How to obtain the image-derived blood concentration from 89Zr-immuno-PET scans.

BACKGROUND: PET scans using zirconium-89 labelled monoclonal antibodies (89Zr-mAbs), known as 89Zr-immuno-PET, are made to measure uptake in tumour and organ tissue. Uptake is related to the supply of 89Zr-mAbs in the blood. Measuring activity concentrations in blood, however, requires invasive blood sampling. This study aims to identify the best delineation strategy to obtain the image-derived blood concentration (IDBC) from 89Zr-immuno-PET scans. METHODS: PET imaging and blood sampling of two 89Zr-mAbs were included, 89Zr-cetuximab and 89Zr-durvalumab. For seven patients receiving 89Zr-cetuximab, PET scans on 1-2 h, 2 and 6 days post-injection (p.i.) were analysed. Five patients received three injections of 89Zr-durvalumab. The scanning protocol for the first two injections consisted of PET scanning on 2, 5 and 7 days p.i. and for the third injection only on 7 days p.i. Blood samples were drawn with every PET scan and the sample-derived blood concentration (SDBC) was used as gold standard for the IDBC. According to an in-house developed standard operating procedure, the aortic arch, ascending aorta, descending aorta and left ventricle were delineated. Bland-Altman analyses were performed to assess the bias (mean difference) and variability (1.96 times the standard deviation of the differences) between IDBC and SDBC. RESULTS: Overall, the activity concentration obtained from the IDBC was lower than from the SDBC. When comparing IDBC with SDBC, variability was smallest for the ascending aorta (20.3% and 17.0% for 89Zr-cetuximab and 89Zr-durvalumab, respectively). Variability for the other regions ranged between 17.9 and 30.8%. Bias for the ascending aorta was - 10.9% and - 11.4% for 89Zr-cetuximab and 89Zr-durvalumab, respectively. CONCLUSIONS: Image-derived blood concentrations should be obtained from delineating the ascending aorta in 89Zr-immuno-PET scans, as this results in the lowest variability with respect to sample-derived blood concentrations.

Validation of simplified uptake measures against dynamic Patlak Ki for quantification of lesional 89Zr-Immuno-PET antibody uptake.

PURPOSE: Positron emission tomography imaging of zirconium-89-labelled monoclonal antibodies (89Zr-Immuno-PET) allows for visualisation and quantification of antibody uptake in tumours in vivo. Patlak linearization provides distribution volume (VT) and nett influx rate (Ki) values, representing reversible and irreversible uptake, respectively. Standardised uptake value (SUV) and tumour-to-plasma/tumour-to-blood ratio (TPR/TBR) are often used, but their validity depends on the comparability of plasma kinetics and clearances. This study assesses the validity of SUV, TPR and TBR against Patlak Ki for quantifying irreversible 89Zr-Immuno-PET uptake in tumours. METHODS: Ten patients received 37 MBq 10 mg 89Zr-anti-EGFR with 500 mg/m2 unlabelled mAbs. Five patients received two doses of 37 MBq 89Zr-anti-HER3: 8-24 mg for the first administration and 24 mg-30 mg/kg for the second. Seven tumours from four patients showed 89Zr-anti-EGFR uptake, and 18 tumours from five patients showed 89Zr-anti-HER3 uptake. SUVpeak, TPRpeak and TBRpeak values were obtained from one to six days p.i. Patlak linearization was applied to tumour time activity curves and plasma samples to obtain Ki. RESULTS: For 89Zr-anti-EGFR, there was a small variability along the linear regression line between SUV (- 0.51-0.57), TPR (- 0.06‒0.11) and TBR (- 0.13‒0.16) on day 6 versus Ki. Similar doses of 89Zr-anti-HER3 showed similar variability for SUV (- 1.3‒1.0), TPR (- 1.1‒0.53) and TBR (- 1.5‒0.72) on day 5 versus Ki. However, for the second administration of 89Zr-anti-HER3 with a large variability in administered mass doses, SUV showed a larger variability (- 1.4‒2.3) along the regression line with Ki, which improved when using TPR (- 0.38-0.32) or TBR (- 0.56‒0.46). CONCLUSION: SUV, TPR and TBR at late time points were valid for quantifying irreversible lesional 89Zr-Immuno-PET uptake when constant mass doses were administered. However, for variable mass doses, only TPR and TBR provided reliable values for irreversible uptake, but not SUV, because SUV does not take patient and mass dose-specific plasma clearance into account.

Calibration of PET/CT scanners for multicenter studies on differentiated thyroid cancer with (124)I.

