caregivers, the volume of the room containing the patient was estimated to be 30 m³, air changes were regarded as once per hour, the daily respiration rate of the caregivers was estimated to be 20 m³, and the caregiver was assumed to always be present in the same room as the patient based on the release criteria for ¹³¹I in Japan [5]. To estimate the internal exposure dose experienced by caregivers, an exposure factor of 0.5 was applied [7].

Results

The time activity curve obtained in the direct measurement of α-particles in the breath of the patient by the α survey meter is shown in Fig. 3. The count rate of α-particles exceeded the measurable range (more than 100 kcpm) at several tens of seconds after the start of administration and then gradually decreased to 20 kcpm until 5 min after the start of administration, showing that radionuclides emitting α-particle were exhaled through the respiration.

Fig. 3

Time activity curve obtained in direct measurement of α-particles in breath of patient by an α survey meter from the start of ²²³RaCl₂ administration. The count rate exceeded the measurable range (100 kcpm) at several tens of seconds after the start of administration

A typical γ-ray spectra obtained for the measurement of a breath bag is shown in Fig. 4 a. A small peak for the 351-keV γ ray of ²¹¹Bi was observed. On the other hand, no γ peak of 269 keV from ²²³Ra was observed. The 351-keV peak disappeared approximately 4 h after the collection of the breath sample, as shown in Fig. 4 b. This finding unambiguously shows that the breath samples from patients treated with ²²³RaCl₂ did not contain ²²³Ra.

Fig. 4

Typical γ-ray spectrum obtained for breath bag measurements using an HPGe detector. Administration dose, 3.8 MBq; breath sampling time, 5 min after the start of administration; measurement start, a 17 min and b approximately 4 h after the end of breath collection

The amount of ²¹⁹Rn contained in the breath samples as determined using γ-ray spectrometry is summarized in Table 1, together with the administration dose of ²²³Ra and the volume of collected breath. The amount of ²¹⁹Rn exhaled in the breath at 1 min after the start of administration varied widely from 14 to 59 kBq, while the amount of ²¹⁹Rn at 5 min after the start of administration was around 10 kBq. The mean value of ²¹⁹Rn per unit volume of breath is shown in Fig. 5. The values were calculated as 90 ± 56 Bq/mL and 28 ± 9 Bq/mL (mean ± standard deviation) at 1 min and 5 min after the start of administration, respectively.

Table 1 Summary of the amounts of ²¹⁹Rn contained in breath samples from patients treated with ²²³RaCl₂

Fig. 5

Mean value of ²¹⁹Rn per unit volume of exhaled breath at 1 min and 5 min after the start of ²²³RaCl₂ administration

The results of the mask measurements using the α survey meter are summarized in Table 2. Small count rates of less than 100 cpm for α-particles were detected on the outside of the masks. On the other hand, no α-particles were detected on the inside of the masks. The count rate on the outside of the masks varied widely depending on the medical staff, and the measurement for one mask showed no detection of α-particles even on the outside of the mask.

Table 2 Summary of measurement results obtained using an α survey meter for N95 masks worn by medical staff

The cumulative amount of exhaled ²¹⁹Rn from the patient via exhaled breath until 72 h after the start of administration (A_{Rn,cumulative}) was calculated as follows:

$$ {A}_{\mathrm{Rn},\mathrm{cumulative}}={A}_{\mathrm{Rn},\mathrm{breath}}\times {V}_{\mathrm{breath}}\times {N}_{\mathrm{respiration}}\times T, $$

where A_{Rn, breath} is the amount of ²¹⁹Rn contained in the unit volume of exhaled breath, V_breath the volume of breath per single respiration (500 mL/respiration), N_respiration the respiration rate per min (12 respiration/min) and T the duration with the assumption that the blood concentration level immediately after the injection of ²²³Ra is maintained (0.99 h). Using 90 ± 56 Bq/mL as A_Rn,breath, which is the amount of ²¹⁹Rn contained in the breath at 1 min after the start of administration, A_{Rn,cumulative} was calculated as 32 MBq. By referring to the release criteria for patients treated with ¹³¹I, the amount of ²¹⁹Rn inhaled by caregivers (A_Rn,inhaled) was estimated using the following formula:

$$ {A}_{\mathrm{Rn},\mathrm{inhaled}}={A}_{\mathrm{Rn},\mathrm{cumulative}}\times \frac{V_{\mathrm{daily}}}{V_{\mathrm{room}}\times {N}_{\mathrm{air}\ \mathrm{change}}}, $$

where V_daily is the daily respiration rate of the caregivers (20 m³/d), V_room the volume of the room containing the patient (30 m³) and N_{air change} the air changes per hour (1/h); A_Rn,inhaled was calculated as 0.89 MBq. The effective dose of ²¹⁹Rn to caregivers (D_eff) was estimated as follows:

$$ {D}_{\mathrm{eff}}={A}_{\mathrm{Rn},\mathrm{inhaled}}\times E\times F, $$

where E is the effective dose coefficient for the inhalation of ²¹⁹Rn (7.9 × 10⁻⁹ mSv/Bq) and F the exposure factor (0.5 [7]); D_eff was estimated to be 3.5 μSv per injection.

