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Biodistribution and radiation dosimetry of [18F]-5-fluorouracil
Applied Radiation and Isotopes 75 (2013) 11–17
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Applied Radiation and Isotopes journal homepage: www.elsevier.com/locate/apradiso
Biodistribution and radiation dosimetry of [18F]-5-fluorouracil Ayako Hino-Shishikura a,n, Akiko Suzuki a, Ryogo Minamimoto a, Kazuya Shizukuishi a, Takashi Oka a, Ukihide Tateishi a, Sadatoshi Sugae b, Yasushi Ichikawa b, Choichi Horiuchi c, Tomio Inoue a a
Department of Radiology, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan c Otorhinolaryngology, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan b
H I G H L I G H T S c c c c c
The radiation dose and biodistribution of [18F]-5-FU were estimated from mouse and human data. The biodistribution of [18F]-5-FU of mouse and human was corresponded. Estimated absorbed radiation doses for organs were moderately correlated between mouse and human. The mean effective [18F]-5-FU dose was higher in human than in mouse. The observed effective doses suggest the feasibility of [18F]-5-FU PET/CT for human studies.
a r t i c l e i n f o
abstract
Article history: Received 20 September 2012 Received in revised form 31 October 2012 Accepted 7 January 2013 Available online 20 January 2013
Purpose: To estimate the radiation dose and biodistribution of 18F-5-fluorouracil ([18F]-5-FU) from positron emission tomography/computed tomography (PET/CT) data, and to extrapolate mouse data to human data in order to evaluate cross-species consistency. Methods: Fifteen cancer patients (head and neck cancer (n ¼ 11), colon cancer (n ¼ 4)) were enrolled. Sequential PET/CT images were acquired for 2 h after intravenous administration of [18F]-5-FU, and the percent of the injected dose delivered to each organ was derived. For comparison, [18F]-5-FU was administered to female BALB/cAJcl-nu/nu nude mice (n ¼ 19), and the percent of the injected dose delivered to mouse organs was extrapolated to the human model. Absorbed radiation dose was calculated using OLINDA/EXM 1.0 software. Results: In human subjects, high [18F]-5-FU uptake was seen in the liver, gallbladder and kidneys. The absorbed dose was highest in the gallbladder wall. In mice, the biodistribution of [18F]-5-FU corresponded to that of humans. Estimated absorbed radiation doses for all organs were moderately correlated, and doses to organs (except the gallbladder and urinary bladder) were significantly correlated between mice and humans. The mean effective [18F]-5-FU dose was higher in humans (0.0124 mSv/MBq) than in mice (0.0058 mSv/MBq). Conclusion: Biodistribution and radiation dosimetry of [18F]-5-FU were compared between humans and mice: biodistribution in mice and humans was similar. Data from mice underestimated the effective dose in humans, suggesting that clinical measurements are needed for more detailed dose estimation in order to ensure radiation safety. The observed effective doses suggest the feasibility of [18F]-5-FU PET/ CT for human studies. & 2013 Elsevier Ltd. All rights reserved.
Keywords: [18F]5-fluorouracil PET/CT Biodistribution Radiation dosimetry
1. Introduction Abbreviations: PET, positron emission tomography; TS, thymidylate synthase; F-RNA, F-ribonucleic acid; [18F]-5-FU, 5-fluorouracil labeled with 18F; DPD, dihydropyrimidine dehydrogenase; FBAL, alpha-fluoro-beta-alanine; OLINDA, Organ Level Internal Dose Assessment Code; DICOM, Digital Imaging and Communications in Medicine; LD-CT, low dose CT; TAC, time activity curve; AUC, area under the curve; ROI, region of interest n Corresponding author. Tel.: þ81 45 787 2696; fax: þ 81 45 786 0369. E-mail address: [email protected] (A. Hino-Shishikura). 0969-8043/$ - see front matter & 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.apradiso.2013.01.014
Positron emission topography (PET) imaging of a chemotherapeutic agent labeled with a positron-emitting radionuclide can noninvasively optimize biodistribution of the agent, and is expected to be a safe and non-invasive method for predicting treatment outcome and adverse effects associated with chemotherapy (van der Veldt et al., 2008). In addition, as PET tracers consist of only
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microgram amounts of unlabeled agents, PET of radiolabelled chemotherapeutic agents can be used in microdose studies. Microdose studies have been suggested as a new strategy for drug development through support of clinical studies and non-clinical safety studies (Wagner and Langer, 2011). A few studies have suggested that PET with radiolabelled anticancer agents, such as 5-fluorouracil labeled with 18F ([18F]-5-FU) or docetaxel labeled with 11 C, may provide a unique means for personalized treatment in cancer patients (Dimitrakopoulou et al., 1993; Kissel et al., 1997; Moehler et al., 1998; van der Veldt et al., 2010). However, administration of extremely low doses of imaging agents may result in pharmacokinetics that differ from pharmacokinetics of therapeutic doses, and therefore more studies are needed to substantiate this concept. Fluoropyrimidines, particularly 5-FU and its prodrugs, are some of the most effective chemotherapeutic agents against various cancers (including metastatic gastrointestinal cancer, breast cancer, and head and neck cancer) (Early Breast Cancer Trialists Collaborative Group, 2005; Corvo et al., 1997; Iqbal and Lenz, 2001; Sobrero et al., 2000). Fluoropyrimidines induce strong cytotoxic effects on tumor cells by blocking thymidylate synthase (TS) and by forming defective F-ribonucleic acid (F-RNA) (Ghoshal and Jacob, 1997). Although 5-FU is widely used, it is still difficult to predict therapeutic responses and adverse effects because of interindividual variations in metabolic activity of 5-FU, of therapeutic concentrations of 5-FU achieved in the tumor and normal organs, and of chemosensitivity of tumors. Personalized chemotherapeutic protocols are needed in order to improve treatment outcomes (van Kuilenburg et al., 2000; Rougier and Mitry, 2009; Hamilton, 2008; Raida et al., 2002). PET studies of [18F]-5-FU (which has a favorable [18F] half-life (t1/2) of 110 min) have already been reported to be useful with respect to prognosis of treatment efficacy, and to have a diagnostic value both in humans and in other mammals (Dimitrakopoulou et al., 1993; Kissel et al., 1997; Moehler et al., 1998; Sugae et al., 2008; Bading et al., 2003; Aboagye et al., 2001; Visser et al., 1996). For certification of the radiation safety of a new radioactive drug, estimations of radiation dose to the whole body and to critical organs derived from a preclinical animal study or human study are needed. For radioactive drugs in research use, the critical organ dose or estimated whole body dose should be within the limitations defined in the FDA guideline 21 CFR 361.1(b)(3)(i). Animal-derived radiation dose estimations has often been considered sufficient to assure the safety of human studies. Estimated radiation exposure associated with [18F]-5-FU based both on measured biodistribution in rats and radioactivity in human urine was reported by Shani et al. (1982) previously, and Kenser et al. also reported estimated radiation exposure based on measured biodistribution in rodents (Kesner et al., 2008), but those were estimated by extrapolation of animal data to human model. To our knowledge, comprehensive [18F]-5-FU dosimetry based on PET imaging conducted in humans has not been reported. In the present study, the absorbed radiation dose of [18F]-5-FU PET was estimated by analyzing the biodistribution data in human volunteers. The biodistribution and absorbed radiation dose from [18F]-5-FU from human imaging data were compared with those extrapolated from animal data in order to evaluate consistency across species and the validity of extrapolation of mouse data to a human model.
