Multimodality image registration quality assurance for conformal three-dimensional treatment planning.

PURPOSE: We present a quality assurance methodology to determine the accuracy of multimodality image registration and fusion for the purpose of conformal three-dimensional and intensity-modulated radiation therapy treatment planning. Registration and fusion accuracy between any combination of computed tomography (CT), magnetic resonance (MR), and positron emission computed tomography (PET) imaging studies can be evaluated. METHODS AND MATERIALS: A commercial anthropomorphic head phantom filled with water and containing CT, MR, and PET visible targets was modified to evaluate the accuracy of multimodality image registration and fusion software. For MR and PET imaging, the water inside the phantom was doped with CuNO(3) and 18F-fluorodeoxyglucose (18F-FDG), respectively. Targets consisting of plastic spheres and pins were distributed throughout the cranium section of the phantom. Each target sphere had a conical-shaped bore with its apex at the center of the sphere. The pins had a conical extension or indentation at the free end. The contours of the spheres, sphere centers, and pin tips were used as anatomic landmark models for image registration, which was performed using affine coordinate-transformation tools provided in a commercial multimodality image registration/fusion software package. Four sets of phantom image studies were obtained: primary CT, secondary CT with different phantom immobilization, MR, and PET study. A novel CT, MR, and PET external fiducial marking system was also tested. RESULTS: The registration of CT/CT, CT/MR, and CT/PET images allowed correlation of anatomic landmarks to within 2 mm, verifying the accuracy of the registration software and spatial fidelity of the four multimodality image sets. CONCLUSIONS: This straightforward phantom-based quality assurance of the image registration and fusion process can be used in a routine clinical setting or for providing a working image set for development of the image registration and fusion process and new software.

64Cu-TETA-octreotide as a PET imaging agent for patients with neuroendocrine tumors.

UNLABELLED: 64Cu (half-life, 12.7 h; beta+, 0.653 MeV [17.4%]; beta-, 0.579 MeV [39%]) has shown potential as a radioisotope for PET imaging and radiotherapy. (111)In-diethylenetriaminepentaacetic acid (DTPA)-D-Phe1-octreotide (OC) was developed for imaging somatostatin-receptor-positive tumors using conventional scintigraphy. With the advantages of PET over conventional scintigraphy, an agent for PET imaging of these tumors is desirable. Here, we show that 64Cu-TETA-OC (where TETA is 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid) and PET can be used to detect somatostatin-receptor-positive tumors in humans. METHODS: Eight patients with a history of neuroendocrine tumors (five patients with carcinoid tumors and three patients with islet cell tumors) were imaged by conventional scintigraphy with (111)In-DTPA-OC (204-233 MBq [5.5-6.3 mCi]) and by PET imaging with 64Cu-TETA-OC (111 MBq [3 mCi]). Blood and urine samples were collected for pharmacokinetic analysis. PET images were collected at times ranging from 0 to 36 h after injection, and the absorbed doses to normal organs were determined. RESULTS: In six of the eight patients, cancerous lesions were visible by both (111)In-DTPA-OC SPECT and 64Cu-TETA-OC PET. In one patient, (111)In-DTPA-OC showed mild uptake in a lung lesion that was not detected by 64Cu-TETA-OC PET. In one patient, no tumors were detected by either agent; however, pathologic follow-up indicated that the patient had no tumors. In two patients whose tumors were visualized with (111)In-DTPA-OC and 64Cu-TETA-OC, 64Cu-TETA-OC and PET showed more lesions than (111)In-DTPA-OC. Pharmacokinetic studies showed that 64Cu-TETA-OC was rapidly cleared from the blood and that 59.2% +/- 17.6% of the injected dose was excreted in the urine. Absorbed dose measurements indicated that the bladder wall was the dose-limiting organ. CONCLUSION: The high rate of lesion detection, sensitivity, and favorable dosimetry and pharmacokinetics of 64Cu-TETA-OC indicate that it is a promising radiopharmaceutical for PET imaging of patients with neuroendocrine tumors.

Radiotherapy and dosimetry of 64Cu-TETA-Tyr3-octreotate in a somatostatin receptor-positive, tumor-bearing rat model.

