Estimation of Clearance Rate of Iodine-131 From Thyroid Cancer Patients Based on Individual Patient’s Characteristic.

Differentiated thyroid carcinomas (DTC) are the most frequent malignancies of the endocrine system in 2015 in Japan. The purpose of this study is to estimate clearance rate of Iodine-131 from thyroid cancer patients based on individual patient’s characteristics. Materials and methods: We conducted retrospective study including 87 cases with DTC who had received RAI from June 2016 till July 2018. Patients who had complete information on primary tumor size (PTS) as mentioned in their histopathology reports, TNM staging, serum TSH (uIU/ml), free-T3 (pg/mL), free-T4 (ng/dL), thyroglobulin level (Tg) (ng/ml) (one month before, on the day of the treatment, and one month after receiving RAI), anti-Tg antibodies (IU/mL), dose of Levothyroxine (before and after RAI), as well as renal function (creatinine, BUN, eGFR), exposure rate (µSv/h) and taken dose (mCi) were included in our study. Results: Univariate analysis showed signicant associations of effective half-life with several factors (gender, body height, body weight, eGFR, size of tumor, dose of Levothyroxine, free-T3 one month after receiving RAI). Conclusion: Effective management of these factors could help the doctors to optimize the occupancy of isolated rooms with higher output, but also reduce the operational cost of the hospital and improving the comfort to patients.


Introduction
Thyroid cancer causes 41,000 cancer deaths worldwide in 2018 1 , and it the most frequent malignancies of the endocrine system in Japan. In 2015, 17,900 new cases of differentiated thyroid carcinomas were diagnosed, and 1,800 patients died from this disease in Japan 2 . The standard of treatment of patients with differentiated thyroid cancer (DTC) is total thyroidectomy followed by radioiodine therapy to destroy any remaining thyroid tissue (i.e. ablation) and/or destroy metastasis 34 .
The recommended doses of radioiodine-131 (RAI) for ablation for low and high risk patients are 1110-3700 MBq (30-100 mCi) and 3700-7400 MBq (100-200 mCi) respectively 56 . Iodine-131 is isotope with physical half-life of 8.05 days and emits beta particles (maximum energy 606 keV) and high energy gamma rays (364 KeV). According publication of ICRP 7 , when Iodine-131 enters the human body, approximately 30% is taken up by thyroid and another 70% is assumed to be excreted in the urine. Iodine-131 is excreted from the thyroid in the form of organic iodine. This organic iodine distributes among all organs and tissue of the body, other than thyroid. 90% of the organic iodine excreted from the thyroid is returned to transfer compartment and the rest is excreted via the feces. Another iodine is excreted by various body liquids, such as saliva, sweat, milk and blood and in exhaled breath can also been measured. Patients who are treated with high doses of RAI are the source of signi cant radiation exposure to medical staff, general public and patients' family members. Radiation exposure from treated patients mainly caused by gamma rays emitted from patients and also by beta particles in case of surface contamination or accidental ingestion.
Precautions are necessary to restrict the radiation exposure to public, to the patients' family and to the staff treating these patients. To address this issue, patients receiving RAI treatment are hospitalized and stay in isolation rooms until exposure rate decrease to safe limit. Number of guidelines and regulations have been established when patients shall be discharged from hospital. Usually DTC patients receiving RAI treatment in Japan are staying in isolated room until exposure rate is less than 30 µSv/h at 1-meter distance from patient. The isolation period of patients varies from 3-7 days and depends upon retained activity in patient's body. Quantity of this retained activity of RAI depends on the amount of remnant functioning thyroid tissue (thyroid bed and distant metastases) and Iodine-131 clearance rate from the body.
The purpose of this study is to estimate clearance rate of Iodine-131 from thyroid cancer patients based on individual patient's characteristics.

Ethics
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The protocol was approved by the ethics committee of Nagasaki university hospital (Protocol Number: 19102110). The ethics committee of Nagasaki university hospital waived the need of informed consent from participants because this research was a retrospective and non-invasive, and the identifying information was not included in the collected data.

Patients
We conducted a retrospective study of the cases of 74 patients with DTC who had received RAI treatment in the period between June 2016 and July 2018 at Nagasaki University Hospital. There were 23 males and 51 females, and their mean age was 58.6 years (range, 14-83 years). We included only those patients who had complete information of primary tumor size (PTS) as mentioned in their histopathology reports, TNM staging, serum TSH (uIU/ml), free-T3 (pg/mL), free-T4 (ng/dL), thyroglobulin level (Tg) (ng/ml) (one month before, on the day of the treatment, and one month after receiving RAI), anti-Tg antibodies (IU/mL), dose of Levothyroxine (before and after RAI), as well as renal function (creatinine, BUN, eGFR), exposure rate (µSv/h) and taken dose (mCi). In Japan, the equation to calculate eGFR 8  According to the American Thyroid Association (ATA) 3 , we strati ed DTC patients in three groups (low risk, intermediate risk, high risk). The group of patients planned for rTSH preparation underwent radioactive iodine ablation soon after surgery and received 0.9mg thyrotropin intramuscularly on two days before I-131 administration. The other group of patients were instructed to be on low iodine diet 2 week before RAI treatment and do not take any iodine containing drug (Levothyroxine withdrawal method) 9 . On the day of RAI administration, patients were instructed to fast 2 hours for food but take at least 1 liter of water to ensure good hydration. Administration is performed on Monday before noon or Wednesday just after noon. Dose of 3700MBq or 5550MBq (100 or 150 mCi) of I-131 capsule is orally taken. Dose is determined by clinical decision (body size, age, volume of metastasis etc). In our hospital xed dose is used. All patients were hospitalized in an isolated room following RAI administration. In isolation room, patients were consulted by nuclear physician about the purpose of RAI, importance of good hydration and bowel clearance as well as necessary steps after getting RAI to minimize radiation exposure to others. Foods are delivered and patients drink bottled water to avoid unintentional iodine intake and to avoid unnecessary environment contamination. Dose rate was measured (immediately, 12h, 24h, 36h, 48h, 60h) at 1 meter distance from anterior mid trunk using NaI scintillation survey meter (Aloka TGS-172 Survey meter). As per Nagasaki University Hospital requirement, patients were released when their dose rate was <30 µSv/h at 1 meter distance. All dose rate measurements were performed after patients emptied their urinary bladder.
Using these dose rates, the effective half-life (E 1/2 ) of I-131 was calculated. The actual effective half-life is determined by two factors, long physical half-life of I-131 and short biological half-life which determined by the biological washout. Considering the small sample time point number to calculate halflife and much longer and xed physical half-life than biological half-life, we determined to use simple mono-exponential tting instead of complex bi-exponential tting for the effective half-life calculation. The measured dose rates cannot be expressed in µSv/h because each patient has different exposure rate, but expressing as ratio is easier for mathematical calculation. Ratio 1 is equal to 1, because it is initial ( rst) dose rate at the time of I-131 administration, ratio 2 is relation of exposure rate of 2 nd measurement to initial exposure rate, etc.