2. Materials and methods 2.1. Synthesis of [18F]-5-FU [18F]-5-FU was synthesized by direct fluorination of uracil (Sigma-Aldrich, St. Louis, MO, USA) in acetic acid (Wako Chemical,
Osaka, Japan) using [18F]F2 (Fowler et al., 1973). Synthesis of [18F]F2 was produced by CYCLONE 18/9 (IBA, Louvain-la-Neuve, Belgium) using the 20Ne (d, a)18F reaction. Quality control included high performance liquid chromatography (HPLC). Typically, 2 mg of [18F]-5-FU with a purity 499% and a specific activity of 200 MBq was obtained. 2.2. PET/CT of [18F]-5-FU in humans 2.2.1. Human volunteers A total of 15 cancer patients (3 women and 12 men; mean age7SD, 65.1713.0 yr; range, 31–84 yr) were included in the study from May 2008 to August 2010. The body weight range was 42–74 kg (mean 7SD, 57.0710.3 kg). Inclusion criteria for the patients were: primary malignant lesions of head and neck (n ¼11), metastasized or recurrent colon cancer (n ¼4), plan to be treated with chemotherapeutic agents including 5-FU or 5-FU prodrugs, and an Eastern Cooperative Oncology Group (ECOG) performance status score of 42. Diagnosis was confirmed by histopathology in 11 cases of head and neck cancer. In 3 cases of recurrent colon cancer, an operation and postoperative chemotherapy (including intravenous or intra-arterial infusion of 5-FU or administration of oral pro-drug of 5-FU (Capecitabine)) had been performed in the past. Recurrence was confirmed based on clinical and imaging findings (contrast-enhanced CT and [18F]FDG PET/CT). In one case of colon cancer, the primary focus in the colon and metastases in the liver and lung were found at the same time. This patient had a past history of tarsus adenocarcinoma, and had already been administrated an oral prodrug of 5-FU (tegafur-uracil) at the time of the study for prevention of recurrence. The present study was approved by the ethics committee of the Yokohama City University Hospital. The experiment was conducted in accordance with the standards of the 1964 Declaration of Helsinki. Informed consent was obtained from each subject before entering the study. 2.2.2. PET/CT procedure PET/CT studies were performed on an integrated PET/CT system (Aquiduo, Toshiba Medical Systems, Tokyo, Japan) that integrates a 16-detector row CT scanner with a lutetium oxyorthosilicate (LSO)-based PET scanner. Each subject was positioned in the supine position on the scanner bed. Low dose CT (LD-CT) without contrast enhancement for transmission was performed according to a protocol as follows: 2 mm section thickness, 10 mA, 120 kV, 0.5 s per CT rotation, a pitch of 15, and with a breath-hold instruction. A total of 185 722.9 MBq (median 203; range 174–226 MBq) of [18F]-5-FU was administrated intravenously in a single bolus injection. Five serial PET scans for two bed positions, one position for the upper abdomen and one position for the tumor (neck or pelvis), were obtained at 0, 10, 20, 30 and 60 min after administration of [18F]-5-FU. A single PET scan from head to thigh was obtained at 120 min. The scan duration per bed position was 1 min at 0, 10, 20 and 30 min, and 2 min at 60, 120 min. The axial field of view of the scanner was 18 cm, and a 64% overlap between bed positions was applied in head to thigh scans, resulting in 6 or 7 bed positions per scan. PET data were acquired in the three-dimensional mode and were reconstructed using an ordered subset expectation maximization algorithm. Reconstructions were performed with four iterations and four subsets. 2.2.3. Radiation dose calculation from PET/CT OLINDA/EXM 1.0 software (Organ Level Internal Dose Assessment Code, Vanderbilt University, Nashville, US (Stabin et al., 2005)) was used to calculate absorbed doses and effective doses
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in each organ. The number of disintegrations of [18F]-5-FU in source organs was required for calculation by OLINDA/EXM, time activity curves (TACs) were drawn from human PET/CT images. All PET/CT images were archived in Digital Imaging and Communications in Medicine (DICOM) format and were reviewed and analyzed using OsiriX MD Imaging Software (Pixmeo SARL, Bernex, Switzerland) (Rosset et al., 2004). Region of interests (ROIs) were manually placed on each organ (brain, heart, kidneys, liver, spleen, gallbladder, thyroid glands, lung, muscle, vertebral bodies, small intestine, upper large intestine, and lower large intestine) to draw TACs. ROIs were placed on the PET images with reference to anatomical localization acquired by LD-CT. ROIs were placed on at least two adjacent slices and average values were adopted. For each dynamic scan, data from each ROI in counts/ pixel were corrected for image duration and tomograph efficiency using the calibration vial data, and were then converted to units of Bq/mL. Individual organ concentrations were calculated by trapezoidal integration of the TACs from the time of injection to the last PET scans at 120 min. The area under the curve (AUC) from 120 min after injection to infinity was estimated by dividing the amount of radioactivity at the 120 min time point by the physical decay constant for [18F], assuming elimination only through radioactive decay. Each source organ radioactivity was determined by multiplying the measured concentration (Bq/mL) by the organ mass, and normalized to an injection dose of 1 MBq. Organ weights of either an OLINDA adult male (or female) phantom or a 15-year-old phantom were used and extrapolated. Organ weights of the 15-year-old phantom were chosen when the body weight of the male subject was smaller than 60 kg. To estimate the absorbed dose of the urinary bladder wall, the voiding bladder model included in the OLINDA software was applied. Urinary excretion of [18F]-5-FU was divided into three fractions according to previously reported pharmacokinetics of 5-FU. The first fraction which represented the excretion of unchanged 5-FU was set to 10% with a 13-min half-life. The second and third fraction represented the excretion of dihydrofluorouracil (FUH2) and alpha-fluoro-beta-alanine (FBAL),
13
the metabolites of 5-FU. They were set to 10% with a 4-hour halflife, and 50% with a 23.9-hour half-life (Heggie et al., 1987). The bladder-voiding interval was set to 60 min. 2.3. Radiation dose calculation from the mouse model Animal experiments were conducted in accordance with the Animal Protection Guidelines of Yokohama City University. Biodistribution data of [18F]-5-FU in mice previously reported by Sugae et al. were used as a reference (Sugae et al., 2008), and more time points were added to compliment the data. Female BALB/cAJcl-nu/nu nude mice (n ¼19) were obtained from CLEA Japan (Tokyo, Japan). At the time of the experiments, all mice were 9–10 weeks of age and weighed 18–22 g. Approximately 1 MBq of [18F]-5-FU was intravenously administered via the tail vein. The mice were euthanized by cervical dislocation under deep anesthesia using isoflurane (Merck, Tokyo, Japan) at 30 min (n ¼7), 60 min (n ¼6) and 120 min (n¼ 6) after radiotracer injection. The organs were harvested, weighed, and counted for radioactivity using a gamma counter (Packard Cobra II, Global Medical Instrumentation, Minneapolis, MN, US). The counted radioactivity was normalized to injected dosage per gram of tissue (%ID/g). Radioactivity of the bone, lung, heart, stomach, small intestine, upper large intestine, lower large intestine, kidney, liver, spleen, pancreas and skeletal muscle were measured to draw TACs. The AUCs of TACs were calculated by trapezoidal integration until 120 min after injection. AUC from 120 min after injection was estimated by the integration to infinity, assuming elimination only by radioactive decay of 18F. AUCs from harvested organs were extrapolated to the OLINDA adult male phantom, following the equation below. ! " ! # g organ % % ðkg TBweight Þanimal ¼ g organ organ human kg TBweight animal human
For the urinary bladder wall estimation, the voiding bladder model included in the OLINDA software was used. Urinary excretion and bladder voiding intervals were set to the same
45
Concentrations of radioactivity (SUV)
40 35
Time after injection (minutes)
30 0
10
20
30
60
120
25 20
15 10 5 0
Fig. 1. SUVs of organ radioactivity derived from sequential PET/CT images of a representative case obtained at 0, 10, 20, 30, 60 and 120 min after administration of [18F]-5-FU. High uptake was seen in the liver, gallbladder and kidneys.
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values that were used in radiation dose calculations for PET/CT in cancer patients.
Table 1 Absorbed organ radiation dose of [18F]5-FU in humans and mice. Organ
5-FU in human mean (mGy/MBq)
SD (mGy/MBq) 5-FU in mouse (mGy/MBq)
Discrepancy (%)
Adrenals Brain Breasts Gallbladder wall LLI wall Small intestine Stomach wall ULI wall Heart wall Kidneys Liver Lungs Muscle Ovaries Pancreas Red marrow Osteogenic cells Skin Spleen Testes Thymus Thyroid Urinary bladder wall Uterus Total body Effective dose (mSv/MBq)
2.82E 02 1.47E 03 2.17E 03 7.99E 02
3.33E 02 1.16E 03 7.11E 04 1.46E 01
3.60E 03 5.06E 03 8.31E 04 5.51E 03
87 244 62 93
4.49E 03 1.14E 02 7.13E 03 9.01E 03 1.14E 02 5.44E 02 7.37E 02 8.54E 03 7.23E 03 5.38E 03 1.53E 02 6.47E 03 4.73E 03
1.05E 03 6.50E 03 2.19E 03 3.43E 03 3.01E 03 2.27E 02 2.06E 02 4.61E 03 2.03E 03 1.46E 03 5.02E 03 1.87E 03 1.37E 03
3.24E 03 3.18E 03 1.73E 03 3.20E 03 3.31E 03 1.68E 02 2.65E 02 3.86E 03 2.16E 03 2.40E 03 4.77E 03 3.56E 03 2.31E 03
28 72 76 64 71 69 64 55 70 55 69 45 51
2.05E 03 1.12E 02 2.20E 03 3.11E 03 3.50E 03 5.30E 02
5.23E 04 2.62E 03 1.26E 03 8.07E 04 1.96E 03 7.63E 03
7.67E-04 3.64E-03 1.33E 03 1.03E 03 7.63E 04 4.37E 02
63 67 39 67 78 18
6.70E 03 6.97E 03 1.21E 02
1.39E 03 1.82E 03 2.82E 03
3.77E 03 2.58E 03 5.82E 03
44 63 52
2.4. Statistical analysis Correlations between human and mouse data were measured by calculating Pearson product–moment correlation coefficients, and were tested at a level of significance of 0.01. The strength of correlation was defined as follows: weak correlation, 0r9r9 o0.3; moderate correlation, 0.3 r9r9 o0.7; and strong correlation, 0.7 r9r9o1.0.