64Cu [T1/2 = 12.8 h; beta+ = 0.655 MeV (19%); beta- = 0.573 MeV (40%)] has shown promise as a radioisotope for targeted radiotherapy. It has been demonstrated previously that the somatostatin analogue 64Cu-TETA-octreotide (64Cu-TETA-OC, where TETA is 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid) significantly inhibited the growth of somatostatin receptor-positive CA20948 rat pancreatic tumors in Lewis rats (C. J. Anderson et al., J. Nucl. Med., 39: 1944-1951, 1998). In this study, we evaluated the radiotherapeutic efficacy of a new 64Cu-labeled somatostatin analogue, 64Cu-TETA-Tyr3-octreotate (64Cu-TETA-Y3-TATE), in CA20948 tumor-bearing rats. A single dose of 15 mCi (555 MBq) of 64Cu-TETA-Y3-TATE was shown to be more effective in reducing tumor burden than the same dose of 64Cu-TETA-OC. In multiple dose experiments, tumor-bearing rats were administered three doses of either 10 or 20 mCi (370 or 740 MBq) of 64Cu-TETA-Y3-TATE at 48-h intervals. Rats given 3x10 mCi (3x370 MBq) showed extended mean survival times compared with rats given a single dose; however, no complete regressions occurred. Complete regression of tumors was observed for all rats treated with 3x20 mCi (3x740 MBq), with no palpable tumors for approximately 10 days; moreover, the mean survival time of these rats was nearly twice that of controls. Toxicity was determined by physical appearance and hematological and enzyme analysis, which revealed no overt toxicity and only transient changes in blood and liver chemistry. Absorbed dose estimates showed the dose-limiting organ to be the kidneys. The radiotherapy results, along with absorbed dose estimates to target and clearance organs, confirm that 64Cu-labeled somatostatin analogues warrant continued consideration as agents for targeted radiotherapy.

High purity production and potential applications of copper-60 and copper-61.

Previously we described the high yield production of 64Cu using a target system designed specifically for low energy, biomedical cyclotrons. In this study, the use of this target system for the production of 60Cu and 61Cu is described and the utility of these isotopes in the labeling of biomolecules for tumor and hypoxia imaging is demonstrated. 60Cu and 61Cu were produced by the 60Ni(p,n)60Cu, 61Ni(p,n)61Cu, and 60Ni(d,n)61Cu nuclear reactions. The nickel target (>99% enriched or natural nickel) was plated onto a gold disk as described previously (54-225 microm thickness) and irradiated (14.7 MeV proton beam and 8.1 MeV deuteron beam). The copper isotopes were separated from the nickel via ion exchange chromatography and the radioisotopic purity was assessed by gamma spectroscopy. Yields of up to 865 mCi of 60Cu have been achieved using enriched 60Ni. 61Cu has been produced with a maximum yield of 144 mCi using enriched 61Ni and 72 mCi using enriched 60Ni. Specific activities (using enriched material) ranged from 80 to 300 mCi/microg Cu for 60Cu and from 20 to 81 mCi/microg Cu for 61Cu. Bombardments of natural Ni targets were performed using both protons and deuterons. Yields and radioisotopic impurities were determined and compared with that for enriched materials. 60Cu was used to radiolabel diacetyl-bis(N4-methylthiosemicarbazone), ATSM. 60Cu-ATSM was injected into rats that had an occluded left anterior descending coronary artery. Uptake of 60Cu-ATSM in the hypoxic region of the heart was visualized clearly using autoradiography. In addition, 60Cu-ATSM was injected into dogs and excellent images of the heart and heart walls were obtained using positron emission tomography (PET). 61Cu was labeled to 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid-octreotide (TETA-octreotide) and the PET images of tumor-bearing rats were obtained up to 2 h postinjection. After decay of the 61Cu, the same rat was injected with 64Cu-TETA-octreotide and the images were compared. The tumor images obtained using 61Cu were found to be superior to those using 64Cu as predicted based on the larger abundance of positrons emitted by 61Cu vs. 64Cu.

Radiotherapy, toxicity and dosimetry of copper-64-TETA-octreotide in tumor-bearing rats.

