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PURPOSE: In-vivo quantification of tumor uptake of 89-zirconium (89Zr)-labelled monoclonal antibodies (mAbs) with PET provides a potential tool in strategies to optimize tumor targeting and therapeutic efficacy. A specific challenge for 89Zr-immuno-PET is low tumor contrast. This is expected to result in interobserver variation in tumor delineation. Therefore, the aim of this study was to determine interobserver reproducibility of tumor uptake measures by tumor delineation on 89Zr-immuno-PET scans.METHODS: Data were obtained from previously published clinical studies performed with 89Zr-rituximab, 89Zr-cetuximab and 89Zr-trastuzumab. Tumor lesions on 89Zr-immuno-PET were identified as focal uptake exceeding local background by a nuclear medicine physician. Three observers independently manually delineated volumes of interest (VOI). Maximum, peak and mean standardized uptake values (SUVmax, SUVpeak and SUVmean) were used to quantify tumor uptake. Interobserver variability was expressed as the coefficient of variation (CoV). The performance of semi-automatic VOI delineation using 50% of background-corrected ACpeak was described.RESULTS: In total, 103 VOI were delineated (3-6 days post injection (D3-D6)). Tumor uptake (median, interquartile range) was 9.2 (5.2-12.6), 6.9 (4.0-9.6) and 5.5 (3.3-7.8) for SUVmax, SUVpeak and SUVmean. Interobserver variability was 0% (0-12), 0% (0-2) and 7% (5-14), respectively (n = 103). The success rate of the semi-automatic method was 45%. Inclusion of background was the main reason for failure of semi-automatic VOI.CONCLUSIONS: This study shows that interobserver reproducibility of tumor uptake quantification on 89Zr-immuno-PET was excellent for SUVmax and SUVpeak using a standardized manual procedure for tumor segmentation. Semi-automatic delineation was not robust due to limited tumor contrast.

Low photon count inCount-splitFor S50p, a total of 92% and 90% features were classified as having good or excellent ICC and SDM respectively, while for S25p, these decreased to 81% and 31%. In total, 148 features (31%) showed robustness to noise with good or moderate ICC and SDM in both S50p and S25p. The number of features classified into the four ICC and SDM categories between S50p and S25p was significantly different statistically.Several radiomic features derived from low SNR

Purpose This pilot study aimed to determine interobserver reliability and ease of use of three workflows for measuring metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in diffuse large B cell lymphoma (DLBCL). Procedures Twelve baseline [18F]FDG PET/CT scans from DLBCL patients with wide variation in number and size of involved organs and lymph nodes were selected from the international PETRA consortium database. Three observers analyzed scans using three workflows. Workflow A: user-defined selection of individual lesions followed by four automated segmentations (41%SUVmax, A50%SUVpeak, SUV≥2.5, SUV≥4.0). For each lesion, observers indicated their “preferred segmentation.” Individually selected lesions were summed to yield total MTV and TLG. Workflow B: fully automated preselection of [18F]FDG-avid structures (SUV≥4.0 and volume≥3ml), followed by removing non-tumor regions with single mouse clicks. Workflow C: preselected volumes based on Workflow B modified by manually adding lesions or removing physiological uptake, subsequently checked by experienced nuclear medicine physicians. Workflow C was performed 3 months later to avoid recall bias from the initial Workflow B analysis. Interobserver reliability was expressed as intraclass correlation coefficients (ICC). Results Highest interobserver reliability in Workflow A was found for SUV≥2.5 and SUV≥4.0 methods (ICCs for MTV 0.96 and 0.94, respectively). SUV≥4.0 and A50%Peak were most and SUV≥2.5 was the least preferred segmentation method. Workflow B had an excellent interobserver reliability (ICC = 1.00) for MTV and TLG. Workflow C reduced the ICC for MTV and TLG to 0.92 and 0.97, respectively. Mean workflow analysis time per scan was 29, 7, and 22 min for A, B, and C, respectively. Conclusions Improved interobserver reliability and ease of use occurred using fully automated preselection (using SUV≥4.0 and volume≥3ml, Workflow B) compared with individual lesion selection by observers (Workflow A). Subsequent manual modification was necessary for some patients but reduced interobserver reliability which may need to be balanced against potential improvement on prognostic accuracy.