3. Results 3.1. Biodistribution of [18F]-5-FU in human volunteers The mean concentration of radioactivity represented by sequential transition of standardized uptake values (SUVs) of organs derived from sequential PET/CT images in human volunteers is shown in Fig. 1. The representative whole body PET/CT image acquired at 120 min after injection of [18F]-5-FU is shown in Fig. 2. The regions exhibiting the highest [18F]-5-FU uptake were the liver, kidneys, gallbladder, intestine and urinary ducts. [18F]-5-FU was excreted through both the renal and the hepatobiliary systems.
3.2. Radiation dose calculation from PET/CT in human volunteers The estimated absorbed dose of [18F]-5-FU for each organ derived from PET/CT images of human volunteers and from harvested organ radioactivity in mice is shown in Table 1. In the human-derived estimation, the absorbed dose was the highest in the gallbladder wall (0.0799 mGy/MBq), which was followed by the liver (0.0737 mGy/MBq), the kidney (0.0544 mGy/MBq) and the urinary bladder wall (0.0530 mGy/MBq). The mean effective dose was estimated to be 0.0121 mSv/MBq. 3.3. Biodistribution of [18F]-5-FU in mice The mean concentration of radioactivity (%ID/g) in each organ harvested from mice is shown in Fig. 3. [18F]-5-FU accumulation was high in the liver and the kidney, and low in the other organs. The highest accumulation of [18F]-5-FU was observed 30 min after administration and reduced thereafter in all organs, except for the bones. 3.4. Radiation dose calculation from the mouse model The estimated absorbed dose of each organ is shown in Table 1. The highest absorbed dose was found in the urinary bladder wall (0.0437 mGy/MBq), followed by the liver (0.0265 mGy/MBq) and the kidneys (0.0168 mGy/MBq). The mean effective dose was estimated to be 0.00582 mSv/MBq. 3.5. Comparison of biodistribution and estimated absorbed radiation dose in humans and mice Fig. 2. PET-CT of a representative case obtained 120 min after injection. Main regions showing [18F]-5-FU uptake are the liver (asterisks), kidney (white arrows), bile duct and gallbladder (white arrowheads) and urinary ducts (black arrows).
Biodistributions of [18F]-5-FU were similar between humans and mice (high accumulation in the hepatobiliary system and
Concentrations of radioactivity (% ID/g)
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7 6 5 Time after injection (hours)
4 3
0.5h (n=7)
2
1h (n=6) 2h (n=6)
1 0
15
liver and kidneys both in humans and mice. The gallbladder also showed high accumulation in humans, but was not investigated in mice. This high accumulation in the liver may represent the catabolism of 5-FU to alpha-fluoro-beta-alanine (FBAL) by dihydropyrimidine dehydrogenase (DPD). DPD is the initial and ratelimiting metabolic enzyme of 5-FU, and is expressed mainly in the liver. FBAL, an inactivated metabolite of 5-FU, is excreted both into the bile and blood, and is finally excreted in the urine and feces. The high accumulation in the kidneys may represent renal excretion of both unchanged [18F]-5-FU and its [18F]-labeled metabolite, such as [18F]-FBAL, [18F]-FUH2 (dihydrofluorouracil), or [18F]-FUPA (a-fluoro-ureidopropionic acid). High accumulation in the gallbladder may represent biliary excretion of metabolite of [18F]-5-FU, such as [18F]-FBAL, [18F]-FUH2, or [18F]-FUPA, which are excreted from hepatic cells and are drained directly into bile ducts (Kissel et al., 1997; Heggie et al., 1987). 4.2. Radiation safety of [18F]-5-FU in comparison with other [18F] PET ligands
Fig. 3. Mean concentrations of radioactivity (%ID/g) of each organ harvested from mice. [18F]-5-FU accumulation was high in the liver and kidneys, and low in the other organs. The highest accumulation of [18F]-5-FU was observed 30 min after administration, and reduced sequentially in all organs, except for the bones.
Mouse derived organ dose (mGy/MBq)
urinary bladder 0.04
0.03
0.02
0.01
gallbladder
The dose-critical organ estimated from human PET/CT data was the gallbladder wall (which received 0.0799 mGy/MBq). According to FDA guideline 21 CFR 361.1(b)(3)(i), the intravenous administration of [18F]-5-FU is limited to 8.94 MBq/kg per study, and to 26.82 MBq/kg per year in a 70 kg man. This limitation was satisfied in the present study, because PET/CT imaging data were obtained with administration of a sufficiently lower dose of [18F]5-FU than this published limit. The estimated radiation dose to the urinary bladder was also high both in humans and mice, perhaps because of the high excretion of [18F]-5-FU in urine. This suggests that the absorbed radiation dose in the urinary bladder wall and other pelvic organs (such as gonad glands and lower large intestine) can be reduced by sequential voiding of urine. The mean absorbed doses to organs associated with [18F]5-FU and compared with two other widely used [18F]-labeled agents, FDG and fluorothymidine (FLT) in Table 2, to validate the
0 0
0.02
0.04
0.06
0.08
Human derived organ dose (mGy/MBq) Fig. 4. Organ-absorbed radiation doses in humans and mice exhibited moderate positive correlations for all organs (r¼ 0.685; p¼ 3.08E 04), and exhibited strong positive correlations for all organs excepting the gallbladder wall and urinary bladder wall (r ¼ 0.953; p ¼2.36E 11).
kidney, and low accumulation in other organs), but the retention time of [18F]-5-FU was shorter in mice than in humans (Figs. 1 and 3). Comparison of the estimated absorbed radiation dose in each organ between humans and mice is shown in Fig. 4. The estimated radiation dose in mice correlated significantly with that in humans for all organs (r¼0.685; p¼3.08E04), except for the gallbladder wall and urinary bladder wall (without the gallbladder wall and urinary bladder wall, r¼0.953; p¼2.36E 11). In the human gallbladder wall, the dose was approximately 15-fold higher than the dose estimated in mice. The estimated effective dose derived from harvested mouse organ data was underestimated by 51.9%, compared to the human-derived estimated effective dose.
4. Discussion 4.1. Biodistribution of [18F]-5-FU In the present study, the biodistribution of [18F]-5-FU was investigated and compared in humans and mice. The observed biodistribution of [18F]-5-FU revealed a high accumulation in the
Table 2 Comparison of estimated organ absorbed dose derived from [18F]5-FU and other previously reported [18F] labeled PET ligands. Organ
5-FU (mGy/MBq)
FDG (Heggie et al., 1987) (mGy/MBq)
FLT (Protection, 1988) (mGy/MBq)
Adrenals Brain Breasts Gallbladder wall LLI wall Small intestine Stomach wall ULI wall Heart wall Kidneys Liver Lungs Muscle Ovaries Pancreas Red marrow Osteogenic cells Skin Spleen Testes Thymus Thyroid Urinary bladder wall Uterus Total body Effective dose (mSv/MBq)
2.82E 02 1.47E-03 2.17E 03 7.99E 02 4.49E 03 1.14E 02 7.13E 03 9.01E 03 1.14E 02 5.44E 02 7.37E 02 8.54E 03 7.23E 03 5.38E 03 1.53E 02 6.47E 03 4.73E 03 2.05E 03 1.12E 02 2.20E 03 3.11E 03 3.50E 03 5.30E 02 6.70E 03 6.97E 03 1.21E 02
1.20E 02 2.80E 02 8.60E 03 1.20E 02 1.50E 02 1.30E 02 1.10E 02 1.20E 02 6.20E 02 2.10E 02 1.10E 02 1.00E 02 1.10E 02 1.50E 02 1.20E 02 1.10E 02 – 1.10E 02 1.10E 02 1.20E 02 1.10E 02 1.00E 02 1.60E 01 2.10E 02 – 1.90E 02
2.10E 02 3.25E 03 8.13E 03 1.65E 02 1.51E 02 1.47E 02 1.37E 02 1.26E 02 1.62E 02 3.52E 02 4.51E 02 9.61E 03 1.58E 02 – 2.24E 02 2.39E 02 1.55E 02 4.30E 03 1.66E 02 1.45E 02 1.05E 02 9.71E 03 1.79E 01 – 1.23E 02 2.80E 02
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radiation safety. Compared with doses associated with FDG or FLT, the individual organ-absorbed doses associated with [18F]-5FU were higher in the gallbladder wall, liver and kidneys, and lower or equivalent in other organs. The effective dose associated with [18F]-5-FU was lower than those associated with FDG and FLT (Hays et al., 2002; Protection, 1988; Vesselle et al., 2003). This data suggest that the risk of radiation exposure associated with [18F]-5-FU is almost similar to those of widely used PET ligands, and assures the radiation safety of [18F]-5-FU in clinical use.