UNLABELLED: The efficacy of 64Cu [T1/2 = 12.7 hr; beta+ (0.655 MeV; 19%); beta- (0.573 MeV; 40%)] as a radioisotope for radiotherapy has been recently established. Here we demonstrate that 64Cu-1,4,8,11 -tetraazacyclotetradecane-N,N',N",N'''-tetraacetic acid (TETA)-octreotide, a somatostatin receptor ligand, inhibits the growth of CA20948 rat pancreatic tumors in Lewis rats at doses that cause minimal toxicity. METHODS: Tumor-bearing rats were administered a single 15 mCi (555 MBq) dose, a fractionated dose of 15 mCi given in 2-3 doses over 2-8 days, or control agents of buffer, unlabeled octreotide or 64Cu-labeled TETA. In certain experiments, blood was removed at times from 4-23 days post-treatment, and a complete blood count along with blood chemistry analyses were obtained. RESULTS: Tumor-growth inhibition was significantly greater in rats injected with a single 15 mCi dose than in rats injected with control agents (p < 0.05). Dose fractionation in two doses, either 1 or 2 days apart, induced significantly increased tumor-growth inhibition compared with rats given a single dose (p < 0.05). The only toxicity observed in treated rats was a decrease in the white blood cell count. This drop was more pronounced in rats treated with a single dose compared with those treated with a fractionated dose. Human absorbed doses of 64Cu-TETA-octreotide to normal organs were estimated from biodistribution data in Lewis rats, and these data indicate that radiotherapy with 64Cu-TETA-octreotide in humans would be feasible. CONCLUSION: Copper-64-TETA-octreotide is a promising radiopharmaceutical for targeted radiotherapy of somatostatin receptor-positive tumors.

Radiation dosimetry of [18F] (N-methyl)benperidol as determined by whole-body PET imaging of primates.

Radiation absorbed doses due to IV administration of [18F](N-methyl) benperidol ([18F]NMB) were estimated by whole-body PET imaging of nonhuman primates. Time-activity curves were obtained for nine compartments (striatum, eyes, heart, lungs, liver, gallbladder, intestines, kidneys, bladder) by using dynamic PET scans of three different baboons given the radiotracer. These time-activity curves were used to calculate the residence times of radioactivity in these tissues. Human absorbed dose estimates were calculated using the updated MIRDOSE 3 S values and assuming the same biodistribution. Based on an average of three studies, the critical organs were the lower large intestine, gallbladder, and liver, receiving doses of 585, 281, and 210 mrad/mCi, respectively. The brain received a dose of 13 mrad/mCi; other organs received doses between 32-77 mrad/mCi. These results indicate that up to 8.5 mCi of [18F]NMB can be safely administered to human subjects for PET studies of D2 receptor binding.

Strategies to improve 3D whole-body PET image reconstruction.

An algorithm is described for three-dimensional whole-body (3DWB) image reconstruction in positron emission tomography. For whole-body applications, improvements to the popular fixed-axial-acceptance-angle technique are achieved by combining axially adjacent projection data available with a long-axis data set. Time-consuming reprojection of unmeasured oblique lines of response is reduced or eliminated by axial overlap of bed positions, while pixel variance and reconstructed axial resolution are made more uniform by the overlap. Improvements in noise and resolution uniformity are accompanied by gains in reconstruction efficiency, and may be optimized against increased acquisition-time due to overlapping acquisition segments and reduced axial coverage. An 11-detector-ring overlap improves axial uniformity in coronal images of a long, uniform cylinder from 23% to 8% with uniform axial resolution. Associated with a 37% improvement in reconstruction time is a 34% reduction in axial coverage for four bed positions. A smaller degree of overlap is found to provide the best trade-off between image uniformity, total scan duration, and reconstruction time because of a proportionally greater reduction in reprojected lines of response. Using a sample optimization scheme, we find a three-ring overlap is best for a 60 cm axial field of view and a five-ring overlap for an 80 cm axial field of view.

Preclinical evaluation of fluorine-18-labeled androgen receptor ligands in baboons.