Purpose Positron emission tomography (PET) with Zirconium-89 (Zr-89)-labeled antibodies can be used for in vivo quantification of antibody uptake. Knowledge about measurement variability is required to ensure correct interpretation. However, no clinical studies have been reported on measurement variability of Zr-89 immuno-PET. As variability due to low signal-to-noise is part of the total measurement variability, the aim of this study was to assess noise-induced variability of Zr-89 -immuno-PET using count-reduced clinical images. Procedures Data were acquired from three previously reported clinical studies with [89Zr]antiCD20 (74 MBq, n = 7), [89Zr]antiEGFR (37 MBq, n = 7), and [89Zr]antiCD44 (37 MBq, n = 13), with imaging obtained 1 to 6 days post injection (D0–D6). Volumes of interest (VOIs) were manually delineated for liver, spleen, kidney, lung, brain, and tumor. For blood pool and bone marrow, fixed-size VOIs were used. Original PET list mode data were split and reconstructed, resulting in two count-reduced images at 50 % of the original injected dose (e.g., 37 MBq74inj). Repeatability coefficients (RC) were obtained from Bland-Altman analysis on standardized uptake values (SUV) derived from VOIs applied to these images. Results The RC for the combined manually delineated organs for [89Zr] antiCD20 (37 MBq74inj) increased from D0 to D6 and was less than 6 % at all time points. Blood pool and bone marrow had higher RC, up to 43 % for 37 MBq74inj at D6. For tumor, the RC was up to 42 % for [89Zr]antiCD20 (37 MBq74inj). For [89Zr]antiCD20, (18 MBq74inj), [89Zr]antiEGFR (18 MBq37inj), and [89Zr]antiCD44 (18 MBq37inj), measurement variability was independent of the investigated antibody. Conclusions Based on this study, noise-induced variability results in a RC for Zr-89-immuno-PET (37 MBq) around 6 % for manually delineated organs combined, increasing up to 43 % at D6 for blood pool and bone marrow, assuming similar biodistribution of antibodies. The signal-to-noise ratio leads to tumor RC up to 42 %. Electronic supplementary material The online version of this article (10.1007/s11307-018-1200-4) contains supplementary material, which is available to authorized users.

89Zr-immuno-PET is a promising noninvasive clinical tool that measures target engagement of monoclonal antibodies (mAbs) to predict toxicity in normal tissues and efficacy in tumors. Quantification of 89Zr-immuno-PET will need to move beyond SUVs, since total uptake may contain a significant non–target-specific contribution. Nonspecific uptake is reversible (e.g., blood volume) or irreversible (due to 89Zr-residualization after mAb degradation). The aim of this study was to assess nonspecific uptake in normal tissues as a first critical step toward quantification of target engagement in normal tissues and tumors using 89Zr-immuno-PET. Methods: Data from clinical studies with 4 89Zr-labeled intact IgG1 antibodies were collected, resulting in a total of 128 PET scans (1–7 d after injection from 36 patients: 89Zr-obinutuzumab [n = 9], 89Zr-cetuximab [n = 7], 89Zr-huJ591 [n = 10], and 89Zr-trastuzumab [n = 10] [denoted as 89Zr-anti-CD20, 89Zr-anti-EGFR, 89Zr-anti-PSMA and 89Zr-anti-HER2, respectively]). Nonspecific uptake was defined as uptake measured in tissues without known target expression. Patlak graphical evaluation of transfer constants was used to estimate the reversible (Vt) and irreversible (Ki) contributions to the total measured uptake for the kidney, liver, lung, and spleen. Baseline values were calculated per tissue combining all mAbs without target expression (kidney: 89Zr-anti-CD20, 89Zr-anti-EGFR, and 89Zr-anti-HER2; liver: 89Zr-anti-CD20; lung: 89Zr-anti-CD20, 89Zr-anti-EGFR, and 89Zr-anti-PSMA; spleen: 89Zr-anti-EGFR and 89Zr-anti-HER2). Results: For the kidney, liver, lung, and spleen, baseline Vt was 0.20, 0.24, 0.09, and 0.24 mL⋅cm−3, respectively, and baseline Ki was 0.7, 1.1, 0.2 and 0.5 μL⋅g−1⋅h−1, respectively. For 89Zr-anti-PSMA, a 4-fold higher Ki was observed for the kidney, indicating target engagement. In this case, nonspecific uptake accounted for 66%, 34%, and 22% of the total signal in the kidney at 1, 3, and 7 d after injection, respectively. Conclusion: This study shows that nonspecific uptake of mAbs for tissues without target expression can be quantified using 89Zr-immuno-PET at multiple time points. These results form a crucial base for measurement of target engagement by therapeutic antibodies in vivo with 89Zr-immuno-PET. For future studies, a pilot phase including at least 3 scans at 1 or more days after injection is required to assess nonspecific uptake as a function of time, to optimize study design for detection of target engagement.