Discussion

This study showed that the amount of ²¹⁹Rn contained in the breath of patients can be quantitatively measured using an HPGe detector based on the detection of the γ peak of the descendant nuclide ²¹¹Bi and a breath collection bag. In addition, the internal radiation exposure of caregivers from ²¹⁹Rn was estimated to be as small as 3.5 μSv per injection. The high count rate of α-particles observed in the direct measurement of the breath of the patient by the α survey meter would be attributed to ²¹⁹Rn, not to the descendant nuclides of ²¹⁹Rn, exhaled through the respiration because the average radioactivity of ²¹¹Bi measured using the HPGe detector was in the order of 10 Bq and the count rate of α-particles from ²¹¹Bi in the measurement with α survey meter would be quite low compared with that from ²¹⁹Rn (in the order of 10 kBq). Although the high count rate of α-particles from ²¹⁹Rn exhaled through the respiration was observed using the α survey meter, the quantitative measurement of the descendant nuclide of ²¹⁹Rn using the HPGe detector in this study clearly shows that the effective dose of ²¹⁹Rn to caregivers is small. The amount of ²¹⁹Rn contained in the breath of a patient at 1 min after the start of administration varied widely, as is shown in Table 1. The reason for this variation can be attributed to the peak shift in the exhalation of ²¹⁹Rn from the breath of patients caused by the manual administration of ²²³RaCl₂.

Since the effective dose coefficient for inhaled ²¹⁹Rn has not been reported, the value for ²¹⁹Rn was estimated based on the effective dose coefficient of ²²²Rn (6.5 × 10⁻⁶ mSv/Bq) [6]. α-Particles emitted from the descendant nuclides are thought to be the main contributors to the effective dose coefficient because their radiation weighting factor is very high compared with those of electrons and γ rays. Since the descendant nuclides of ²¹⁹Rn would decay before clearance because of their short half-lives, analogous to those of ²²²Rn [8], and the total α-particle energy from the descendant nuclides of ²¹⁹Rn would be roughly the same as that of ²²²Rn, the effective dose coefficient of ²¹⁹Rn can be estimated by correcting the effective dose coefficient of ²²²Rn with its effective half-life. Using the biological half-life of 55 min for Rn [9] (effective half-lives of 3.95 s for ²¹⁹Rn and 54.5 min for ²²²Rn), the effective dose coefficient of ²¹⁹Rn was estimated to be 7.9 × 10⁻⁹ mSv/Bq (= 6.5 × 10⁻⁶ mSv/Bq × 3.95 s/54.5 min).

For the mask measurements, the observed α-particles were considered to have originated from ²¹¹Bi, which was in transient radioactive equilibrium with a ²¹¹Pb parent (half-life 36.1 min) because the half-life of ²¹⁹Rn is very short. The N95 mask was capable of catching the descendant nuclides of ²¹⁹Rn, that had attached to dust or aerosol particles, on the surface of the mask, but it was not thought to be capable of blocking the inhalation of ²¹⁹Rn. If ²¹⁹Rn had passed through the N95 mask, α-particles from the descendant nuclides of ²¹⁹Rn that had decayed during and after passing through the mask would have been detectable on the inside of the mask. However, α-particles were not detected on the inside of the masks in the present study. Therefore, ²¹⁹Rn is considered to have not reached the mouths of the medical staff. The reason for the variation in the count rate observed for measurements made for the outside of the masks, as shown in Table 2, is probably due to the change in the amounts of ²¹⁹Rn and its descendant nuclides reaching the medical staff via the airflow in the injection room. The radioactivity of ²¹¹Bi caught by the mask, as calculated based on the measured count rate of α-particles, is expected to correspond to less than 10 Bq at the measurement start time using the instrument efficiency of 35.1%/2π written in the calibration certificate of the survey meter and an α branch of 99.724% for ²¹¹Bi. Although the radioactivity of the descendant nuclides of ²¹⁹Rn caught by the mask was relatively small, wearing the N95 mask appeared to protect the internal exposure of the medical staff.

The effective dose from the inhalation of ²¹⁹Rn experienced by caregivers was estimated to be 3.5 μSv per patient injection. This value is significantly lower than the dose of 5 mSv per episode for caregivers recommended by the International Commission on Radiological Protection (ICRP) [10, 11]; therefore, the internal radiation exposure from ²¹⁹Rn should not affect the release criteria for patients who have been treated with ²²³RaCl₂ in Japan.

Conclusions

The amount of ²¹⁹Rn contained in the breath of patients treated with ²²³Ra was determined using γ-ray spectrometry with an HPGe detector and breath collection bags. Although a small peak for γ rays of ²¹¹Bi originating from ²¹⁹Rn contained in the breath was observed, the estimated internal radiation exposure to caregivers via the inhalation of ²¹⁹Rn was small and should not affect the release criteria of patients who have been treated with ²²³RaCl₂.