BACKGROUND: Studies on imaging of differentiated thyroid cancer (DTC) using (124)I often require a multicenter approach, as the prevalence of DTC is low. Calibration of participating scanners is required to obtain comparable quantification. As determination of a well-defined range of recovery coefficients is complicated for various reasons, a simpler approach based on the assumption that the iodine uptake is highly focal with a background that significantly lacks radioactivity might be more efficient. For each scanner, a linear conversion between known and observed activity can be derived, allowing quantification that can be traced to a common source for all scanners within one study-protocol. The aim of this paper is to outline a procedure using this approach in order to set up a multicenter calibration of PET/CT scanners for (124)I. METHODS: A cylindrical polyethylene phantom contained six 2-ml vials with reference activities of ~2, 10, 20, 100, 400, and 2000 kBq, produced by dilution from a known activity. The phantom was scanned twice on PET/CT scanners of participating centers within 1 week. For each scanner, the best proportional and linear fit between measured and known activities were derived and based on statistical analyses of the results of all scanners; it was determined which fit should be applied. In addition, a Bland-Altman analysis was done on calibrated activities with respect to reference activities to asses the relative precision of the scanners. RESULTS: Nine Philips (vendor A) and nine Siemens (vendor B) PET/CT scanners were calibrated in a time period of 3 days before and after the reference time. No significant differences were detected between the two subsequent scans on any scanner. Six fitted intercepts of vendor A were significantly different from zero, so the linear model was used. Intercepts ranged from -8 to 26 kBq and slopes ranged from 0.80 to 0.98. Bland-Altman analysis of calibrated and reference activities showed that the relative error of calibrated activities was smaller than that of uncalibrated activities. CONCLUSIONS: A simplified multicenter calibration procedure for PET/CT scans that show highly focal uptake and negligible background is feasible and results in more precise quantification. Our procedure can be used in multicenter (124)I PET scans focusing on (recurrent) DTC.

Rapid decrease in delivery of chemotherapy to tumors after anti-VEGF therapy: implications for scheduling of anti-angiogenic drugs.

Current strategies combining anti-angiogenic drugs with chemotherapy provide clinical benefit in cancer patients. It is assumed that anti-angiogenic drugs, such as bevacizumab, transiently normalize abnormal tumor vasculature and contribute to improved delivery of subsequent chemotherapy. To investigate this concept, a study was performed in non-small cell lung cancer (NSCLC) patients using positron emission tomography (PET) and radiolabeled docetaxel ([(11)C]docetaxel). In NSCLC, bevacizumab reduced both perfusion and net influx rate of [(11)C]docetaxel within 5 hr. These effects persisted after 4 days. The clinical relevance of these findings is notable, as there was no evidence for a substantial improvement in drug delivery to tumors. These findings highlight the importance of drug scheduling and advocate further studies to optimize scheduling of anti-angiogenic drugs.

Optimizing an online SPE-HPLC method for analysis of (R)-[11C]1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide [(R)-[11C]PK11195] and its metabolites in humans.

(R)-[11C]PK11195 is used as a positron emission tomography tracer for activated microglia in several neurological disorders. Quantification of specific binding requires a metabolite-corrected plasma input function. In this study, a high-performance liquid chromatography (HPLC) procedure with online solid phase extraction was modified for analyzing (R)-[11C]PK11195 plasma samples, yielding total sample recoveries of more than 98%. When applied to human studies, the use of two HPLC systems enabled analysis of up to seven plasma samples under regular conditions. Online radioactivity detection was compared with offline sample measurements of HPLC profiles. Offline measurements provided the most reliable results especially for late plasma samples. In 10 patients, an average decrease of parent compound from 94.6% at 2.5 min to 45.2% at 1 h after administration was observed.

Validation of a multiwell gamma-counter for measuring high-pressure liquid chromatography metabolite profiles.

OBJECTIVES: The purpose of this study was to verify the accuracy and reproducibility of a multiwell counter to assess its suitability for use within human PET studies in which metabolizing (11)C tracers are used. Such tracers often require metabolite analysis for deriving plasma metabolite-corrected input curves. High-pressure liquid chromatography (HPLC) with on-line activity measurement is often unreliable for later plasma samples due to the poor sensitivity of the on-line activity detector. Fraction collector obtained HPLC samples that are counted in a separate high-sensitivity well counter can be an alternative to overcome poor counting statistics. METHODS: Several experiments to evaluate background counting, reproducibility, and linearity were performed to validate the accuracy, precision, and detection limits of the well counter. In addition, measurements on a series of samples resembling activity profiles as seen within human (11)C-flumazenil studies were performed to evaluate the performance of the well counter for clinically relevant data. RESULTS: The tests proved that the well counter detection limit, linearity, and reproducibility were more than sufficient in circumstances as seen during patient studies for samples with both high and low activity. CONCLUSION: The use of a multiwell counter is a good alternative for the on-line activity detector of the HPLC, allowing derivation of plasma metabolite fractions with high accuracy and reproducibility.

Measurement of 18F-FDG concentrations in blood samples: comparison of direct calibration and standard solution methods.

OBJECTIVE: The purpose of this study was to compare the accuracy and reliability of 2 well counter methods for measuring the activity concentration of (18)F-FDG in blood samples. METHODS: Three to 5 blood samples from 154 patient studies were weighed and measured in a well counter. The (18)F-FDG activity concentration was derived using, first, a direct calibration factor to convert measured well counter readings into activity concentration and, second, a comparison of measured counts with those of a specified standard solution. RESULTS: The ratio between the activity concentration results of the 2 methods was 0.996 +/- 0.033, indicating that the methods provided equal results. CONCLUSION: Because the standard solution method is more prone to human error, less reproducible, and more labor intensive, preference should be given to the direct calibration method.