Internal dose assessment of lymphoma 18F-FDG Positron Emission Tomography (PET) scan

This study aimed to assess the internal radiation exposure of patients who have undergone a Positron Emission Tomography (PET) scan using 18F-FDG radiopharmaceutical. A total of 24 patients (8 men, 16 women, with an average age of 43.88 ± 18.57 years and weight of 57.54 ± 13.04 kg) who had been diagnosed with lymphoma were administered with 300.80 ± 23.09 MBq of 18F-FDG for a PET scan of the whole body. The IDAC-Dose 2.1 program, developed by the International Commission on Radiological Protection (ICRP), was used to measure absorbed and effective doses. The organs selected for absorbed dose analysis were the breast, kidneys, adrenals, liver, and brain, with the brain receiving the highest absorbed dose and the breast receiving the lowest absorbed dose. The effective dose for all patients was 4.85 ± 0.37 mSv, and the ratio of the effective dose to the administered activity was 1.611 × 10−2 mSv/MBq. The safety of the current practice using 18F-FDG PET scan was ascertained, given that the ratio of effective dose to administered activity was lower than 1.9 x 10−2 mSv/MBq.


Introduction
The utilization of PET scan as a diagnostic procedure in Nuclear Medicine is essential in providing a distinct understanding of the molecular and metabolic changes associated with lymphoma patients [1,2].A small amount of radiotracer 18 F-FDG is administered intravenously to assess abnormalities within the body.In the body, 18 F-FDG is taken up and metabolized in areas of cancer cells and emits positrons, which then interact with nearby electrons, producing 511 keV gamma rays that can be detected by a PET detector.However, exposure to radiation within the body during a PET scan may have risks of biological harmful effects, depending on the amount of the radiotracer administered [3][4][5].These biological harmful effects of radiation can be divided into deterministic and stochastic effects.High doses of radiation can lead to deterministic effects, while doses of around 100 mSv or less can cause stochastic effects [6][7][8][9].The quantification of the amount of radiation exposure within the body is known as an internal dose assessment.It is essential for radiation protection to optimize the dose given in a clinical setting, and this must be evaluated periodically [10,11].
Studies have found that internal dose assessment in nuclear medicine is essential for determining the potential health risks associated with radiation exposure [12,13].This assessment is typically categorized into three distinct measurements, which are absorbed, equivalent, and effective dose.Absorbed dose measures the physical energy absorbed, while equivalent and effective dose takes into account the biological effectiveness of the radiation and the potential stochastic health effects, respectively [6,14,15].It is typically conducted after scanning to ensure that the patient has received an appropriate and safe radiation exposure.Utilization of the 18 F-FDG radiopharmaceutical in PET scan is primarily for oncology studies such as lymphoma [16][17][18].Investigating both radiation dose and the risk of radiation exposure, particularly the induction of stochastic effects, is an important area of research [5].
Previous studies have shown that it is difficult to precisely determine the absorbed dose in internal dose assessment because of the human body's complexity and the anatomy differences that can affect the dose calculation [19].This notion has been corroborated by Andersson et al. [5], who developed a model to estimate radiation dose that includes the biokinetic behavior of radionuclides and the anatomical structure of the human body.To guarantee that patients are exposed to the necessary radiation dose, it is imperative to conduct regular internal dose assessments [20].Nevertheless, there is limited research exploring the internal dose assessment in cancer patients with lymphoma, taking into account both the biokinetic behavior of radionuclides within the body and patient characteristics.This study aimed to evaluate the correlation between the administered activity of 18 F-FDG, effective dose, patient weight, and organ absorbed dose.IDAC-Dose 2.1, a well-known software program for internal dose assessment, was utilized to calculate the effective dose and organ-absorbed dose.The results of this study may provide justification of the radiation exposure from PET scan using 18 F-FDG in nuclear medicine procedures.This is to ensure the safety of lymphoma patients from the damaging effects of ionizing radiation, in line with the principle of radiation protection.

Study design
This study was a retrospective study conducted in a diagnostic center in the Klang Valley.The study used the PET-CT system (SIEMENS Biograph 64, Erlangen, Germany).Approval from the ethical committee (ID no:14-606-20966) was obtained, and no consent was necessary due to its retrospective nature.To ensure accurate and reliable imaging, the scanner adopted a lutetium oxyorthosilicate (LSO) scintillation detector with a high light output and stopping power.The detector provide 29 photons per keV and a linear attenuation coefficient of 511 keV, with a decay time of 40 ns.An energy resolution of 10.1% was achieved at 511 keV.The scanner was calibrated according to the Ministry of Health guidelines for clinical and research studies.

