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CLINICAL INVESTIGATIONS |
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Key Words: 64Cu • octreotide • PET • 111In
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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An attractive radionuclide for PET imaging is 64Cu (half-life, 12.7 h; 39% ß- [0.579 MeV]; 17.4% ß+ [0.653 MeV]; 43.6% electron capture). 64Cu can be produced by either a reactor (4) or a medical cyclotron (5). Recently, a method was developed at Washington University School of Medicine to produce large quantities of 64Cu (up to 37 GBq) on demand using a biomedical cyclotron (5). 64Cu also has shown potential as a therapeutic radionuclide. In radioimmunotherapy studies, we showed that 64Cu-labeled monoclonal antibody 1A3 caused complete tumor regression with no regrowth of tumors in a well-established animal model (6,7).
We showed that 64Cu-TETA-OC (where TETA is 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid) had a similar biodistribution to 111In-DTPA-OC in a tumor-bearing rat model (8). In targeted radiotherapy studies, 64Cu-TETA-OC inhibited the growth of tumors in the same tumor-bearing rat model (9). PET imaging of tumors using low doses of 64Cu-TETA-OC could also be used to determine individual absorbed doses before therapy with either 64Cu- or 67Cu-labeled OC. For these reasons, we are investigating 64Cu-TETA-OC as a PET imaging agent for patients with neuroendocrine tumors.
In this study, we compared 64Cu-TETA-OC and PET with 111In-DTPA-OC and conventional scintigraphy in eight patients with a history of neuroendocrine tumors. The blood and urine clearance of 64Cu-TETA-OC was determined, and absorbed doses to normal organs were measured from the PET images.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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111In-DTPA-OC was prepared using the OctreoScan kit provided by the manufacturer (Mallinckrodt, Inc., St. Louis, MO). Patients received an injection of 204–233 MBq (5.5–6.3 mCi) 111In-DTPA-OC labeled to 10 µg DTPA-OC.
Patients
Patients who were scheduled for routine imaging with 111In-DTPA-OC were eligible for 64Cu-TETA-OC and PET. Eight patients (six men, two women; age range, 45–70 y) with a history of neuroendocrine tumors who were being evaluated with 111In-DTPA-OC as part of their routine clinical evaluation also underwent PET with 64Cu-TETA-OC at our institution. This investigation was approved by the Human Studies Committee and the Radioactive Drug Research Committee at Washington University School of Medicine. Each patient gave informed consent before participating in the study. In all patients but one, the 111In-DTPA-OC was administered before 64Cu-TETA-OC. The time between administration of 111In-DTPA-OC and 64Cu-TETA-OC ranged from -1 to 40 d (mean time, 14 d).
Imaging
PET imaging was performed with an ECAT EXACT scanner (Siemens/CTI, Knoxville, TN). Single-photon imaging was also performed on each patient using a dual-head Genesys scanner (ADAC Laboratories, Milpitas, CA) fitted with medium-energy collimators. Conventional scintigraphy was performed after injection of 204–233 MBq (5.5–6.3 mCi) 111In-DTPA-OC. All patients underwent whole-body planar scintigraphy at 4 and 24 h. The whole-body planar study consisted of anterior and posterior views proceeding from head to toe at 6 cm/min. All but one patient underwent SPECT (imaging of the chest and abdomen at 24 h in one patient and at 4 and 24 h in one patient; imaging of only the abdomen at 24 h in two patients, at 4 h in one patient, and at 4 and 24 h in two patients). Full-field SPECT was performed without attenuation correction on the chest and abdomen for 20 min each. On a separate day, PET was performed after intravenous injection of approximately 111 MBq (3.0 mCi) 64Cu-TETA-OC in an antecubital vein. Delay intervals ranging from 0 to 24 h between injection and imaging were evaluated, from which an optimal delay of 4–5 h was selected as providing the best combination of image quality and lesion-to-background contrast. Five of the eight PET studies were performed to estimate the radiation dosimetry of 64Cu-TETA-OC. In these patients, the entire torso was scanned to allow complete determination of the activity biodistribution throughout the body. In the other three patients, only a single bed position was used, covering 16 cm axially around the suspected tumor region. At each bed position, the study consisted of static (if delayed) or dynamic (if at injection) data acquisition, 20 min in duration, followed by a 2- to 3-min transmission scan. From the transmission scan, segmented attenuation maps were derived (10) and used to apply full attenuation correction to the emission image volume. PET and SPECT images were reconstructed using filtered backprojection (Hanning filter, cutoff of 0.8 Nyquist) and were volume rendered for cinegraphic viewing.