Purpose In-vivo quantification of tumor uptake of 89-zirconium (89Zr)-labelled monoclonal antibodies (mAbs) with PET provides a potential tool in strategies to optimize tumor targeting and therapeutic efficacy. A specific challenge for 89Zr-immuno-PET is low tumor contrast. This is expected to result in interobserver variation in tumor delineation. Therefore, the aim of this study was to determine interobserver reproducibility of tumor uptake measures by tumor delineation on 89Zr-immuno-PET scans. Methods Data were obtained from previously published clinical studies performed with 89Zr-rituximab, 89Zr-cetuximab and 89Zr-trastuzumab. Tumor lesions on 89Zr-immuno-PET were identified as focal uptake exceeding local background by a nuclear medicine physician. Three observers independently manually delineated volumes of interest (VOI). Maximum, peak and mean standardized uptake values (SUVmax, SUVpeak and SUVmean) were used to quantify tumor uptake. Interobserver variability was expressed as the coefficient of variation (CoV). The performance of semi-automatic VOI delineation using 50% of background-corrected ACpeak was described. Results In total, 103 VOI were delineated (3–6 days post injection (D3-D6)). Tumor uptake (median, interquartile range) was 9.2 (5.2–12.6), 6.9 (4.0–9.6) and 5.5 (3.3–7.8) for SUVmax, SUVpeak and SUVmean. Interobserver variability was 0% (0–12), 0% (0–2) and 7% (5–14), respectively (n = 103). The success rate of the semi-automatic method was 45%. Inclusion of background was the main reason for failure of semi-automatic VOI. Conclusions This study shows that interobserver reproducibility of tumor uptake quantification on 89Zr-immuno-PET was excellent for SUVmax and SUVpeak using a standardized manual procedure for tumor segmentation. Semi-automatic delineation was not robust due to limited tumor contrast. Electronic supplementary material The online version of this article (10.1007/s00259-019-04377-6) contains supplementary material, which is available to authorized users.