UNLABELLED: A noninvasive method for detecting and quantifying androgen receptors (AR) in metastatic prostate cancer may be helpful in choosing the method of treatment and in better understanding the pathophysiology of this disease. Nine previously synthesized fluorinated androgens exhibited high affinity binding to AR and showed AR-mediated uptake in the ventral and dorsal prostate of the rat. Further evaluation of these agents for PET imaging is needed since sex hormone binding globulin (SHBG), a glycoprotein which binds androgens with high affinity, is absent in rat blood but is present at high levels in the blood of primates. We chose to study three of the nine fluoro-androgens by PET in the baboon. METHODS: In this study, 16beta-[18F]fluoro-5 alpha-dihydrotestosterone (I), 16beta-[18F]fluoromibolerone (II) and 20-[18F]fluoromibolerone (III) were synthesized and studied in both a young and old male baboon using PET. Blood samples were withdrawn in three of the 10 studies and analyzed for total radioactivity and percent unmetabolized radioligand. Tissue radioactivity was evaluated semiquantitatively, using prostate absolute, standard and target to nontarget uptake values. RESULTS: Prostate uptake was observed with all three 18F-androgens. At 60 min postinjection, compound I gave the highest prostate to soft tissue ratios in both baboons and prostate uptake was shown to be AR-mediated by blocking uptake through the coadministration of testosterone. Compound I gave the highest level of unmetabolized radioligand present in blood up to 45 min postinjection, and gave a 37-fold greater prostate-to-bone ratio at 2 hr postinjection in baboons compared to rats. The favorable behavior of this compound in the baboon may be related to its high affinity for SHBG. CONCLUSION: All three compounds can be used to determine AR-positive tissue in primates. Compound I was selected for the evaluation of AR in men with prostate cancer using PET.

Dosimetry of copper-64-labeled monoclonal antibody 1A3 as determined by PET imaging of the torso.

UNLABELLED: We present biodistribution and dosimetry results for 64Cu-benzyl-TETA-MAb 1A3 from 15 human subjects injected with this tracer as determined by serial PET imaging of the torso. METHODS: PET imaging was used to quantify in vivo tracer biodistribution at two time points after injection. Absorbed dosimetry calculated using MIRD-11 and the updated MIRDOSE3 was compared with estimates obtained using rat biodistribution data. RESULTS: By measuring activity concentrations in the torso, and extrapolating for the whole body using standard organ and tissue volumes, we were able to account for 93% of the injected radiopharmaceutical over a range of imaging times from 0 to 36 hr postinjection. Based on PET imaging and the MIRD-11 schema, the liver and spleen are the critical organs with average absorbed doses of 0.12 and 0.10 mGy/MBq (0.44 and 0.39 rad/mCi). The revised MIRDOSE3 scheme yields similar values for these and other organs but also results in a dose of 0.14 mGy/MBq (0.53 rad/mCi) to the heart wall. In the rat, the large intestine is the critical organ at 0.14 mGy/MBq (0.52 rad/mCi), while liver and kidneys each receive 0.11 mGy/MBq (0.41 rad/mCi). Some disparities in absorbed doses determined by these methods are evident but are a result of dissimilar biodistributions in rats and humans. For most organs, rat extrapolated values are higher than the human measurements with PET. CONCLUSION: This study shows that torso PET imaging can quantitatively measure the whole-body biodistribution of a radiopharmaceutical as long as it has relatively slow pharmacokinetics.

Positron tomographic assessment of estrogen receptors in breast cancer: comparison with FDG-PET and in vitro receptor assays.

UNLABELLED: The purpose of this study was to assess the results of PET with 16 alpha-[18F]fluoro-17 beta-estradiol (FES) and [18F]fluoro-2-deoxy-D-glucose (FDG) to validate the concordance between tumor estrogen-receptor (ER) status as determined by FES-PET and in vitro assays and to assess the relationship between tumor metabolic activity determined by FDG-PET and tumor ER status, both of which may provide information about tumor aggressiveness and prognosis. METHODS: We studied 32 patients with primary breast masses and 21 patients with clinical or radiological evidence of recurrent/metastatic breast carcinoma. A diagnosis of breast carcinoma was subsequently proven in 43 patients (24 primary, 15 metastatic and 4 recurrent tumors). In vitro assessment of ER status was available for 40 malignant lesions (23 primary and 17 metastatic/recurrent). The patients underwent PET with both FES and FDG, and the uptake of each tracer within each lesion was evaluated qualitatively as well as semiquantitatively using the standardized-uptake-value (SUV) method. RESULTS: We found good overall agreement (88%) between in vitro ER assays and FES-PET. This degree of agreement is similar to that observed between replicate in vitro assays (with discordances due to interlaboratory, interassay and specimen variability). We were, however, unable to demonstrate any significant relationship between tumor FDG uptake and ER status or between tumor FDG and tumor FES uptake in these patients. CONCLUSION: These results indicate that in vitro ER assays and/or FES-PET provide unique direct information about breast cancer ER status that cannot be obtained indirectly by FDG-PET.