derived data. For voiding-bladder estimation, the half-life and fractionation of 5-FU and its metabolites were cited from previously reported human data, and the same parameters were adopted for all subjects. Individualized half-life estimation obtained by sequential measurement of [18F]-5-FU activity in the urinary tract could provide a more precise dose estimation.
4.3. Similarity and discrepancies between species
Biodistribution and radiation dosimetry of [18F]-5-FU were compared between humans and mice. The biodistribution in mice was in accordance with that in humans. Mouse data underestimated the effective dose in humans, suggesting that clinical measurements are needed for a more detailed estimation to ensure radiation safety. The observed effective doses suggest the feasibility of [18F]-5-FU PET/CT for human studies.
The biodistribution of [18F]-5-FU appeared to be correlated between humans and mice, and estimated organ radiation doses exhibited a moderate to strong positive correlation between humans and mice. This suggests that mouse-derived data can be used for prediction of the biodistribution and of the radiation critical organ in humans. Although the distribution of [18F]-5-FU corresponded between human and mouse data, the overall absorbed doses in organs (except for brain and effective dose) were underestimated in mouse data compared with humanderived PET/CT data. One reason for this could be that the [18F]-5-FU was metabolized faster by DPD and the residence time of [18F]-5-FU was shorter in the mouse. This could be because the activity of DPD in the liver is higher in mice than in humans (Sludden et al., 1998). This suggests that with estimation of the irradiation dose of new radioactive drugs, simple extrapolation of preclinical mouse data to a human model inevitably has the risk of underestimation or overestimation, and that the error rate is high in organs that participate in metabolism and excretion of the drugs. 4.4. Limitations This study includes some limitations. The biodistribution of [18F]-5-FU was compared in cancer patients and normal mice. The metabolism and biodistribution of [18F]-5-FU might be slightly different between cancer patients and normal human subjects, because the activity of DPD (the rate-limiting enzyme of the degeneration of 5-FU) is modulated both in tumor tissue and normal tissue (Raida et al., 2002; Etienne et al., 1995; McLeod et al., 1998). This difference in biodistribution might have led to a slight modulation of the absorbed doses in different organs and of the overall effective dose. The administrated dose of [18F]-5-FU per body weight was quite different between mice and humans, and this difference might also have modulated the biodistribution slightly. For radiation dose estimation that was derived from experimental animal data, organs were collected from mice at 30, 60 or 120 min after administration of [18F]-5-FU. However, considering the fast metabolism of 5-FU in the mouse body, measurements at earlier time points would have been helpful for a more reliable extrapolation (Sludden et al., 1998). The absorbed dose of the mouse gastrointestinal tract has the possibility of inherent underestimation due to technical error, since some of the radioactive contents in the feces can be lost during the organharvesting process. The absorbed dose of the mouse gallbladder could have been underestimated, because gallbladders were not harvested in this study. To estimate the absorbed dose of the gallbladder in human subjects, TACs from 0 to 120 min were integrated, and the dose at 120 min was integrated to infinity assuming elimination only by radioactive decay. This might have led to overestimation of the absorbed dose of the gallbladder, because the [18F]-5-FU in bile might have gradually drained into duodenum, and further through the small intestine and colon. To estimate urinary tract absorption, the voiding-bladder model in the OLINDA software was adopted for both human- and mouse-
5. Conclusion
Acknowledgments The authors declare that they have no conflict of interest. This study was partially funded by grants awarded by the New Energy and Industrial Technology Development Organization. We thank Dr. H. Endo and Dr. C. Theeraladanon for the synthesis of [18F]5-FU. We also thank our nuclear medicine technologists for acquiring PET/CT scans. References Aboagye, E.O., Saleem, A., Cunningham, V.J., Osman, S., Price, P.M., 2001. Extraction of 5-fluorouracil by tumor and liver: a noninvasive positron emission tomography study of patients with gastrointestinal cancer. Cancer Res. 61, 4937–4941. Bading, J.R., Yoo, P.B., Fissekis, J.D., Alauddin, M.M., D’Argenio, D.Z., Conti, P.S., 2003. Kinetic modeling of 5-fluorouracil anabolism in colorectal adenocarcinoma: a positron emission tomography study in rats. Cancer Res. 63, 3667–3674. Corvo, R., Giaretti, W., Sanguineti, G., Geido, E., Bacigalupo, A., Orecchia, R., et al., 1997. Chemoradiotherapy as an alternative to radiotherapy alone in fast proliferating head and neck squamous cell carcinomas. Clin. Cancer Res. 3, 1993–1997. Dimitrakopoulou, A., Strauss, L.G., Clorius, J.H., Ostertag, H., Schlag, P., Heim, M., et al., 1993. Studies with positron emission tomography after systemic administration of fluorine-18-uracil in patients with liver metastases from colorectal carcinoma. J. Nucl. Med. 34, 1075–1081. Early Breast Cancer, 2005. Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15year survival: an overview of the randomised trials. Lancet 365, 1687-717. Etienne, M.C., Cheradame, S., Fischel, J.L., Formento, P., Dassonville, O., Renee, N., et al., 1995. Response to fluorouracil therapy in cancer patients: the role of tumoral dihydropyrimidine dehydrogenase activity. J. Clin. Oncol. 13, 1663–1670. Fowler, J.S., Finn, R.D., Lambrecht, R.M., Wolf, A.P., 1973. The synthesis of 18F-5fluorouracil. VII. J. Nucl. Med. 14, 63–64. Ghoshal, K., Jacob, S.T., 1997. An alternative molecular mechanism of action of 5-fluorouracil, a potent anticancer drug. Biochem. Pharmacol. 53, 1569–1575. Hamilton, S.R., 2008. Targeted therapy of cancer: new roles for pathologists in colorectal cancer. Mod. Pathol. 21 (Suppl 2), S23–S30. Hays, M.T., Watson, E.E., Thomas, S.R., Stabin, M., 2002. MIRD dose estimate report no. 19: radiation absorbed dose estimates from 18F-FDG. J. Nucl. Med. 43, 210–214. Heggie, G.D., Sommadossi, J.P., Cross, D.S., Huster, W.J., Diasio, R.B., 1987. Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. Cancer Res. 47, 2203–2206. Iqbal, S., Lenz, H.J., 2001. Determinants of prognosis and response to therapy in colorectal cancer. Curr. Oncol. Rep. 3, 102–108. Kesner, A.L., Hsueh, W.A., Czernin, J., Padgett, H., Phelps, M.E., Silverman, D.H., 2008. Radiation dose estimates for [18F]5-fluorouracil derived from PET-based and tissue-based methods in rats. Mol. Imaging Biol. 10, 341–348. Kissel, J., Brix, G., Bellemann, M.E., Strauss, L.G., Dimitrakopoulou-Strauss, A., Port, R., et al., 1997. Pharmacokinetic analysis of 5-[18F]fluorouracil tissue concentrations measured with positron emission tomography in patients with liver metastases from colorectal adenocarcinoma. Cancer Res. 57, 3415–3423. McLeod, H.L., Sludden, J., Murray, G.I., Keenan, R.A., Davidson, A.I., Park, K., et al., 1998. Characterization of dihydropyrimidine dehydrogenase in human colorectal tumours. Br. J. Cancer 77, 461–465.
