Radiation Safety Issues in Y-90 Microsphere Selective Hepatic Radioembolization Therapy: Possible Radiation Exposure from the Patients (2024)

Abstract

Keywords: Radiation safety, Y-90 microsphere, Selective hepatic radio-embolization therapy, Liver tumor, Hepatocellular carcinoma

Introduction

Transarterial chemoembolization (TACE) is the major treatment option for the unresectable primary or secondary liver malignancies. Although the majority of the technique is based on bland embolization and chemoembolization techniques, yttrium-90 (Y-90) microsphere radioembolization therapy (RET) represents an alternate transarterial embolization option. There are ample data that support the use of Y-90 microspheres for primary and metastatic liver tumors [1–4]. Meanwhile, the patient who has been administered radioisotopes acts as a radiation source to others: caring healthcare personnel, family members and also to non-related individuals in streets, commuters and public places. The radiation safety and protection is one of the major issues in the treatment of disease by administration of radioisotopes such as I-131 or Y-90 [5, 6].

Yittrium-90 is a pure beta-emitter, with a decay energy of 0.94MeV and the average penetration depth in human tissue is 2.4mm. In the form of microspheres, it is suitable for selective arterial injection. The physical half-life of Y-90 is 64.2 h. The radiation exposure from a ‘radioactive’ patient who has been implanted with pure beta-emitters is very limited, unless the patient has an open wound that could make a possible leak from the body [7].

The external radiation exposure by a pure beta-emitter such as Y-90 is mainly from bremsstrahlung radiation. The radiation safety issues in using Y-90 radioisotope have already been well evaluated with Y-90-labeled Zevalin (ibritumomab tiuxetan) treatment and it is well recognized that Y-90 Zevalin therapy can be safely done on an outpatient basis using only universal precautions [8]. The typically administered dose of Y-90 Zevalin is 777–1,110MBq (21–30mCi), with a maximum of 1,184MBq [8, 9]. A study showed that the family members who had close contact with patients who had been treated with Y-90 Zevalin had a minimal radiation exposure of 3.5 mrem (0.035mSv) [10]. On the other hand, the maximum administering dose of Y-90 microspheres is up to 3GBq, much higher dose than Zevalin. The biodistribution of microspheres after liver RET is mainly localized and confined to embolized liver; somewhat different from Zevalin therapy, in which the administration is via systemic circulation.

Therefore, careful consideration needs to be given in determining when the patient can be released from medical confinement, and patient release must follow the national and regional regulations. The Atomic Energy Act of the Republic of Korea limits the maximum permissible dose to nonoccupational exposure to 5mSv. The Public Notification (Go-Si) No. 2008-45 of Ministry of Education, Science and Technology stipulated that medical use of radioisotopes must comply with this regulation [11, 12]. According to this regulation, the licensee may release patients if it can be demonstrated that the total effective dose equivalent (TEDE) to another individual from exposure to a released patient is not likely to exceed 5mSv (500 mrem). In addition, licensees must provide a released patient with written instructions on recommended actions to maintain the dose to other individuals as low as reasonably achievable if the dose to any other individual is likely to exceed 1mSv (100 mrem).

The purpose of this study was to focus on radiation safety considerations after the treatment of patients with Y-90 microspheres. We serially measured the radiation exposure emitting from the patients after the Y-90 microsphere implantation. We carefully evaluated the possible radiation exposure dose by bremsstrahlung radiation to other individuals on the basis of measured exposure rates and administered activity, respectively. We calculated the total effective dose equivalent (TEDE) based on the ‘measured’ radiation exposure rate at the time of patient release as well as estimated ‘theoretical’ TEDE according to the administered activity for each consecutive patient. We compared the results by each method to evaluate which method can estimate the real TEDE more reasonably and to determine when we can release patients from confinement at the earliest time complying with the patient release criteria.