IDAC-Dose 2.1 program
To determine the absorbed organ dose and effective dose of lymphoma patients, this study incorporated the IDAC-Dose 2.1 program.The program contains a list of 83 source regions and 47 target organs to be utilized.The organs chosen for this study were the breast, kidneys, adrenals, liver, and brain.The biokinetic data of 18 F-FDG (fluoro-2-deoxy-D-glucose) radiopharmaceutical was expressed as cumulated activity per administered activity Ã/Ao, with the unit of measurement being hours (h).The cumulative activity in the organ was mathematically defined as Equation (1).
where   and   (∑   = 1), is a biological half-time to the fraction of the nuclide, Fs and with Ti,eff as the uptake half-time [5].The data was entered into IDAC-Dose 2.1 program according to the type of radiopharmaceutical.Since 18 F-FDG was administered, most biokinetic data were referred to in the ICRP Publication 106.Hence, the program used the amount of administered activity for selected patients to determine the effective dose. 18F-FDG radiopharmaceutical 18 F radionuclide was artificially created before it was radiolabelled with a sugar derivative.This sugar molecule contains a leaving group (trifluoromethanesulfonyl or triflate) and four protecting groups (tetra-acetyl).Nucleophilic substitution was used to radiolabel mannose triflate with F -by adding F - with Kryptofix 2.2.2 and potassium carbonate to the molecule in anhydrous acetonitrile.The protecting groups were then removed through hydrolysis by refluxing in hydrochloric acid at 130°C for 15 minutes.FDG was obtained by passing the hydrolysate through a C-18 Sep-Pak column, which is a solid phase extraction column made of C-18 silica-based material.The final solution was filtered and diluted with saline to purify and formulate the final FDG product.

Dosage administration
The administration of 18 F-FDG was contingent upon the patient's blood glucose level.If the level was lower than 7.0 mmol/L, a dose of 296 MBq was administered to those weighing 40 kg or more.For those with a lower weight, a lower dose was prescribed.However, a physician's consultation was required if the level was higher than 7.0 mmol/L.The precise amount of 18 F-FDG administered was calculated according to the residual in the syringe.After injection, the patient was instructed to remain recumbent and silent for 45-60 minutes in order to minimize uptake of 18 F-FDG in the muscles until the completion of the PET scan.Scanning and image reconstruction were acquired using a Siemens Biograph 64 PET-CT scanner.

Sampling of data
This study documented data on 24 lymphoma patients who were administered with 18 F-FDG during PET scans.The data included the administered activity, demographic characteristics (age, weight, FBG, height, BMI, race, and gender), date of scanning, type of examination, and scan duration.The data was entered and structured in Microsoft Excel, and then IDAC-Dose 2.1 was employed to calculate the effective dose and organ absorbed dose for each patient.

Statistical analysis
The internal dose data was further analysed using Pearson's correlation coefficient, Spearman's rank correlation and Analysis of Variance (ANOVA).A significance level of 0.05 was adopted and any pvalue lower than this was considered significant.Box plots and scatter plots were used to illustrate the distribution and relationship of the study.The results of the statistical analysis were presented in tables and figures.

Patient classification
This study retrospectively analyzed 24 patients, with a mean age of 43.88 ± 18.57 years, weight of 57.54 ± 13.04 kg, FBG levels of 4.26 ± 1.1 mmol/L, BMI of 23.06 ± 4.25 kg/m 2 , and an administered activity of 300.8 ± 23.09 MBq.The age of the patients ranged from 14 to 71 years, their weight from 35.9 to 86.1 kg, FBG levels from 2. 3  The effective dose of the 24 lymphoma patients who underwent PET scan was determined to be 4.85 ± 0.37 mSv, with the mean 18 F-FDG administered activity being 300.80 ± 23.09 MBq.Patient P01 received the highest dose of 6.58 mSv, while the lowest dose was observed in P13 at 3.85 mSv.The average mSv/MBq was 1.611 × 10 -2 , which fell within the limit set by ICRP Publication 106 (1.9 × 10 -2 mSv/MBq).The results showed that the administered activity and patient characteristics such as age, weight, FBG, and BMI had a significant influence on the calculated effective dose.The administered activity had the highest correlation with the effective dose.
A linear relationship between the administered activity and the effective dose was clearly visible, as shown in Figure 1.A Pearson correlation coefficient (PCC) was computed to assess the linear relationship between the two variables, resulting in a correlation of r 2 = 0.9999.This suggests that the administered activity is an important factor in determining the effective dose and other unknown variables.Furthermore, the high coefficient of determination (r 2 =0.9999) indicated a very low variability in the graph and a very high goodness of fit of the data.For the purpose of internal dose assessment, the model was simplified, and other independent variables were assumed to be constant.According to ICRP-103, there is no distinction in effective dose between male and female, which is contrary to ICRP-106.Moreover, the biokinetic distribution of the patients was not evaluated and was simply referred to the reference person, which is commonly applied for diagnostic purposes only.Therefore, it can be concluded that administered activity is the main independent variable affecting the effective dose in this study.