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Moehler, M., Dimitrakopoulou-Strauss, A., Gutzler, F., Raeth, U., Strauss, L.G., Stremmel, W., 1998. 18F-labeled fluorouracil positron emission tomography and the prognoses of colorectal carcinoma patients with metastases to the liver treated with 5-fluorouracil. Cancer 83, 245–253. Protection. ICoR, 1988. ICRP Publication 53. Radiation dose to patients from radiopharmaceuticals. Annals of the ICRP, 18. Raida, M., Kliche, K.O., Schwabe, W., Hausler, P., Clement, J.H., Behnke, D., et al., 2002. Circadian variation of dihydropyrimidine dehydrogenase mRNA expression in leukocytes and serum cortisol levels in patients with advanced gastrointestinal carcinomas compared to healthy controls. J. Cancer Res. Clin. Oncol. 128, 96–102. Rougier, P., Mitry, E., 2009. Targeted biotherapy: a revolution in the management of patients with colorectal cancer? Gastroenterol. Clin. Biol. 33, 672–680. Rosset, A., Spadola, L., Ratib, O., 2004. OsiriX: an open-source software for navigating in multidimensional DICOM images. J. Digit Imaging 17, 205–216. Shani, J., Young, D., Schlesinger, T., Siemsen, J.K., Chlebowski, R.T., Bateman, J.R., Wolf, W., 1982. Dosimetry and preliminary human studies of 18F-5fluorouracil. Int. J. Nucl. Med. Biol. 9, 25–35. Sludden, J., Hardy, S.C., VandenBranden, M.R., Wrighton, S.A., McLeod, H.L., 1998. Liver dihydropyrimidine dehydrogenase activity in human, cynomolgus monkey, rhesus monkey, dog, rat and mouse. Pharmacology 56, 276–280. Sobrero, A., Kerr, D., Glimelius, B., Van Cutsem, E., Milano, G., Pritchard, D.M., et al., 2000. New directions in the treatment of colorectal cancer: a look to the future. Eur. J. Cancer 36, 559–566. Stabin, M.G., Sparks, R.B., Crowe, E., 2005. OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J. Nucl. Med. 46, 1023–1027.
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Sugae, S., Suzuki, A., Takahashi, N., Minamimoto, R., Cheng, C., Theeraladanon, C., et al., 2008. Fluorine-18-labeled 5-fluorouracil is a useful radiotracer for differentiation of malignant tumors from inflammatory lesions. Ann. Nucl. Med. 22, 65–72. van der Veldt, A.A., Hendrikse, N.H., Smit, E.F., Mooijer, M.P., Rijnders, A.Y., Gerritsen, W.R., et al., 2010. Biodistribution and radiation dosimetry of 11 C-labeled docetaxel in cancer patients. Eur. J. Nucl. Med. Mol. Imaging 37 (10), 1950–1958. van der Veldt, A.A., Luurtsema, G., Lubberink, M., Lammertsma, A.A., Hendrikse, N.H., 2008. Individualized treatment planning in oncology: role of PET and radiolabelled anticancer drugs in predicting tumour resistance. Curr. Pharm Des. 14, 2914–2931. van Kuilenburg, A.B., Haasjes, J., Richel, D.J., Zoetekouw, L., Van Lenthe, H., De Abreu, R.A., et al., 2000. Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracilassociated toxicity: identification of new mutations in the DPD gene. Clin. Cancer Res. 6, 4705–4712. Vesselle, H., Grierson, J., Peterson, L.M., Muzi, M., Mankoff, D.A., Krohn, K.A., 2003. 18 F-Fluorothymidine radiation dosimetry in human PET imaging studies. J. Nucl. Med. 441482–1488 Visser, G.W., van der Wilt, C.L., Wedzinga, R., Peters, G.J., Herscheid, J.D., 1996. 18Fradiopharmacokinetics of [18F]-5-fluorouracil in a mouse bearing two colon tumors with a different 5-fluorouracil sensitivity: a study for a correlation with oncological results. Nucl. Med. Biol. 23, 333–342. Wagner, C.C., Langer, O., 2011. Approaches using molecular imaging technology—use of PET in clinical microdose studies. Adv. Drug Deliv. Rev. 63, 539–546.
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Applied Radiation and Isotopes journal homepage: www.elsevier.com/locate/apradiso
Biodistribution and radiation dosimetry of [18F]-5-fluorouracil Ayako Hino-Shishikura a,n, Akiko Suzuki a, Ryogo Minamimoto a, Kazuya Shizukuishi a, Takashi Oka a, Ukihide Tateishi a, Sadatoshi Sugae b, Yasushi Ichikawa b, Choichi Horiuchi c, Tomio Inoue a a
Department of Radiology, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan c Otorhinolaryngology, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan b
H I G H L I G H T S c c c c c
The radiation dose and biodistribution of [18F]-5-FU were estimated from mouse and human data. The biodistribution of [18F]-5-FU of mouse and human was corresponded. Estimated absorbed radiation doses for organs were moderately correlated between mouse and human. The mean effective [18F]-5-FU dose was higher in human than in mouse. The observed effective doses suggest the feasibility of [18F]-5-FU PET/CT for human studies.
a r t i c l e i n f o
abstract
Article history: Received 20 September 2012 Received in revised form 31 October 2012 Accepted 7 January 2013 Available online 20 January 2013
Purpose: To estimate the radiation dose and biodistribution of 18F-5-fluorouracil ([18F]-5-FU) from positron emission tomography/computed tomography (PET/CT) data, and to extrapolate mouse data to human data in order to evaluate cross-species consistency. Methods: Fifteen cancer patients (head and neck cancer (n ¼ 11), colon cancer (n ¼ 4)) were enrolled. Sequential PET/CT images were acquired for 2 h after intravenous administration of [18F]-5-FU, and the percent of the injected dose delivered to each organ was derived. For comparison, [18F]-5-FU was administered to female BALB/cAJcl-nu/nu nude mice (n ¼ 19), and the percent of the injected dose delivered to mouse organs was extrapolated to the human model. Absorbed radiation dose was calculated using OLINDA/EXM 1.0 software. Results: In human subjects, high [18F]-5-FU uptake was seen in the liver, gallbladder and kidneys. The absorbed dose was highest in the gallbladder wall. In mice, the biodistribution of [18F]-5-FU corresponded to that of humans. Estimated absorbed radiation doses for all organs were moderately correlated, and doses to organs (except the gallbladder and urinary bladder) were significantly correlated between mice and humans. The mean effective [18F]-5-FU dose was higher in humans (0.0124 mSv/MBq) than in mice (0.0058 mSv/MBq). Conclusion: Biodistribution and radiation dosimetry of [18F]-5-FU were compared between humans and mice: biodistribution in mice and humans was similar. Data from mice underestimated the effective dose in humans, suggesting that clinical measurements are needed for more detailed dose estimation in order to ensure radiation safety. The observed effective doses suggest the feasibility of [18F]-5-FU PET/ CT for human studies. & 2013 Elsevier Ltd. All rights reserved.