Materials and Methods

Results

Total 20 administrations of Y-90 SIR microspheres were done in 18 patients (Table1). The average administered activity was 1.2 ± 0.77 (0.28–2.97) GBq (Table2). The measurements of ambient exposure rates during the period of 0-3h, 4-12h, 13-24h, and 25-72h are listed in the Table2. The average exposure rates from patients were as follows: measurements at 10cm from patient’s abdomen during these time periods were 14.1 ± 16.1, 8.23 ± 8.52, 4.03 ± 3.67, and 5.7 ± 7.2 mR/h, respectively; measurements at 10cm from the puncture site during these time periods were 3.38 ± 3.32, 1.71 ± 1.4, 1.4 ± 1.0, and 1.42 ± 1.2 mR/h, respectively; measurements at 1m from the patient during these time periods were 0.33 ± 0.39, 0.1 ± 0.07, 0.12 ± 0.1, 0.34 ± 0.4 mR/h, respectively (Table2 and Fig.1).

The estimated ‘theoretical’ TEDE according to the administered activity was calculated using Eq.2 and the values are listed in the Table3. The values of theoretical TEDE at 1m from the patient are in the range of 0.8–10 μSv. These values are are only 0.08–1% of the maximum permissible effective dose equivalent of 1mSv, the limit below which the licensee can release a patient without any written documents. This finding suggests that if an individual were continuously in contact with a patient for 25% of the time from administration of the isotope until its total decay, that individual would receive a TEDE far less than 1mSv.

It is more realistic to calculate TEDE based on the actual measurement of ambient exposure rate than to theoretically estimate TEDE based on administered activity in the daily practical situation. In usual daily medical practice, it is easier to measure exposure rate in certain time intervals. The measured TEDE calculated using Eq.3 is in the range of 2.31–185 μSv (Table3), which is only 0.23–18.5% of the maximum permissible effective dose equivalent of 1mSv. The measured TEDEs tend to be higher than the theoretical TEDEs and the ratio of measured to theoretical TEDE is from 1.28 to 65.99 (Table3). It seems that this wide variety of difference of ratio is partly due to variation of tumor location and measurement geometry. Again the measured TEDE is also far less than the maximum permissible TEDE of 1mSv (Fig.2).

Discussions

Patients who were administered radioisotopes for diagnostic or therapeutic purposes are radioactive for some period of time after administration and may expose other individuals and the environment to radiation. Calculation of radiation of the absorbed effective dose equivalent to other individuals is necessary for radiation safety concerns. Radioprotection precautions must consider the characteristics of administered radioisotopes [16, 27, 28]. Greater concerns should be exercised when dealing with therapeutic procedures.

In 1996, the USNRC issued a new regulation that allowed for the release of patients from medical confinement if the expected TEDE to individuals exposed to the patient is not likely to exceed 5mSv. The radiation safety licensee should also issue documents to the patients explaining possible restriction of activities to reduce possible radiation exposure to other individuals as low as reasonably achievable if the patient exposure to the other people is likely to exceed 1mSv [6, 17, 18, 29].

The USNCRP recommended that the maximum permissible effective dose equivalent for the ‘non-pregnant adult family member’ should be limited to 5mSv and for members of the general public, children and pregnant women to 1mSv [30]. A ‘family member’ is any person who spends a considerable amount of time with the patient on a regular basis, providing support, comfort and care. A ‘member of the general public’ is any individual who is not a patient undergoing treatment, not a family member of such a patient, and not an occupationally exposed individual participating in the care and management of such a patient [18, 30]. Zanzonico et al. [18] suggested that such standards for the family members of radionuclide therapy patients should not be as restrictive as those for members of the general public, since family members knowingly and willingly accept their radiation burden and radionuclide therapy is an infrequent event during the patient’s lifetime.