Purpose: Treatment of patients with diffuse large B cell lymphoma (DLBCL) includes rituximab, an anti-CD20 monoclonal antibody (mAb). Insufficient tumor targeting might cause therapy failure. Tumor uptake of 89Zirconium (89Zr)-mAb is a potential imaging biomarker for tumor targeting, since it depends on target antigen expression and accessibility. The aim of this pilot study was to describe the performance of 89Zr-labeled-rituximab-PET to assess CD20 targeting in patients with relapsed/refractory DLBCL. Methods: Six patients with biopsy-proven DLBCL were included. CD20 expression was assessed using immunohistochemistry (IHC). 74 MBq 89Zr-rituximab (10 mg) was administered after the therapeutic dose of rituximab. Immuno-PET scans on day 0, 3 and 6 post injection (D0, D3 and D6 respectively) were visually assessed and quantified for tumor uptake. Results: Tumor uptake of 89Zr-rituximab and CD20 expression were concordant in 5 patients: for one patient, both were negative, for the other four patients visible tumor uptake was concordant with CD20-positive biopsies. Intense tumor uptake of 89Zr-rituximab on PET (SUVpeak = 12.8) corresponded with uniformly positive CD20 expression on IHC in one patient. Moderate tumor uptake of 89Zr-rituximab (range SUVpeak = 3.2-5.4) corresponded with positive CD20 expression on IHC in three patients. In one patient tumor uptake of 89Zr-rituximab was observed (SUVpeak = 3.8), while the biopsy was CD20-negative. Conclusions: This study suggests a positive correlation between tumor uptake of 89Zr-rituximab and CD20 expression in tumor biopsies, but further studies are needed to confirm this. This result supports the potential of 89Zr-rituximab-PET as an imaging biomarker for CD20 targeting. For clinical application of 89Zr-rituximab-PET to guide individualized treatment, further studies are required to assess whether tumor targeting is related to clinical benefit of rituximab treatment in individual patients.

Selection of the right drug for the right patient is a promising approach to increase clinical benefit of targeted therapy with monoclonal antibodies (mAbs). Assessment of in vivo biodistribution and tumor targeting of mAbs to predict toxicity and efficacy is expected to guide individualized treatment and drug development. Molecular imaging with positron emission tomography (PET) using zirconium-89 ((89)Zr)-labeled monoclonal antibodies also known as (89)Zr-immuno-PET, visualizes and quantifies uptake of radiolabeled mAbs. This technique provides a potential imaging biomarker to assess target expression, as well as tumor targeting of mAbs. In this review we summarize results from initial clinical trials with (89)Zr-immuno-PET in oncology and discuss technical aspects of trial design. In clinical trials with (89)Zr-immuno-PET two requirements should be met for each (89)Zr-labeled mAb to realize its full potential. One requirement is that the biodistribution of the (89)Zr-labeled mAb (imaging dose) reflects the biodistribution of the drug during treatment (therapeutic dose). Another requirement is that tumor uptake of (89)Zr-mAb on PET is primarily driven by specific, antigen-mediated, tumor targeting. Initial trials have contributed toward the development of (89)Zr-immuno-PET as an imaging biomarker by showing correlation between uptake of (89)Zr-labeled mAbs on PET and target expression levels in biopsies. These results indicate that (89)Zr-immuno-PET reflects specific, antigen-mediated binding. (89)Zr-immuno-PET was shown to predict toxicity of RIT, but thus far results indicating that toxicity of mAbs or mAb-drug conjugate treatment can be predicted are lacking. So far, one study has shown that molecular imaging combined with early response assessment is able to predict response to treatment with the antibody-drug conjugate trastuzumab-emtansine, in patients with human epithelial growth factor-2 (HER2)-positive breast cancer. Future studies would benefit from a standardized criterion to define positive tumor uptake, possibly supported by quantitative analysis, and validated by linking imaging data with corresponding clinical outcome. Taken together, these results encourage further studies to develop (89)Zr-immuno-PET as a predictive imaging biomarker to guide individualized treatment, as well as for potential application in drug development.