Keywords: [18F]5-fluorouracil PET/CT Biodistribution Radiation dosimetry
1. Introduction Abbreviations: PET, positron emission tomography; TS, thymidylate synthase; F-RNA, F-ribonucleic acid; [18F]-5-FU, 5-fluorouracil labeled with 18F; DPD, dihydropyrimidine dehydrogenase; FBAL, alpha-fluoro-beta-alanine; OLINDA, Organ Level Internal Dose Assessment Code; DICOM, Digital Imaging and Communications in Medicine; LD-CT, low dose CT; TAC, time activity curve; AUC, area under the curve; ROI, region of interest n Corresponding author. Tel.: þ81 45 787 2696; fax: þ 81 45 786 0369. E-mail address: [email protected] (A. Hino-Shishikura). 0969-8043/$ - see front matter & 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.apradiso.2013.01.014
Positron emission topography (PET) imaging of a chemotherapeutic agent labeled with a positron-emitting radionuclide can noninvasively optimize biodistribution of the agent, and is expected to be a safe and non-invasive method for predicting treatment outcome and adverse effects associated with chemotherapy (van der Veldt et al., 2008). In addition, as PET tracers consist of only
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microgram amounts of unlabeled agents, PET of radiolabelled chemotherapeutic agents can be used in microdose studies. Microdose studies have been suggested as a new strategy for drug development through support of clinical studies and non-clinical safety studies (Wagner and Langer, 2011). A few studies have suggested that PET with radiolabelled anticancer agents, such as 5-fluorouracil labeled with 18F ([18F]-5-FU) or docetaxel labeled with 11 C, may provide a unique means for personalized treatment in cancer patients (Dimitrakopoulou et al., 1993; Kissel et al., 1997; Moehler et al., 1998; van der Veldt et al., 2010). However, administration of extremely low doses of imaging agents may result in pharmacokinetics that differ from pharmacokinetics of therapeutic doses, and therefore more studies are needed to substantiate this concept. Fluoropyrimidines, particularly 5-FU and its prodrugs, are some of the most effective chemotherapeutic agents against various cancers (including metastatic gastrointestinal cancer, breast cancer, and head and neck cancer) (Early Breast Cancer Trialists Collaborative Group, 2005; Corvo et al., 1997; Iqbal and Lenz, 2001; Sobrero et al., 2000). Fluoropyrimidines induce strong cytotoxic effects on tumor cells by blocking thymidylate synthase (TS) and by forming defective F-ribonucleic acid (F-RNA) (Ghoshal and Jacob, 1997). Although 5-FU is widely used, it is still difficult to predict therapeutic responses and adverse effects because of interindividual variations in metabolic activity of 5-FU, of therapeutic concentrations of 5-FU achieved in the tumor and normal organs, and of chemosensitivity of tumors. Personalized chemotherapeutic protocols are needed in order to improve treatment outcomes (van Kuilenburg et al., 2000; Rougier and Mitry, 2009; Hamilton, 2008; Raida et al., 2002). PET studies of [18F]-5-FU (which has a favorable [18F] half-life (t1/2) of 110 min) have already been reported to be useful with respect to prognosis of treatment efficacy, and to have a diagnostic value both in humans and in other mammals (Dimitrakopoulou et al., 1993; Kissel et al., 1997; Moehler et al., 1998; Sugae et al., 2008; Bading et al., 2003; Aboagye et al., 2001; Visser et al., 1996). For certification of the radiation safety of a new radioactive drug, estimations of radiation dose to the whole body and to critical organs derived from a preclinical animal study or human study are needed. For radioactive drugs in research use, the critical organ dose or estimated whole body dose should be within the limitations defined in the FDA guideline 21 CFR 361.1(b)(3)(i). Animal-derived radiation dose estimations has often been considered sufficient to assure the safety of human studies. Estimated radiation exposure associated with [18F]-5-FU based both on measured biodistribution in rats and radioactivity in human urine was reported by Shani et al. (1982) previously, and Kenser et al. also reported estimated radiation exposure based on measured biodistribution in rodents (Kesner et al., 2008), but those were estimated by extrapolation of animal data to human model. To our knowledge, comprehensive [18F]-5-FU dosimetry based on PET imaging conducted in humans has not been reported. In the present study, the absorbed radiation dose of [18F]-5-FU PET was estimated by analyzing the biodistribution data in human volunteers. The biodistribution and absorbed radiation dose from [18F]-5-FU from human imaging data were compared with those extrapolated from animal data in order to evaluate consistency across species and the validity of extrapolation of mouse data to a human model.
2. Materials and methods 2.1. Synthesis of [18F]-5-FU [18F]-5-FU was synthesized by direct fluorination of uracil (Sigma-Aldrich, St. Louis, MO, USA) in acetic acid (Wako Chemical,
Osaka, Japan) using [18F]F2 (Fowler et al., 1973). Synthesis of [18F]F2 was produced by CYCLONE 18/9 (IBA, Louvain-la-Neuve, Belgium) using the 20Ne (d, a)18F reaction. Quality control included high performance liquid chromatography (HPLC). Typically, 2 mg of [18F]-5-FU with a purity 499% and a specific activity of 200 MBq was obtained. 2.2. PET/CT of [18F]-5-FU in humans 2.2.1. Human volunteers A total of 15 cancer patients (3 women and 12 men; mean age7SD, 65.1713.0 yr; range, 31–84 yr) were included in the study from May 2008 to August 2010. The body weight range was 42–74 kg (mean 7SD, 57.0710.3 kg). Inclusion criteria for the patients were: primary malignant lesions of head and neck (n ¼11), metastasized or recurrent colon cancer (n ¼4), plan to be treated with chemotherapeutic agents including 5-FU or 5-FU prodrugs, and an Eastern Cooperative Oncology Group (ECOG) performance status score of 42. Diagnosis was confirmed by histopathology in 11 cases of head and neck cancer. In 3 cases of recurrent colon cancer, an operation and postoperative chemotherapy (including intravenous or intra-arterial infusion of 5-FU or administration of oral pro-drug of 5-FU (Capecitabine)) had been performed in the past. Recurrence was confirmed based on clinical and imaging findings (contrast-enhanced CT and [18F]FDG PET/CT). In one case of colon cancer, the primary focus in the colon and metastases in the liver and lung were found at the same time. This patient had a past history of tarsus adenocarcinoma, and had already been administrated an oral prodrug of 5-FU (tegafur-uracil) at the time of the study for prevention of recurrence. The present study was approved by the ethics committee of the Yokohama City University Hospital. The experiment was conducted in accordance with the standards of the 1964 Declaration of Helsinki. Informed consent was obtained from each subject before entering the study. 2.2.2. PET/CT procedure PET/CT studies were performed on an integrated PET/CT system (Aquiduo, Toshiba Medical Systems, Tokyo, Japan) that integrates a 16-detector row CT scanner with a lutetium oxyorthosilicate (LSO)-based PET scanner. Each subject was positioned in the supine position on the scanner bed. Low dose CT (LD-CT) without contrast enhancement for transmission was performed according to a protocol as follows: 2 mm section thickness, 10 mA, 120 kV, 0.5 s per CT rotation, a pitch of 15, and with a breath-hold instruction. A total of 185 722.9 MBq (median 203; range 174–226 MBq) of [18F]-5-FU was administrated intravenously in a single bolus injection. Five serial PET scans for two bed positions, one position for the upper abdomen and one position for the tumor (neck or pelvis), were obtained at 0, 10, 20, 30 and 60 min after administration of [18F]-5-FU. A single PET scan from head to thigh was obtained at 120 min. The scan duration per bed position was 1 min at 0, 10, 20 and 30 min, and 2 min at 60, 120 min. The axial field of view of the scanner was 18 cm, and a 64% overlap between bed positions was applied in head to thigh scans, resulting in 6 or 7 bed positions per scan. PET data were acquired in the three-dimensional mode and were reconstructed using an ordered subset expectation maximization algorithm. Reconstructions were performed with four iterations and four subsets. 2.2.3. Radiation dose calculation from PET/CT OLINDA/EXM 1.0 software (Organ Level Internal Dose Assessment Code, Vanderbilt University, Nashville, US (Stabin et al., 2005)) was used to calculate absorbed doses and effective doses