The Atomic Energy Act (Weon Ja Ryeok Beop) of the Republic of Korea also limits the maximum permissible absorbed dose by nonoccupational exposure to 5mSv. The Public Notification (Gosi) No. 2008-45 promulgated by the Ministry of Education, Science and Technology (MEST) stipulated that medical use of radioisotopes must comply with this regulation [11, 12]. According to the MEST Public Notification No. 2008-45, the licensee may release patients if it can be demonstrated that the TEDE to another individual from exposure to a released patient is not likely to exceed 5mSv (500 mrem). In addition, the licensee must provide a released patient with written instruction on the recommended modulation of actions to maintain the dose to other individuals as low as reasonably achievable if the dose to any other individual is likely to exceed 1mSv (100 mrem) [11, 12].

Selective intra-arterial radioembolization therapy (SIRET) involves administration of Y-90 microspheres into the hepatic arterial circulation via the transarterial catheter, following which the radioactive microspheres preferentially target a hypervascular tumor within the liver. This results in the tumor receiving a high dose of radiation [1–4]. Recently, Y-90 resin microspheres have been approved by the United States Food and Drug Administration (USFDA) and also by the Korean Food and Drug Administration (KFDA) as medical devices. Once injected, they are permanently implanted into an hepatic tumor [7, 15]. Y-90 is a pure beta-emitter with average decaying energy of 0.93MeV and the average penetration depth in human tissue is 2.5mm. The physical half-life of Y-90 is 64.2 h. Because only beta-rays emit from the embolized Y-90 microsphere within the body, the radiation exposure from the patient is very limited unless the patient has an open wound that can make microspheres leak from the body [7].

Possible radiation exposure to other individuals from internally administered gamma-ray emitting radioisotopes is well recognized and there are ample reports [17, 18, 27, 28]. For the gamma-emitting radioisotopes, the TEDE can be calculated using the specific gamma-ray exposure rate constants and physical half-lives for radionuclides typically used in nuclear medicine are given in the USNRC Regulatory Guide 8.39, Appendix A [17].

Because the external exposure by Y-90 is not by gamma radiation and external beta-dose would be negligible, the specific gamma-ray exposure rate constant is not applicable in this situation. The USNRC Regulatory Guide does not even list a specific gamma-ray (exposure rate) constant for Y-90; as stated, the activity is not from beta-emissions [17]. High energy beta-emitters such as Y-90, however, can produce sufficient in vivo bremsstrahlung. Several researchers postulated that external radiation exposure by Y-90 is generally ignored and patient restrictions are not required for radiation safety purpose. The USNRC regulatory guide did not apply the activity limits and dose-rate limits of patient release for pure beta-emitters such as Y-90 because, as it stated, of the minimal exposures to members of the public resulting from activities normally administered for diagnostic or therapeutic purposes [23].

However, these reports only considered the exposure in theoretical estimation [24, 25]. Yet the radiation dose from the bremsstrahlung radiation is not well recognized, the resulting radiation hazard may therefore be of some concern, at least theoretically, and should be systematically evaluated [25]. We believe that the contribution of such radiation should be carefully considered and clarified in regard to determining when the patient can be released from medical confinement, to meet the regulatory requirements.

We estimated theoretically the exposure dose rate by bremsstrahlung radiation using Eq.2. For the calculation of ‘theoretical’ TEDE, it is necessary to know the ‘specific bremsstrahlung constant.’ The term ‘specific bremsstrahlung constant’ is a conceptual and thus artificial quantity analogous to the specific gamma-ray constant for photons and the bremsstrahlung constant is several orders of magnitude less than the specific gamma-ray constant [24, 25]. The theoretical values of TEDE based on administered activity are listed in Table3. Using Eq.3, we could estimate the TEDE that an individual is likely to receive from exposure to the radioactive patient at a distance of 1m. The assumption of TEDE by using an occupancy factor, E, of 25% at 1 m is conservative in most normal situations because, when bremsstrahlung radiation emits from the body, it is largely attenuated by body tissue, so that the real measurement of exposure rate is quite low [17, 24, 26].

We observed in this study that the values of estimated theoretical TEDE at 1m from the patient are in the range of 0.9–10 μSv (Table3). These values are only 0.09–1.0% of the maximum permissible effective dose equivalent of 1mSv. This finding suggests that if an individual were continuously in contact with the patient for 25% of time from the day of isotope administration until total decay of the isotope, the individual would receive a TEDE far less than 1mSv.

