Comparison between planar and single-photon emission computed tomography images for radiation intensity quantication in iodine-131 scintigraphy

This study aimed to evaluate the feasibility of quantifying iodine-131 ( 131 I) accumulation in scintigraphy images and compare planar and single-photon emission computed tomography (SPECT) images to estimate 131 I radioactivity in patients receiving radioactive iodine therapy for thyroid cancer. We evaluated 72 sets of planar and SPECT images acquired between February 2017 and December 2018. Simultaneously, we placed a reference 131 I capsule next to the patient during image acquisition. We evaluated the correlation between the intensity of the capsule in the images and the capsule dose and estimated the radiation dose at the thyroid bed. The mean capsule dose was 2.14 MBq (range, 0.63–4.31 MBq). The correlation coecients (p-value) between capsule dose and maximum and mean intensities in both planar and SPECT images were 0.93 (p < 0.01), 0.96 (p < 0.01), 0.60 (p < 0.01), and 0.47 (p < 0.01), respectively. The mean intensities of planar images show the highest correlation coecients. Based on a regression equation, the average radiation dose in the thyroid bed was 5.9 MBq. In conclusion, planar images reected the radiation dose more accurately than SPECT images. The regression equation allows to determine the dose in other regions, such as the thyroid bed or sites of distant metastasis.


Introduction
The most common cancer in the endocrine system is thyroid cancer 1 , and its most frequent type differentiated thyroid cancer (DTC), such as papillary and follicular carcinomas, being found in over 90% of cases.
After total thyroidectomy, radioactive iodine (RAI) therapy with iodine-131( 131 I) is a widely accepted treatment for DTC 2 . According to the guidelines, the aims of RAI therapy are divided into three categories 3 : ablation of the remnant thyroid tissue to simplify follow-up, adjuvant therapy for microscopic lesions to decrease the risk of recurrence or distant metastasis, and treatment for tangible residual or metastatic diseases.
Generally, the dose of 131 I drug is hardly de ned based on the tumor or normal tissue; instead, the radioactivity of RAI drugs is empirically xed. For example, 1,110 MBq su ce for remnant ablation, while adjuvant therapy requires 3,700 to 7,400 MBq, according to guidelines 3 . Some reports administered 131 I drug based on bone marrow or blood level dosimetry, but it is not a popular procedure 4 . Although there are some general models to simulate the kinetics of radioisotopes in humans, such as the medical internal radiation dose method 5 , there is no established method to evaluate the strength of tumor or normal tissue radiation in RAI therapy with 131 I in single patients.
Planar imaging or single-photon emission computed tomography (SPECT) has been used for qualitative evaluation of radioisotope distributions, with some reports focusing on the quantitative analysis of several low-energy radioisotopes, such as 99m Tc, 123 I, etc. [6][7][8] . These quantitative values are used to evaluate treatment response or predictive factors in the oncology eld. In the eld of RAI therapy, 131 I distribution can be evaluated with scintigraphy acquired with a gamma camera a few days after 131 I drug administration. However, in general, it is di cult to quantitatively evaluate 131 I uptake, because of the elevated energy of its gamma rays, collimator penetration, and artifacts, which cannot be disregarded in quantitative analysis. As a result, thus far, there is no quantitative analysis or direct comparison between planar and SPECT images of 131 I scintigraphy.
We hypothesized that we could quantitatively estimate 131 I uptake based on the known radiation dose source, which is placed to be taken by the same camera at the same time. In this study, we developed methods for the quantitative evaluation of 131 I uptake in planar and SPECT images using scintigraphy. In addition, based on quantitative analysis, we estimated the radiation dose at the thyroid bed in patients with thyroid cancer who underwent RAI therapy.

Comparison between the planar and SPECT images
We successfully obtained 131 I intensity data in all images using the treatment planning support system.  Table 1). The mean intensities of planar images show the highest correlation coe cients. In post hoc power analysis, the statistical power was 0.98, when two-sided, the effective size was 0.5, and the alpha error 0.01. Based on the mean intensities in planar images, the regression equation can be expressed as y(dose) = 0.0845 x (mean intensity in the planar image). Table 1 The relationship between the intensity and the actual radiation dose.