Correlation of the weight of patients to the effective dose
Figure 2 illustrates the effective dose distribution depending on the patients' weight.Two data points, 6.14 mSv and 3.85 mSv, were identified as outliers and were found to be associated with subject P01 and subject P13 respectively.Upon further investigation, it was determined that the high effective dose for patient P01 was justified because the data was collected during the previous protocol with a higher administered activity.On the other hand, Patient P13 had a low effective dose due to their low BMI of 16.06.According to standard practice, the dose administered to an underweight patient should not exceed 296 MBq.However, it was discovered that another patient (P09) in the underweight category received 300.81MBq of administered activity which exceeded the expected value.This was likely an error in the administered activity for patient P09.To gain a deeper understanding of the correlation between patient weight and effective dose, patients' weight was divided into categorical data as illustrated in Figure 3.An ANOVA test was performed to assess whether any statistical differences existed between these groups.To ensure the accuracy of the significance test, outliers were removed from the analysis, resulting in 22 patients being evaluated.The analysis results indicated that patients over 40 kg had an effective dose within the range of 5 mSv, while those with a weight below 40 kg had an effective dose below 5 mSv.  2 suggests that the administered activity generally increases with higher BMI categories.It could be that patients with a higher BMI were given higher doses of administered activity due to their weight.However, for the BMI range of 30-39.9, the mean and Q3 values of administered activity are lower.This could be attributed to the fact that this BMI range is associated with obesity.Therefore protocols such as time-of-flight and interactive reconstruction have been implemented to reduce the radiation exposure risk [21,22].The median administered activity follows a similar pattern, with slightly higher values in the higher BMI categories.Additionally, the quartile ranges of administered activity for each BMI category are relatively narrow, indicating that there may not be a significant variability in administered activity within each category.This can be attributed to the fact that the brain requires 95% of ATP to function properly, provided through glucose metabolism and 18 F-FDG being a glucose analogue.ANOVA and post hoc test (Tukey test) analysis revealed that there was a statistically significant difference between each of the organs except for a pair of the breast-kidney organ (P < 0.05).A linear connection between effective dose and administered activity was noticed, with a high level of accuracy.As the administered dose increased, the effective dose also increased.However, a threshold of 40 kg of patient's weight was identified, with the administered activity calculated to be 296 ± 9.99 MBq for patients with a weight of 40 kg or more and below 296 MBq for those with a weight lower than 40 kg.This suggests that the effective dose is higher for patients weighing more than 40 kg, but no further linear increase is observed after this threshold.
This study is restricted by its small sample size of 24 patients.This decreases the accuracy of the analysis, making certain statistical analyses out of reach.Furthermore, the sample population was restricted to those with lymphoma, and the study was conducted in a single center, which may have impacted the results.To improve the research, it could be conducted in multiple nuclear medicine imaging centers to compare the effective doses between them.Additionally, the accuracy of the effective dose can be enhanced by calculating biokinetic data for each patient based on the behavior of radiopharmaceuticals injected into their body.Additionally, further research and comparison between the various radiopharmaceuticals used in PET scan and different protocols in PET settings could be conducted to refine the results and minimize radiation exposure in PET scan.

Conclusion
This study assessed the radiation dose of an 18 F-PET scan for lymphoma.It was determined that the effective dose was linearly proportional to the administered activity and patient weight.The organ doses were validated using the IDAC-Dose 2.1 program based on the ICRP Publication 106.The highest absorbed dose was found in the brain, followed by the liver, adrenals, kidneys, and finally, the breast.A statistical significance was observed between the organ-absorbed doses, except for the breast and

Figure 1 .
Figure 1.Distribution of the effective dose (mSv) against the administered dose (MBq).

Figure 2 .
Figure 2. Distribution of effective dose based on weight.

Figure 3 .
Figure 3. Box plot graph of effective dose against groups of weight.

Figure 4 .
Figure 4. Box plot graph of absorbed dose for different organs.