Because the radioisotope is confined in the patient’s abdomen, there could be a significant attenuation of low energy bremsstrahlung radiation while traveling within the body. So, the actual radiation dose may be different from the theoretically calculated TEDE based on administered activity. The ‘measured’ exposure dose equivalent calculated by actual measurement of ambient exposure rate can be different from estimated ‘theoretical’ exposure dose [28]. According to our observation, the ‘measured’ TEDEs are generally higher than those of ‘theoretical’ TEDEs as the ratio of ‘measured’ TEDE to ‘theoretical’ TEDE (Dm/Dt ratio) is from 1.28 to 65.99 (Table3). This wide variety of ratio seems to be partly due to variability of tumor location and measurement geometry. These results are contrary to the observation by Siegel et al. [27] and Willegagnon et al. [28], who dealt with gamma radiation and observed that measured TEDE is lower than theoretical TEDE. To our knowledge, this is the first report that compares the theoretical TEDE with measured TEDE in Y-90 microsphere RET. The reason for the higher values for measured TEDE and wide variation of measurement is not clearly elucidated. We think that the reason for this contradiction and variation is partly because of the type of radiation, i.e., gamma-ray versus bremsstrahlung, and partly because of difference in the biodistribution. For the calculation of theoretical TEDE, it is assumed that biodistribution is even within the body, but for the measured TEDE, it directly represents the measurement of the ambient radiation exposure. Although the measured TEDE is higher than the theoretical TEDE, the measured TEDE is far less than the maximum permissible TEDE of 1mSv.

Gulec and Siegel [24] reported that in all proposed situations of exposure to patients administered 3GBq of Y-90 microspheres, the estimated bremsstrahlung doses were very small, in the range of 0.05–0.21mSv to the total decay. It has been reported that at approximately 6 h after the administration of 2.1GBq, the average activity of Y-90 microspheres, doses at 0.25, 0.5, and 1m from patient’s abdomen measured 18.8, 9.2, and 1.5mSv/h, respectively [15]. This indicated that no patient restrictions are required for radiation safety purpose. Zanzonico et al. [25], postulated that the maximum allowable administered activity of Y-90, in terms of release criteria, is 1,420GBq based on the assumption using Eq.2.

In the present study, all the individuals were administered a dose of less than 3GBq. The measured TEDE calculated using Eq.3 is in the range of 0.002–0.18mSv, i.e., 0.2–18% of the maximum permissible effective dose equivalent of 1mSv (Table3). Again, the measured TEDE is far less than the maximum permissible TEDE of 1mSv in present study population of Y-90 microsphere therapy of less than 3GBq. However, because the actual measured TEDE tends to be higher than the theoretical TEDE, as in this observation, it is a more conservative way to use values of measured TEDE in determining patient release.

In general, for patients treated with Y-90 microspheres of less than 3GBq of activity, record keeping or issuing of an instruction document is not needed according to the NRC and Korean national regulation.

Conclusions

We measured the ambient radiation exposure rate from the patient after administration of Y-90 microspheres and estimated the total effective dose equivalent by exposure to the patients. The total effective dose equivalent caused by the Y-90 microsphere administered patient is very low, even from the time of administration. It is very safe in terms of radiation safety to other individuals when Y-90 microsphere administration therapy is done with doses of less than 3GBq. Because the ‘measured’ TEDE tends to be higher than the ‘theoretical’ TEDE, it is recommended to use measured TEDE in determining patient release after Y-90 microsphere administration.

Acknowledgements

This work was supported by the Phase IV study of Yttrium-90 Microspheres (SIR-Spheres) Therapy for the Treatment of Unresectable Hepatocellular Carcinoma (HM-SS-2008) sponsored by Hoin Medibiz Co. We thank Hoin Medibiz Co. for supply of Y-90 resin microspheres.

References