The 111In-DTPA-OC and 64Cu-TETA-OC images were examined qualitatively. The criteria for interpretation were those routinely used in scintigraphic imaging. The PET images were examined by a nuclear medicine physician, and the interpretation of the images was based on knowledge of normal biodistribution of 64Cu-TETA-OC derived from animal models. Foci of abnormal radiotracer uptake were recorded on a four-point scale (0 = no uptake; + = mild uptake; ++ = moderate uptake; and +++ = intense uptake).
Measurement of 64Cu Activity in Blood and Urine of Patients
64Cu activity in the blood and urine was measured in a gamma counter (Beckman, Arlington Heights, IL) containing a NaI crystal. Two blood samples were drawn per patient at times ranging from 1.5 to 22 h after injection of 64Cu-TETA-OC. Urine was collected from patients (from two to six samples per patient) at times ranging from 1.5 to 27 h after injection.
Human Absorbed Dose Measurements from Patient PET Images
For evaluation of biodistribution and calculation of dosimetry, five of the eight PET studies involved imaging the chest and abdomen at different times (0 and 4 h in two patients, 5 and 24 h in two patients, and 5 h in one patient) after administration of 64Cu-TETA-OC. All but one of the patients were imaged twice.
Activity was observed mainly in the liver, spleen, kidneys, bladder, and tumors. Regions of interest (ROIs) were drawn on the PET images of the five dosimetry study patients to measure the total activity in these organs. For the liver, the average activity concentration was calculated from ROIs traced inside and encompassing most of the organ for five to six adjacent slices. The average activity concentration in the liver was then multiplied by the estimated liver volume. For the other visible organs, ROIs were drawn around the entire organ. The total activity in these organs was thus directly measured. In addition, ROIs were traced around the heart to evaluate the activity concentration in the blood. The blood activity concentration was measured by the average maximum value in the slices containing the lower left ventricle. Finally, elliptic ROIs were drawn in several adjacent slices of the lower abdomen beside the bladder to measure the average soft-tissue activity concentration. The red marrow activity concentration, Arm, was calculated from the blood activity concentration, Abl, in proportion to the mass of the red marrow, mrm, and assuming a hematocrit value of 39%, as follows (11): Arm = Ablmrm0.19/(1 - 0.39).
Measurements were repeated for each time point. The percentage of injected activity in each organ immediately after the injection (at to+) was calculated from its estimated blood volume. This decision was based on the assumption that the bolus of activity distributes uniformly throughout the body immediately after the injection. The fractions of injected activity at to+ were 4.9% for the liver, 5.9% for the lungs, 1.5% for the spleen, 1.4% for the kidneys, 3.7% for the bones, and 10% for the heart.
A time–activity curve was drawn for each organ combining the data from all patients. The measured organ activities were corrected for decay to the time of the start of the scan to simplify the subsequent fitting procedure. The time–activity curves were fitted with a sum of one or two exponentials in which the parameters were determined by a least squares minimization procedure. The fitted functions were then integrated analytically (including physical decay) to give the residence times. Dose calculation was performed by the MIRD methodology in which the S values were calculated with the MIRDOSE3.0 program using the adult male model. Along with any unaccounted activity, the soft-tissue activity and 72% of the blood activity were assigned to the remainder of the body as a MIRD source organ. Although some activity was seen to accumulate in the tumors, this contribution could not be included under the MIRD scheme. Instead, the tumor activity was assumed to be distributed uniformly throughout the body. An uptake function was fitted to the time-cumulated urine data from all patients. The absorbed fraction and the filling half-time were used in the MIRDOSE3 bladder model (12) along with a voiding period of 4 h to obtain the residence time of the bladder contents.