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in each organ. The number of disintegrations of [18F]-5-FU in source organs was required for calculation by OLINDA/EXM, time activity curves (TACs) were drawn from human PET/CT images. All PET/CT images were archived in Digital Imaging and Communications in Medicine (DICOM) format and were reviewed and analyzed using OsiriX MD Imaging Software (Pixmeo SARL, Bernex, Switzerland) (Rosset et al., 2004). Region of interests (ROIs) were manually placed on each organ (brain, heart, kidneys, liver, spleen, gallbladder, thyroid glands, lung, muscle, vertebral bodies, small intestine, upper large intestine, and lower large intestine) to draw TACs. ROIs were placed on the PET images with reference to anatomical localization acquired by LD-CT. ROIs were placed on at least two adjacent slices and average values were adopted. For each dynamic scan, data from each ROI in counts/ pixel were corrected for image duration and tomograph efficiency using the calibration vial data, and were then converted to units of Bq/mL. Individual organ concentrations were calculated by trapezoidal integration of the TACs from the time of injection to the last PET scans at 120 min. The area under the curve (AUC) from 120 min after injection to infinity was estimated by dividing the amount of radioactivity at the 120 min time point by the physical decay constant for [18F], assuming elimination only through radioactive decay. Each source organ radioactivity was determined by multiplying the measured concentration (Bq/mL) by the organ mass, and normalized to an injection dose of 1 MBq. Organ weights of either an OLINDA adult male (or female) phantom or a 15-year-old phantom were used and extrapolated. Organ weights of the 15-year-old phantom were chosen when the body weight of the male subject was smaller than 60 kg. To estimate the absorbed dose of the urinary bladder wall, the voiding bladder model included in the OLINDA software was applied. Urinary excretion of [18F]-5-FU was divided into three fractions according to previously reported pharmacokinetics of 5-FU. The first fraction which represented the excretion of unchanged 5-FU was set to 10% with a 13-min half-life. The second and third fraction represented the excretion of dihydrofluorouracil (FUH2) and alpha-fluoro-beta-alanine (FBAL),
13
the metabolites of 5-FU. They were set to 10% with a 4-hour halflife, and 50% with a 23.9-hour half-life (Heggie et al., 1987). The bladder-voiding interval was set to 60 min. 2.3. Radiation dose calculation from the mouse model Animal experiments were conducted in accordance with the Animal Protection Guidelines of Yokohama City University. Biodistribution data of [18F]-5-FU in mice previously reported by Sugae et al. were used as a reference (Sugae et al., 2008), and more time points were added to compliment the data. Female BALB/cAJcl-nu/nu nude mice (n ¼19) were obtained from CLEA Japan (Tokyo, Japan). At the time of the experiments, all mice were 9–10 weeks of age and weighed 18–22 g. Approximately 1 MBq of [18F]-5-FU was intravenously administered via the tail vein. The mice were euthanized by cervical dislocation under deep anesthesia using isoflurane (Merck, Tokyo, Japan) at 30 min (n ¼7), 60 min (n ¼6) and 120 min (n¼ 6) after radiotracer injection. The organs were harvested, weighed, and counted for radioactivity using a gamma counter (Packard Cobra II, Global Medical Instrumentation, Minneapolis, MN, US). The counted radioactivity was normalized to injected dosage per gram of tissue (%ID/g). Radioactivity of the bone, lung, heart, stomach, small intestine, upper large intestine, lower large intestine, kidney, liver, spleen, pancreas and skeletal muscle were measured to draw TACs. The AUCs of TACs were calculated by trapezoidal integration until 120 min after injection. AUC from 120 min after injection was estimated by the integration to infinity, assuming elimination only by radioactive decay of 18F. AUCs from harvested organs were extrapolated to the OLINDA adult male phantom, following the equation below. ! " ! # g organ % % ðkg TBweight Þanimal ¼ g organ organ human kg TBweight animal human
For the urinary bladder wall estimation, the voiding bladder model included in the OLINDA software was used. Urinary excretion and bladder voiding intervals were set to the same
45
Concentrations of radioactivity (SUV)
40 35
Time after injection (minutes)
30 0
10
20
30
60
120
25 20
15 10 5 0
Fig. 1. SUVs of organ radioactivity derived from sequential PET/CT images of a representative case obtained at 0, 10, 20, 30, 60 and 120 min after administration of [18F]-5-FU. High uptake was seen in the liver, gallbladder and kidneys.
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values that were used in radiation dose calculations for PET/CT in cancer patients.
Table 1 Absorbed organ radiation dose of [18F]5-FU in humans and mice. Organ
5-FU in human mean (mGy/MBq)
SD (mGy/MBq) 5-FU in mouse (mGy/MBq)
Discrepancy (%)
Adrenals Brain Breasts Gallbladder wall LLI wall Small intestine Stomach wall ULI wall Heart wall Kidneys Liver Lungs Muscle Ovaries Pancreas Red marrow Osteogenic cells Skin Spleen Testes Thymus Thyroid Urinary bladder wall Uterus Total body Effective dose (mSv/MBq)
2.82E 02 1.47E 03 2.17E 03 7.99E 02
3.33E 02 1.16E 03 7.11E 04 1.46E 01
3.60E 03 5.06E 03 8.31E 04 5.51E 03
87 244 62 93
4.49E 03 1.14E 02 7.13E 03 9.01E 03 1.14E 02 5.44E 02 7.37E 02 8.54E 03 7.23E 03 5.38E 03 1.53E 02 6.47E 03 4.73E 03
1.05E 03 6.50E 03 2.19E 03 3.43E 03 3.01E 03 2.27E 02 2.06E 02 4.61E 03 2.03E 03 1.46E 03 5.02E 03 1.87E 03 1.37E 03
3.24E 03 3.18E 03 1.73E 03 3.20E 03 3.31E 03 1.68E 02 2.65E 02 3.86E 03 2.16E 03 2.40E 03 4.77E 03 3.56E 03 2.31E 03
28 72 76 64 71 69 64 55 70 55 69 45 51
2.05E 03 1.12E 02 2.20E 03 3.11E 03 3.50E 03 5.30E 02
5.23E 04 2.62E 03 1.26E 03 8.07E 04 1.96E 03 7.63E 03
7.67E-04 3.64E-03 1.33E 03 1.03E 03 7.63E 04 4.37E 02
63 67 39 67 78 18
6.70E 03 6.97E 03 1.21E 02
1.39E 03 1.82E 03 2.82E 03
3.77E 03 2.58E 03 5.82E 03
44 63 52
2.4. Statistical analysis Correlations between human and mouse data were measured by calculating Pearson product–moment correlation coefficients, and were tested at a level of significance of 0.01. The strength of correlation was defined as follows: weak correlation, 0r9r9 o0.3; moderate correlation, 0.3 r9r9 o0.7; and strong correlation, 0.7 r9r9o1.0.
3. Results 3.1. Biodistribution of [18F]-5-FU in human volunteers The mean concentration of radioactivity represented by sequential transition of standardized uptake values (SUVs) of organs derived from sequential PET/CT images in human volunteers is shown in Fig. 1. The representative whole body PET/CT image acquired at 120 min after injection of [18F]-5-FU is shown in Fig. 2. The regions exhibiting the highest [18F]-5-FU uptake were the liver, kidneys, gallbladder, intestine and urinary ducts. [18F]-5-FU was excreted through both the renal and the hepatobiliary systems.
3.2. Radiation dose calculation from PET/CT in human volunteers The estimated absorbed dose of [18F]-5-FU for each organ derived from PET/CT images of human volunteers and from harvested organ radioactivity in mice is shown in Table 1. In the human-derived estimation, the absorbed dose was the highest in the gallbladder wall (0.0799 mGy/MBq), which was followed by the liver (0.0737 mGy/MBq), the kidney (0.0544 mGy/MBq) and the urinary bladder wall (0.0530 mGy/MBq). The mean effective dose was estimated to be 0.0121 mSv/MBq. 3.3. Biodistribution of [18F]-5-FU in mice The mean concentration of radioactivity (%ID/g) in each organ harvested from mice is shown in Fig. 3. [18F]-5-FU accumulation was high in the liver and the kidney, and low in the other organs. The highest accumulation of [18F]-5-FU was observed 30 min after administration and reduced thereafter in all organs, except for the bones. 3.4. Radiation dose calculation from the mouse model The estimated absorbed dose of each organ is shown in Table 1. The highest absorbed dose was found in the urinary bladder wall (0.0437 mGy/MBq), followed by the liver (0.0265 mGy/MBq) and the kidneys (0.0168 mGy/MBq). The mean effective dose was estimated to be 0.00582 mSv/MBq. 3.5. Comparison of biodistribution and estimated absorbed radiation dose in humans and mice Fig. 2. PET-CT of a representative case obtained 120 min after injection. Main regions showing [18F]-5-FU uptake are the liver (asterisks), kidney (white arrows), bile duct and gallbladder (white arrowheads) and urinary ducts (black arrows).
Biodistributions of [18F]-5-FU were similar between humans and mice (high accumulation in the hepatobiliary system and
Concentrations of radioactivity (% ID/g)
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7 6 5 Time after injection (hours)
4 3
0.5h (n=7)
2
1h (n=6) 2h (n=6)
1 0
15
liver and kidneys both in humans and mice. The gallbladder also showed high accumulation in humans, but was not investigated in mice. This high accumulation in the liver may represent the catabolism of 5-FU to alpha-fluoro-beta-alanine (FBAL) by dihydropyrimidine dehydrogenase (DPD). DPD is the initial and ratelimiting metabolic enzyme of 5-FU, and is expressed mainly in the liver. FBAL, an inactivated metabolite of 5-FU, is excreted both into the bile and blood, and is finally excreted in the urine and feces. The high accumulation in the kidneys may represent renal excretion of both unchanged [18F]-5-FU and its [18F]-labeled metabolite, such as [18F]-FBAL, [18F]-FUH2 (dihydrofluorouracil), or [18F]-FUPA (a-fluoro-ureidopropionic acid). High accumulation in the gallbladder may represent biliary excretion of metabolite of [18F]-5-FU, such as [18F]-FBAL, [18F]-FUH2, or [18F]-FUPA, which are excreted from hepatic cells and are drained directly into bile ducts (Kissel et al., 1997; Heggie et al., 1987). 4.2. Radiation safety of [18F]-5-FU in comparison with other [18F] PET ligands
Fig. 3. Mean concentrations of radioactivity (%ID/g) of each organ harvested from mice. [18F]-5-FU accumulation was high in the liver and kidneys, and low in the other organs. The highest accumulation of [18F]-5-FU was observed 30 min after administration, and reduced sequentially in all organs, except for the bones.