Statistical analysis
All statistical analyses were performed using the JMP Pro14 software. Univariate correlation analysis was used to compare factors which made in uence on clearance of Iodine-131. All factors are expressed as median (1 st quartile, 3 rd quartile) values. P-values less than 0.05 were considered signi cant.

Patients' characteristics
The patients' characteristics are listed in Table 1. There were 74 patients (23 males and 51 females), and their mean age was 58.6 (range 14-83) years.
The distribution of TNM staging and risk of structural disease recurrence is presented in Table 2. The serum levels of hormones at the different points of time are presented in Table 3. The exposure rates of patients are listed in Table 4. Among the serum levels of hormones only free-T3 taken 4 weeks after receiving radioactive iodine have showed signi cant association with effective half-life (see Table 6). As the T3 is the hormone of human metabolism, we tried to nd association of free-T3 with body weight and height, however no signi cant association was found.

Discussion
In the present study we found difference of some physiological parameters according to effective half-life of Iodine-131. We also found that serum level free-T3 4 weeks after receiving RAI therapy was correlated with clearance rate of Iodine-131 from human body. Interestingly, serum levels of thyroid hormones did not show any correlation with physiological parameters, such as body weight and body height.
Radioactive Iodine-131 has been routinely used for ablation remnant thyroid and/or therapy of metastasis after total thyroidectomy in thyroid cancer patients for many years. Major concern for medical staff, general public and patients is radiation exposure caused by high energy gamma rays and risk of contamination by beta particles of RAI 10,11 . In Japan, patients receiving RAI must be admitted in isolation and release once dose rate at 1 meter distance is less than 30 µSv/h.
In this study we have evaluated usefulness of different factors for clearance rate of iodine-131 from human body and early discharge from isolation room.
Previous study 1213 has shown a longer effective half-life in male than female patients who received RAI for thyroid cancer due to an aggressive course of disease in males. Our study supports that previous ndings.
In this study we found that patients with larger body weight and body height have longer effective halflife than patients with smaller body weight and height. It can be explained simply, that bigger body needs more time to excrete iodine-131 from the body.
For preparation for RAI therapy, levothyroxine need to be withdrawn, which induce state of hypothyroidism in patients and lead to a reduction in glomerular ltration rate and retention of iodine-131 18 . Consumption of large amounts of liquids is encouraged mainly after one day post-therapy administration to enable the excretion of free iodine-131 from blood circulation, on considering that after this period of time all free iodine-131 will produce only body irradiation without any impact on patient therapy 16 . In our study we found that eGFR is related with effective half-life. It can be explained that better kidney function related with faster clearance.
We identi ed the fact that serum level of free-T3 4 weeks after RAI is related with clearance rate. To nd an explanation of our ndings, we performed comparison between serum level of hormones and body weight/height. No statistically signi cant correlation was found. We do not have perceptible explanation for this nding in our study. Probably, number of patients was too small.
No signi cant association between serum level of TSH, Tg and free-T4 has also been reported by other studies 12 . Our ndings also support their results.
We recognize that there are several limitations in our study. First -Acquisition and patient follow-up were retrospective. We did not analyze prospectively in uence of each factor on clearance rate. Second -we did not measure urinary iodine concentration for precise calculation of effective half-life of RAI. Third -The sample size of patients with differentiated thyroid carcinoma who underwent for radioactive iodine therapy was small, which may limit our conclusions. Fourth -we did not consider behavioral factors, like the number of baths the patients are taking, that may have an impact on the obtained dose rates.

Conclusion
Findings of our study would be important for treating nuclear physicians to utilize their treatment facilities in an e cient way to accommodate more patients to receive RAI treatment. Occupancy of limited facilities for 3 or more days contributes to increase waiting time and signi cant delays in administration of RAI treatment and this has a signi cant negative impact on survival of these patients 19 . Furthermore, prolong internment also enhances the treatment cost and has its own psychological and logistic impacts on patients and families. We consider that effective management of these factors could help the doctors to optimize the occupancy of isolated rooms with higher output, but also reduce the operational cost of the hospital and improving the comfort to patients.