Introduction Une etude ancillaire du LYSA de l’etude de phase Ib/II de l’obinutuzumab, anticorps monoclonal anti-CD20 humanise de type II, combine au lenalidomide pour le traitement des lymphomes refractaires ou en rechute (GALEN) s’est interessee a la biodistribution de l’anticorps par l’imagerie et la pharmacocinetique. Les 6 premiers patients etaient evalues a deux temps de leur traitement et la suite de l’etude dependait de l’analyse intermediaire prevue apres ces 6 patients, dont les resultats sont presentes ici. Materiel et methodes Les patients, inclus dans le protocole GALEN, pouvaient participer a cette etude ancillaire a condition d’etre âges d’au moins 50 ans et de presenter un lymphome folliculaire (consentement specifique) non precedemment traite. Les 6 patients etaient examines deux fois : juste apres la 1ere perfusion d’obinutuzumab (cycle 1) et 3 semaines plus tard, apres la 4e perfusion (cycle 2). Le radiomarquage de l’obinutuzumab (fourni par Hoffman LaRoche Ltd) au zirconium 89 etait realise par l’Universite d’Amsterdam (Pays-Bas). Apres chaque injection lente de 37 MBq de 89Zr-obinutuzumab, 6 prelevements sanguins etaient realises a 5–10, 45–60, 120–135 min, j + 1, j + 3 et j + 6 et 3 acquisitions TEP-TDM « low dose » a 1 h, j + 3 et j + 6 (acquisitions d’une heure, sur PET Advance RX HD 16, GEMS pour 5, sur Biograph mCT flow, Siemens pour le dernier). Les examens ont ete interpretes de facon centralisee et separement par deux medecins nucleaires. Resultats Les 6 premiers patients (5 h, 1 f) ont ete inclus d’avril 2016 a mars 2017. La biodistribution de l’anticorps sur les tissus sains etait similaire entre les deux injections. A l’exception d’un patient, les lesions hypermetaboliques sur la TEP-FDG pretherapeutique etaient vues sur les acquisitions de j + 3 et/ou j + 6 en immunoTEP. Lors de la 2e injection (cycle 2), le nombre de lesions fixant l’anticorps etait plus faible que lors de la 1re injection (cycle 1), sans que la taille des lesions n’apparaisse comme un critere majeur de persistance ou non. L’existence d’une fixation de l’anticorps au cycle 2 ne se traduisait pas par un echec du traitement lors du suivi. Conclusion L’apport des informations fournies lors de la 2e injection (cycle 2) ne sont pas apparues suffisantes pour que celle-ci soit realisee pour les patients suivants et les 9 patients restant a inclure (dernier patient inclus en janvier 2018) n’ont recu qu’une seule injection de 89Zr-obinutuzumab, apres le cycle 1.

Immuno-PET is an appealing concept in the detection of tumors and planning of antibody-based therapy. For this purpose, the long-lived positron emitter 89Zr (half-life, 78.4 h) recently became available. The aim of the present first-in-humans 89Zr immuno-PET study was to assess safety, biodistribution, radiation dose, and quantification of the 89Zr-labeled chimeric monoclonal antibody (cmAb) U36 in patients with head and neck squamous cell carcinoma (HNSCC). In addition, the performance of immuno-PET for detecting lymph node metastases was evaluated, as described previously. Methods: Twenty HNSCC patients, scheduled to undergo surgical tumor resection, received 75 MBq of 89Zr-cmAb U36 (10 mg). Immuno-PET scans were acquired at 1, 24, 72, or 144 h after injection. The biodistribution of the radioimmunoconjugate was evaluated by ex vivo radioactivity measurement in blood and in biopsies from the surgical specimen obtained at 168 h after injection. Uptake levels and residence times in blood, tumors, and organs of interest were derived from quantitative immuno-PET studies, and absorbed doses were calculated using OLINDA/EXM 1.0. The red marrow dose was calculated using the residence time for blood. Results:89Zr-cmAb U36 was well tolerated by all subjects. PET quantification of blood-pool activity in the left ventricle of the heart showed a good agreement with sampled blood activity (difference equals 0.2% ± 16.9% [mean ± SD]) except for heavy-weight patients (>100 kg). A good agreement was also found for the assessment of mAb uptake in primary tumors (mean deviation, −8.4% ± 34.5%). The mean absorbed red marrow dose was 0.07 ± 0.02 mSv/MBq and 0.09 ± 0.01 mSv/MBq in men and women, respectively. The normal organ with the highest absorbed dose was the liver (mean dose, 1.25 ± 0.27 mSv/MBq in men and 1.35 ± 0.21 mSv/MBq in women), thereafter followed by kidneys, thyroid, lungs, and spleen. The mean effective dose was 0.53 ± 0.03 mSv/MBq in men and 0.66 ± 0.03 mSv/MBq in women. Measured excretion via the urinary tract was less than 3% during the first 72 h. Conclusion:89Zr immuno-PET can be safely used to quantitatively assess biodistribution, uptake, organ residence times, and radiation dose, justifying its further clinical exploitation in the detection of tumors and planning of mAb-based therapy.