Mouse derived organ dose (mGy/MBq)
urinary bladder 0.04
0.03
0.02
0.01
gallbladder
The dose-critical organ estimated from human PET/CT data was the gallbladder wall (which received 0.0799 mGy/MBq). According to FDA guideline 21 CFR 361.1(b)(3)(i), the intravenous administration of [18F]-5-FU is limited to 8.94 MBq/kg per study, and to 26.82 MBq/kg per year in a 70 kg man. This limitation was satisfied in the present study, because PET/CT imaging data were obtained with administration of a sufficiently lower dose of [18F]5-FU than this published limit. The estimated radiation dose to the urinary bladder was also high both in humans and mice, perhaps because of the high excretion of [18F]-5-FU in urine. This suggests that the absorbed radiation dose in the urinary bladder wall and other pelvic organs (such as gonad glands and lower large intestine) can be reduced by sequential voiding of urine. The mean absorbed doses to organs associated with [18F]5-FU and compared with two other widely used [18F]-labeled agents, FDG and fluorothymidine (FLT) in Table 2, to validate the
0 0
0.02
0.04
0.06
0.08
Human derived organ dose (mGy/MBq) Fig. 4. Organ-absorbed radiation doses in humans and mice exhibited moderate positive correlations for all organs (r¼ 0.685; p¼ 3.08E 04), and exhibited strong positive correlations for all organs excepting the gallbladder wall and urinary bladder wall (r ¼ 0.953; p ¼2.36E 11).
kidney, and low accumulation in other organs), but the retention time of [18F]-5-FU was shorter in mice than in humans (Figs. 1 and 3). Comparison of the estimated absorbed radiation dose in each organ between humans and mice is shown in Fig. 4. The estimated radiation dose in mice correlated significantly with that in humans for all organs (r¼0.685; p¼3.08E04), except for the gallbladder wall and urinary bladder wall (without the gallbladder wall and urinary bladder wall, r¼0.953; p¼2.36E 11). In the human gallbladder wall, the dose was approximately 15-fold higher than the dose estimated in mice. The estimated effective dose derived from harvested mouse organ data was underestimated by 51.9%, compared to the human-derived estimated effective dose.
4. Discussion 4.1. Biodistribution of [18F]-5-FU In the present study, the biodistribution of [18F]-5-FU was investigated and compared in humans and mice. The observed biodistribution of [18F]-5-FU revealed a high accumulation in the
Table 2 Comparison of estimated organ absorbed dose derived from [18F]5-FU and other previously reported [18F] labeled PET ligands. Organ
5-FU (mGy/MBq)
FDG (Heggie et al., 1987) (mGy/MBq)
FLT (Protection, 1988) (mGy/MBq)
Adrenals Brain Breasts Gallbladder wall LLI wall Small intestine Stomach wall ULI wall Heart wall Kidneys Liver Lungs Muscle Ovaries Pancreas Red marrow Osteogenic cells Skin Spleen Testes Thymus Thyroid Urinary bladder wall Uterus Total body Effective dose (mSv/MBq)
2.82E 02 1.47E-03 2.17E 03 7.99E 02 4.49E 03 1.14E 02 7.13E 03 9.01E 03 1.14E 02 5.44E 02 7.37E 02 8.54E 03 7.23E 03 5.38E 03 1.53E 02 6.47E 03 4.73E 03 2.05E 03 1.12E 02 2.20E 03 3.11E 03 3.50E 03 5.30E 02 6.70E 03 6.97E 03 1.21E 02
1.20E 02 2.80E 02 8.60E 03 1.20E 02 1.50E 02 1.30E 02 1.10E 02 1.20E 02 6.20E 02 2.10E 02 1.10E 02 1.00E 02 1.10E 02 1.50E 02 1.20E 02 1.10E 02 – 1.10E 02 1.10E 02 1.20E 02 1.10E 02 1.00E 02 1.60E 01 2.10E 02 – 1.90E 02
2.10E 02 3.25E 03 8.13E 03 1.65E 02 1.51E 02 1.47E 02 1.37E 02 1.26E 02 1.62E 02 3.52E 02 4.51E 02 9.61E 03 1.58E 02 – 2.24E 02 2.39E 02 1.55E 02 4.30E 03 1.66E 02 1.45E 02 1.05E 02 9.71E 03 1.79E 01 – 1.23E 02 2.80E 02
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radiation safety. Compared with doses associated with FDG or FLT, the individual organ-absorbed doses associated with [18F]-5FU were higher in the gallbladder wall, liver and kidneys, and lower or equivalent in other organs. The effective dose associated with [18F]-5-FU was lower than those associated with FDG and FLT (Hays et al., 2002; Protection, 1988; Vesselle et al., 2003). This data suggest that the risk of radiation exposure associated with [18F]-5-FU is almost similar to those of widely used PET ligands, and assures the radiation safety of [18F]-5-FU in clinical use.
derived data. For voiding-bladder estimation, the half-life and fractionation of 5-FU and its metabolites were cited from previously reported human data, and the same parameters were adopted for all subjects. Individualized half-life estimation obtained by sequential measurement of [18F]-5-FU activity in the urinary tract could provide a more precise dose estimation.
4.3. Similarity and discrepancies between species
Biodistribution and radiation dosimetry of [18F]-5-FU were compared between humans and mice. The biodistribution in mice was in accordance with that in humans. Mouse data underestimated the effective dose in humans, suggesting that clinical measurements are needed for a more detailed estimation to ensure radiation safety. The observed effective doses suggest the feasibility of [18F]-5-FU PET/CT for human studies.
The biodistribution of [18F]-5-FU appeared to be correlated between humans and mice, and estimated organ radiation doses exhibited a moderate to strong positive correlation between humans and mice. This suggests that mouse-derived data can be used for prediction of the biodistribution and of the radiation critical organ in humans. Although the distribution of [18F]-5-FU corresponded between human and mouse data, the overall absorbed doses in organs (except for brain and effective dose) were underestimated in mouse data compared with humanderived PET/CT data. One reason for this could be that the [18F]-5-FU was metabolized faster by DPD and the residence time of [18F]-5-FU was shorter in the mouse. This could be because the activity of DPD in the liver is higher in mice than in humans (Sludden et al., 1998). This suggests that with estimation of the irradiation dose of new radioactive drugs, simple extrapolation of preclinical mouse data to a human model inevitably has the risk of underestimation or overestimation, and that the error rate is high in organs that participate in metabolism and excretion of the drugs. 4.4. Limitations This study includes some limitations. The biodistribution of [18F]-5-FU was compared in cancer patients and normal mice. The metabolism and biodistribution of [18F]-5-FU might be slightly different between cancer patients and normal human subjects, because the activity of DPD (the rate-limiting enzyme of the degeneration of 5-FU) is modulated both in tumor tissue and normal tissue (Raida et al., 2002; Etienne et al., 1995; McLeod et al., 1998). This difference in biodistribution might have led to a slight modulation of the absorbed doses in different organs and of the overall effective dose. The administrated dose of [18F]-5-FU per body weight was quite different between mice and humans, and this difference might also have modulated the biodistribution slightly. For radiation dose estimation that was derived from experimental animal data, organs were collected from mice at 30, 60 or 120 min after administration of [18F]-5-FU. However, considering the fast metabolism of 5-FU in the mouse body, measurements at earlier time points would have been helpful for a more reliable extrapolation (Sludden et al., 1998). The absorbed dose of the mouse gastrointestinal tract has the possibility of inherent underestimation due to technical error, since some of the radioactive contents in the feces can be lost during the organharvesting process. The absorbed dose of the mouse gallbladder could have been underestimated, because gallbladders were not harvested in this study. To estimate the absorbed dose of the gallbladder in human subjects, TACs from 0 to 120 min were integrated, and the dose at 120 min was integrated to infinity assuming elimination only by radioactive decay. This might have led to overestimation of the absorbed dose of the gallbladder, because the [18F]-5-FU in bile might have gradually drained into duodenum, and further through the small intestine and colon. To estimate urinary tract absorption, the voiding-bladder model in the OLINDA software was adopted for both human- and mouse-
5. Conclusion
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