Human Absorbed Dose Estimates from Baboon PET Images
The biodistribution of 64Cu-TETA-OC was also determined in a 25-kg male baboon by PET imaging. This study was performed in compliance with the Guidelines for the Care and Use of Research Animals established by the Animal Studies Committee of Washington University School of Medicine. Images of the animal’s torso were acquired at approximately 30-min intervals from 0 to 3 h and then again at 24 h after injection. The baboon was anesthetized with isoflurane during the first 3-h imaging session and then was allowed to recover. The baboon was placed in approximately the same position the following day, anesthetized with isoflurane, and imaged for 30 min. Activity concentration values were derived from the PET images as previously described (13). The absorbed fraction and filling half-time were used in the MIRDOSE3 bladder model (12) along with a voiding period of 4 h to obtain the residence time of the bladder contents.
Blood samples were collected from the baboon at 6, 20, 40, 60, and 120 min after injection of 64Cu-TETA-OC. The percentage injection dose (%ID) in the blood at those times was determined, and the data were used to determine blood clearance.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Absorbed Dose Estimates from Baboon Imaging
PET imaging of a nonhuman primate was performed to estimate the human absorbed doses before beginning human PET imaging studies. The estimated human absorbed doses from the baboon PET images, in comparison with estimated human absorbed doses from rat biodistribution data (9), are listed in Table 1. The baboon PET data suggest that the dose-limiting organ is the bladder wall (0.17 mGy/MBq [0.62 rad/mCi]), followed by the kidneys (0.13 mGy/MBq [0.49 rad/mCi]). The largest discrepancy between dosimetry calculated from rats to baboons is in the intestinal absorbed doses. Rodents show excretion patterns significantly different from those of primates, and this fact is indicated by the data.
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Pharmacokinetic Analysis
Blood samples were obtained from patients during their imaging sessions. 64Cu-TETA-OC cleared rapidly from the blood. The amount in the blood varied from patient to patient; however, by 4 h after injection, 7.9 ± 3.7 %ID remained (range, 3.2–13.5 %ID). From 6 to 22 h after injection, the activity in the blood decreased further, with the amount in the blood ranging from 0.8 to 6.6 %ID (mean, 3.3 ± 2.3 %ID). The large differences in blood-pool data are most likely related to patient-to-patient variation, possibly because of differing tumor burden. Urine excretion also varied between patients. During the first 4 h after injection, the amount excreted in the urine was 44.6 ± 10.6 %ID, and the amount during 27 h was 63.7 ± 18.6 %ID.
Human Dosimetry from Patient PET
Using PET data from five patients, the absorbed doses of 64Cu-TETA-OC to the normal organs were measured. Time–activity curves are shown in Figure 3. Residence times were determined for seven tissues in which most of the 64Cu activity was localized, and they are listed in Table 3. From these data, the absorbed doses listed in Table 1 were determined. Residence times measured in the organs listed in Table 3 account for 35% of the maximum residence time, whereas 47% of activity was excreted in the urine. As predicted from the estimated absorbed doses from the rodent and baboon PET data, the human PET data indicate that the bladder wall is the dose-limiting organ, with an absorbed dose of 0.25 mGy/MBq (0.94 rad/mCi). This dose was calculated assuming emptying of the bladder at 4 h after injection. Other organs with higher absorbed doses include the liver (0.092 mGy/MBq [0.34 rad/mCi]), kidneys (0.078 mGy/MBq [0.29 rad/mCi]), and spleen (0.070 mGy/MBq [0.26 rad/mCi]). The intestinal dose was relatively low, as was the dose to the bone marrow.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Urinary excretion of 111In-DTPA-OC has been reported by several investigators (3,15,16). Although the reports vary, generally the total excretion during 24 h ranged from 65 to 85 %ID. In a study of 10 patients, Krenning et al. (3) reported a mean cumulative urinary excretion of 25 %ID at 3 h, 50 %ID at 6 h, and 85 %ID at 24 h. The cumulative urinary excretion of 64Cu-TETA-OC was similar to that of 111In-DTPA-OC, for which excretion was 26.0 ± 12.3 %ID at 2 h, 44.6 ± 10.6 %ID at 4 h, and 63.7 ± 18.6 %ID at 27 h after injection. A few patients had an extensive tumor burden, and they excreted less 64Cu-TETA-OC.
