Page 125 - 89Zr-Immuno-PET:Towards a Clinical Tool to Guide Antibody-based Therapy in Cancer
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                                Interobserver reproducibility of 89Zr-immuno-PET
INTRODUCTION
Therapy with monoclonal antibodies (mAbs) has greatly improved the outcome of
cancer patients (1). However, treatment failure due to the biology of the disease is
a substantial problem. In addition to disease-related factors, therapy-related
factors have been found to be responsible (2). There is mainly information on pharmacokinetics in blood, whereas tumor targeting is crucial for mAb efficacy.
Therefore, in-vivo quantification of antibody uptake in tumors is of interest in
strategies to improve the efficacy of antibody treatment (e.g. using optimized pharmacokinetic models in early drug development to improve dosing schedules).
PET imaging with zirconium-89 (89Zr)-labeled mAbs provides a non-invasive tool
to visualize and quantify mAb tumor uptake (3), providing that biodistribution of
the radiolabeled mAb represents that of the total mAb dose (radiolabeled and
unlabeled). The number of clinical studies on 89Zr-labeled mAbs, also referred to
as 89Zr-immuno-PET, increased in recent years (4). Sources of measurement
errors (including factors as interobserver reproducibility of tumor uptake quantification and noise induced variability) should be known to define true 6 biological differences. A standardized method of data acquisition and tumor
uptake quantification forms the basis for obtaining experimental data that will allow such an understanding.
For quantification of tumor uptake, a volume of interest (VOI) is delineated. Subsequently, a tumor uptake measure is selected to characterize tumor uptake. Maximum (max) or peak standard uptake values (SUVmax and SUVpeak, respectively) provide information on a limited part of the tumor. Mean standardized uptake values (SUVmean) and total lesion uptake (TLU) serve to capture the entire lesion. In clinical studies, tumor uptake is quantified at a single (late) timepoint, or at multiple timepoints. Additionally, quantification of tumor uptake at an early timepoint (D0) can be considered, for example to estimate the blood volume fraction of the tumor.
For imaging of mAbs, 89Zr is considered a suitable radioactive isotope due to its long half-life (t1/2=78.4h), which matches the slow kinetics of large-sized proteins. Consequences of imaging with 89Zr are low positron abundance and relatively high radiation exposure, resulting in lower injected doses compared to 18F. Therefore, lower signal to noise ratios due to lower count rates may result in interobserver variability of tumor uptake quantification in 89Zr-immuno-PET. Other specific challenges for 89Zr-immuno-PET tumor delineation and
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