Discussion
In the present study, we were able to calculate radiation doses from scintigraphy images. By comparing planar and SPECT images, we determined the proper image to estimate the radiation dose based on scintigraphy, nding that planar images are appropriate for radiation dose estimation.
Recently, the importance of dosimetry has increased in nuclear medicine, especially in radioisotope therapy, because the absorbed dose of the tumor directly correlates with effectiveness. Although several studies have reported on quantitative dose estimations for radioiodines, such as 99m Tc and 123 I in scintigraphy, to the best of our knowledge, this is the rst report to suggest the possibility of dose estimation in 131 I scintigraphy.
There are some commercial tools for the quantitative analysis of bone scintigraphy. For example, the bone scan index in BONENAVI (Fuji lm RI Pharma Co. Ltd., Tokyo, Japan) with planar images and standardized update values in GI-BONE (AZE, Tokyo, Japan) with SPECT images are famous [9][10][11] . These quantitative indicators are used for the prediction or evaluation of therapeutic effects or predictive factors for survival in the oncology eld 12,13 . With progress in this study and the accumulation of more data points, we could predict the therapeutic effect or survival rate in the treatment of DTC.
There have been several attempts to quantitatively evaluate 131 I. However, the purpose of these reports was different from that of this study, and none aimed to directly compare planar and SPECT images in 131 I scintigraphy.
Planar images re ected the radiation dose more accurately than SPECT images in this study, and according to the post hoc analysis, this result was reproducible and robust. We expected that SPECT images would show a better correlation between the actual dose and intensity because SPECT images are acquired using CT images with absorption compensation. In addition, the spatial resolution of SPECT images is better than that of planar images, calculating the absorbed dose with CT images, such as external beam radiotherapy, more convenient. However, the results were not consistent with our expectations. There were some SPECT images including a strong halo around the 131 I capsule, and the intensity count was overestimated with the strong halo.
This study had some limitations. First, this was a single-center investigation with a small number of patients. However, we were able to standardize the imaging acquisition protocol in the planar and SPECT images. Second, we could not verify the results of this study. The radiation dose could be estimated based on the images, but the dose accuracy was not validated. Further research on other systems, such as the image viewers used in nuclear medicine diagnosis, is needed to validate our results. Finally, we only evaluated one imaging time point. We could not evaluate 131 I redistribution or distribution changes during RAI therapy. Multiple images must be acquired to evaluate the dynamics of the 131 I distribution.
We are planning on conducting another study to examine these distribution patterns both in time and space.
In conclusion, using a regression equation, we can determine the 131 I dose in other regions, such as the thyroid bed or sites of distant metastasis. This value can be useful for the prediction of treatment results or the calculation of the actual 131 I absorbed dose.

Image acquisition and analysis
We evaluated 72 sets of planar and SPECT images acquired between February 2017 and December 2018 in patients who underwent high-dose RAI therapy in our hospital. The inclusion criteria were as follows: (1) total thyroidectomy and pathologically proven DTC, (2) high-dose RAI therapy as adjuvant therapy or cancer treatment for metastases in an inpatient setting, and (3) available images for imaging analysis. The exclusion criterion was the refusal by patients to provide their images for this study. Thirty-two patients received RAI therapy as adjuvant therapy (prescribed dose was 3,700 MBq = 100 mCi), and 40 did for cancer treatment (prescribed dose was 4,810-5,550 = 130-150 mCi). The preparation of the RAI therapy was performed with thyroid hormone withdrawal (n = 39) or recombinant human thyroidstimulating hormone (n = 43). Forty-seven patients received RAI therapy for the rst time. Image acquisition was performed 3 days after 131 I administration using a gamma camera with high-energy collimators (In nia Hawkeye4, GE Healthcare, Milwaukee, USA). Planar images were acquired in the patient's whole body at 15 cm/min, and the exposure time per pixel was 160 s. The matrix size was 256 × 1024 pixels. SPECT images were acquired in a 64 × 64 matrix with step and shoot mode, and 60 projections for 10 s each. Computed tomography (CT) images were acquired with tube potentials of 140 kV and a tube current of 2.5 mA. The slice thickness was 5 mm, and the CT rotated at 2.6 rotations per minute.
We placed 131 I capsules near the patient's arm to calculate the radiation dose on the test date, and planar and SPECT/CT images were acquired together with the reference. These images were transferred to a commercial treatment planning system for radiotherapy (MIM Maestro version 6.4, MIM Software, Cleveland, USA) and checked. We set the 5 cm diameter of the region of interest (ROI) on the 131 I capsules where radiation was calculated on the day of examination and measured the intensity of the accumulation (Fig. 1). We measured the maximum and mean intensity in the ROI on planar and SPECT images and evaluated the relationship between ROIs intensities and the actual radiation dose. We tried to predict the function to estimate the radiation dose; we also estimated the radiation dose at the thyroid bed in patients who underwent RAI therapy for the rst time in the same way as the reference capsule.
Statistical analysis and ethical approval All statistical analyses were performed using R software (version 3.3.1) 16 . We calculated Pearson's correlation coe cient between the image intensity and the actual radiation dose and p-value. We de ned a p-value < 0.05 as statistically signi cant. We used a simple linear regression model to predict the function underlying the radiation dose. We also calculated the statistical power after the evaluation. This study was performed in accordance with the 1964 Declaration of Helsinki and all subsequent revisions and followed the recommendations of the Ethical Guidelines for Medical and Health Research Involving Human Subjects. This study was approved by the Institutional Review Board (Kyoto University of Graduate School and Faculty of Medicine and Kyoto University Hospital Ethics Committee) and was performed using the opt-out method posted on our hospital website. Written informed consent was obtained from all participants of using their images for this study.

Data availability
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.