RadioimmunoPET: detection of colorectal carcinoma with positron-emitting copper-64-labeled monoclonal antibody.

UNLABELLED: Detection of tumor foci may be improved by combining the selective tumor-targeting properties of a monoclonal antibody with the superior sensitivity and contrast resolution of PET. METHODS: An anti-colorectal carcinoma monoclonal antibody (MAb 1A3) was labeled with 64Cu, a positron-emitting radionuclide, by use of a bifunctional chelate (bromoacetamidobenzyl-TETA) and evaluated in 36 patients with suspected advanced primary or metastatic colorectal cancer. After radiopharmaceutical injection (5-20 mg protein, 10 mCi 64Cu), PET was performed once or twice, 4 to 36 hr later. All patients had CT scans and 18 patients were also studied with [18F]fluorodeoxyglucose (FDG) PET. RESULTS: In 29 patients, one or more tumor sites (n = 56) were proven, in 5 patients the absence of active tumor was confirmed and in the remaining 2, tumor status is not yet confirmed. Of the 56 confirmed tumor sites, 40 were detected by MAb-PET as foci of increased activity (sensitivity 71%). The positive predictive value of MAb-PET was excellent, ranging from 89% (40/45) to 96% (43/45), depending on the ultimate classification of three image-positive, but as yet unconfirmed tumor sites. Also, MAb-PET detected 11 new occult tumor sites, including 9 small abdominopelvic foci less than 2.0 cm in diameter that were not detected by CT or MRI. There were no complications, but significantly elevated HAMA titers were found in 28% of the 29 patients tested 1 to 12 mo after injection. There was no apparent dose-related effect from 5 to 20 mg MAb 1A3. CONCLUSION: These Phase I/II results suggest that PET with radiolabeled MAbs (radioimmunoPET) may have important applications in clinical oncology, particularly for detecting smaller colorectal tumor foci in the abdomen or pelvis and for determining accurate dosimetry.

Preparation, biodistribution and dosimetry of copper-64-labeled anti-colorectal carcinoma monoclonal antibody fragments 1A3-F(ab')2.

UNLABELLED: Antibody fragments labeled with a radiometal using bifunctional chelates generally undergo renal clearance followed by trapping of the metabolites, leading to high radiation doses to the kidneys. Copper-64-labeled BAT-2IT-1A3-F(ab')2 was recently reported to accumulate in colorectal tumors in an animal model, however, kidney uptake was also high. In this study, the preparation of 64Cu-BAT-2IT-1A3-F(ab')2 was optimized to reduce the renal uptake. METHODS: The bifunctional chelate 6-bromoacetamidobenzyl-1,4,8,11-tetraazacyclotetradecane-N,N ',N",N'"-tetraacetic acid (BAT) was conjugated to 1A3-F(ab')2 using the linking agent 2-iminothiolane (2IT). The conjugation reaction produced 20% of a lower molecular weight (molecular wieght) impurity found to be TETA-1A3-Fab'. The conjugation procedure was optimized to include FPLC purification of the BAT-2IT-1A3-F(ab')2 from TETA-1A3-Fab' after conjugation prior to labeling with 64Cu. The biodistribution of 64Cu-labeled FPLC-purified and unpurified conjugates was determined in normal Sprague-Dawley rats and tumor bearing Golden Syrian hamsters. Human absorbed doses were calculated from rat biodistribution data and PET imaging of a baboon. RESULTS: Upon FPLC purification of the BAT-2IT-1A3-F(ab')2, the immunoreactivity of 64Cu-labeled 1A3-F(ab')2 was significantly improved over that of non-FPLC-purified 64Cu-BAT-2IT-1A3-F(ab')2, and the kidney uptake was decreased in normal rats. The biodistribution in hamsters showed some improvement in both tumor uptake and kidney clearance with FPLC-purified 64Cu-BAT-2IT-1A3-F(ab')2. CONCLUSION: The improved dosimetry of 64Cu-labeled FPLC purified BAT-2IT-1A3-F(ab')2 should more readily allow this agent to be investigated clinically to image colorectal cancer using PET.