Blood clearance of 64Cu-TETA-OC was similar to that of 111In-DTPA-OC at the earlier times; however, 111In-DTPA-OC cleared to a greater extent from the blood at later times. In a comparison study between 111In-DTPA-OC and 111In-DOTA-Tyr3-OC, both agents showed approximately 10 %ID in the blood at 2 h after injection, with approximately 1 %ID remaining at 24 h (16). We observed approximately 8 %ID at 4 h, with clearance to approximately 3 %ID at 22 h after injection. The retention of 64Cu in the blood was not entirely surprising, because we found that in rats, 64Cu-TETA-OC also did not completely clear from the circulation (8). Recently, using a superoxide dismutase–specific assay, we showed that in rat liver, 64Cu dissociates from 64Cu-TETA-OC and binds to superoxide dismutase (17). Mirick et al. (18) reported that 67Cu-BAT-2IT-Lym-1 (where BAT = 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid and 2IT = 2-iminothiolane) dissociated and that 67Cu bound to ceruloplasmin, causing retention of 67Cu in the blood. In the patients administered 64Cu-TETA-OC, some dissociation of 64Cu likely occurred, with subsequent binding to plasma proteins. Future patient PET imaging studies will include metabolite analyses of blood and urine.
A preliminary evaluation of absorbed doses in normal organs, performed by averaging PET data from five patients, showed that the urinary bladder was the dose-limiting organ (0.25 mGy/MBq [0.94 rad/mCi]). This finding was predicted from human absorbed dose measurements estimated from rat biodistribution and baboon PET imaging data. The dose to the urinary bladder using baboon PET imaging data and human PET data was determined using the MIRDOSE3 bladder model (12) along with a voiding period of 4 h to obtain the residence time of the bladder contents. If patients were to be given intravenous fluids or asked to drink large quantities of fluids, the voiding time could be decreased to 1 h, which would reduce the absorbed dose to 0.062 mGy/MBq (0.23 rad/mCi). The liver would than be the dose-limiting organ (0.091 mGy/MBq [0.34 rad/mCi]).
Although the human absorbed dose estimates from rats, nonhuman primates, and humans indicate the bladder wall to be the dose-limiting organ, significant differences are seen when different species are used to estimate dosimetry. The use of rodent biodistribution data is generally thought to give a worst-case estimate of absorbed doses to normal organs; however, the data in Table 1 suggest that the use of rat biodistribution data underestimates the dose to the liver and spleen. As shown in Figure 3D, the percentage injected activity of 64Cu-TETA-OC in the liver increases over time. 64Cu may dissociate from the TETA chelator in human liver to a greater extent than it does in rat or baboon liver, and this dissociation may be responsible for the higher absorbed dose. The human dosimetry data also show the spleen to have a considerably higher absorbed dose than was extrapolated from rodent and baboon data. One proposal is that somatostatin regulates immune function in humans and that, therefore, SSRs are present in the spleen (19). The cumulative time–activity curve for the spleen (Fig. 3E) shows that the data are highly variable among the different patients, and a large error is therefore associated with the absorbed dose value. The absorbed dose to the spleen from 111In-DTPA-OC measured in humans is consistent with our data obtained with 64Cu-TETA-OC and PET (15).
Overall, the normal-organ dosimetry suggests that PET imaging with 111 MBq (3 mCi) 64Cu-TETA-OC gave reasonable absorbed doses to normal organs, with the urinary bladder (the critical organ) receiving less than 20 mGy (3 rad). In future PET imaging studies, the administered dose will be raised to approximately 518 MBq (14 mCi) and the patients will be asked to drink large quantities of fluids and to void frequently. We anticipate that these changes will provide higher image quality with less than 50 mGy (5 rad) to the urinary bladder or liver.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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For correspondence or reprints contact: Carolyn J. Anderson, PhD, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd., Campus Box 8225, St. Louis, MO 63110.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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= values determined from PET data; • = patient 1; 
= patient 2; 
= patient 6; 
= patient 7; and 
= patient 8.