Purpose: Immuno–positron emission tomography (PET), the combination of PET with monoclonal antibodies (mAb), is an attractive option to improve tumor detection and to guide mAb-based therapy. The long-lived positron emitter zirconium-89 (89Zr) has ideal physical characteristics for immuno-PET with intact mAbs but has never been used in a clinical setting. In the present feasibility study, we aimed to evaluate the diagnostic imaging performance of immuno-PET with 89Zr-labeled-chimeric mAb (cmAb) U36 in patients with squamous cell carcinoma of the head and neck (HNSCC), who were at high risk of having neck lymph node metastases. Experimental Design: Twenty HNSCC patients, scheduled to undergo neck dissection with or without resection of the primary tumor, received 75 MBq 89Zr coupled to the anti-CD44v6 cmAb U36 (10 mg). All patients were examined by computed tomography (CT) and/or magnetic resonance imaging (MRI) and immuno-PET before surgery. Six patients also underwent PET with 18F-fluoro-2-deoxy-d-glucose. Immuno-PET scans were acquired up to 144 hours after injection. Diagnostic findings were recorded per neck side (left or right) as well as per lymph node level (six levels per side), and compared with histopathologic outcome. For this purpose, the CT/MRI scores were combined and the best of both scores was used for analysis. Results: Immuno-PET detected all primary tumors (n = 17) as well as lymph node metastases in 18 of 25 positive levels (sensitivity 72%) and in 11 of 15 positive sides (sensitivity 73%). Interpretation of immuno-PET was correct in 112 of 121 operated levels (accuracy 93%) and in 19 of 25 operated sides (accuracy 76%). For CT/MRI, sensitivities of 60% and 73% and accuracies of 90% and 80% were found per level and side, respectively. In the six patients with seven tumor-involved neck levels and sides, immuno-PET and 18F-fluoro-2-deoxy-d-glucose PET gave comparable diagnostic results. Conclusion: In this study, immuno-PET with 89Zr-cmAb U36 performed at least as good as CT/MRI for detection of HNSCC lymph node metastases.

The purpose of this study was to determine the correlation between the (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) standardized uptake value (SUV) and the diffusion-weighted magnetic resonance imaging (MRI) apparent diffusion coefficient (ADC) in newly diagnosed diffuse large B-cell lymphoma (DLBCL). Pretreatment FDG-PET and diffusion-weighted MRI of 21 patients with histologically proven DLBCL were prospectively analyzed. In each patient, maximum, mean and peak standardized uptake value (SUV) was measured in the lesion with visually highest FDG uptake and in the largest lesion. Mean ADC (ADCmean, calculated with b-values of 0 and 1000 s/mm(2)) was measured in the same lesions. Correlations between FDG-PET metrics (SUVmax, SUVmean, SUVpeak) and ADCmean were assessed using Pearson's correlation coefficients. In the lesions with visually highest FDG uptake, no significant correlations were found between the SUVmax, SUVmean, SUVpeak and the ADCmean (P=0.498, P=0.609 and P=0.595, respectively). In the largest lesions, there were no significant correlations either between the SUVmax, SUVmean, SUVpeak and the ADCmean (P=0.992, P=0.843 and P=0.894, respectively). The results of this study indicate that the glycolytic rate as measured by FDG-PET and changes in water compartmentalization and water diffusion as measured by the ADC are independent biological phenomena in newly diagnosed DLBCL. Further studies are warranted to assess the complementary roles of these different imaging biomarkers in the evaluation and follow-up of DLBCL.