Use of digital front-end electronics for optimization of a modular PET detector.

The sensitivity and resolution of a new 3D modular BGO detector system for positron emission tomography (PET) was examined in terms of its effect on the signal to noise ratio in the final image. The detector system uses custom hardware and firmware to adjust sensitivity and resolution to achieve optimum performance. This system utilizes lookup up tables (LUT) containing individually tailored positioning and energy windows to assure that events are correctly distributed among the detector elements. Without customizing the LUT, and for a common energy window, sensitivity was found to vary as much as a factor of 3.5 and resolution as much as 50% from center to edge within a single detector module. Eight different LUT configurations were tested, varying both energy window and positioning criteria. Typical intrinsic resolutions and sensitivities of the detector elements were determined in all configurations. The effect of nonuniformity of sensitivity of the detector system on image noise was evaluated by imaging uniform cylinders over a wide range of accumulated events. The effect of counting statistics in the measurement of detector sensitivities for the normalization of sinogram data was determined independently. The best of the LUT configurations provided an 16% improvement in effective sensitivity, while also providing a 10% improvement in the average intrinsic spatial resolution relative to the default configuration of the PET system.

Design features and performance of a PET system for animal research.

The design features of a PET system designed for animal studies are described and its performance evaluated. The system employs a two-dimensional modular detector array consisting of bismuth germanate detector elements that are 3.5 mm (transaxially) by 6.25 mm (axially) by 30 mm (deep). These arrays are optically coupled to a pair of dual-photo-multiplier tubes (PMT). The detector ring is 64 cm in diameter with a field of view (FOV) of 40 cm by 5.4 cm axially, acquiring 15 slices at 3.4 mm spacing. These features include: (1) digitization of PMT signals from each block for improved position and energy discrimination of coincident events and (2) dual-window energy discrimination for simultaneous but separate acquisition of photopeak and scatter data. Intrinsic resolution averages 3.5 mm at the center of the FOV, while reconstructed resolution (ramp filter) ranges from 3.8 mm at the center of the FOV to 4.6 mm at an 8 cm radius. Axial resolution averages 4.4 and 4.9 mm and sensitivity averages 4.2 and 6.1 kcps/microCi/cc for cross planes and enhanced direct planes, respectively. Randoms fraction is high due to reduced interplane shielding, giving a peak true count rate of 103 kcps for a 10 cm cylinder. Scatter as a fraction of trues is 16% for a 10 cm cylinder at a lower energy threshold of 350 keV. All parameters are sensitive to energy threshold. Spatial resolution improves by 11% transaxially and 9% axially, scatter fraction drops to 10%, and overall sensitivity drops by 48% when the threshold value is increased from 350 keV to 450 keV.

Assessment of accuracy of PET utilizing a 3-D phantom to simulate the activity distribution of [18F]fluorodeoxyglucose uptake in the human brain.

A three-dimensional brain phantom has been developed to simulate the activity distributions found in human brain studies currently employed in positron emission tomography (PET). The phantom has a single contiguous chamber and utilizes thin layers of lucite to provide apparent relative concentrations of 5, 1, and 0 for gray matter, white matter, and CSF structures, respectively. The phantom and an ideal image set were created from the same set of data. Thus, the user has a basis for comparing measured images with an ideal set that allows a quantitative evaluation of errors in PET studies with an activity distribution similar to that found in patients. The phantom was employed in a study of the effect of deadtime and scatter on accuracy in quantitation on a current PET system. Deadtime correction factors were found to be significant (1.1-2.5) at count rates found in clinical studies. Deadtime correction techniques were found to be accurate to within 5%. Scatter in emission and attenuation correction data consistently caused 5-15% errors in quantitation, whereas correction for scatter in both types of data reduced errors in accuracy to less than 5%.