Imaging microvascular changes in nonocular oncological clinical applications by optical coherence tomography angiography: a literature review.

BACKGROUND: Optical coherence tomography angiography (OCTA) is an emerging imaging modality that enables noninvasive visualization and analysis of tumor vasculature. OCTA has been particularly useful in clinical ocular oncology, while in this article, we evaluated OCTA in assessing microvascular changes in clinical nonocular oncology through a systematic review of the literature. METHOD: The inclusion criterion for the literature search in PubMed, Web of Science and Scopus electronic databases was the use of OCTA in nonocular clinical oncology, meaning that all ocular clinical studies and all ocular and nonocular animal, phantom, ex vivo, experimental, research and development, and purely methodological studies were excluded. RESULTS: Eleven articles met the inclusion criteria. The anatomic locations of the neoplasms in the selected articles were the gastrointestinal tract (2 articles), head and neck (1 article) and skin (8 articles). CONCLUSIONS: While OCTA has shown great advancements in ophthalmology, its translation to the nonocular clinical oncology setting presents several limitations, with a lack of standardized protocols and interpretation guidelines posing the most significant challenge.

Imaging perfusion changes in oncological clinical applications by hyperspectral imaging: a literature review.

BACKGROUND: Hyperspectral imaging (HSI) is a promising imaging modality that uses visible light to obtain information about blood flow. It has the distinct advantage of being noncontact, nonionizing, and noninvasive without the need for a contrast agent. Among the many applications of HSI in the medical field are the detection of various types of tumors and the evaluation of their blood flow, as well as the healing processes of grafts and wounds. Since tumor perfusion is one of the critical factors in oncology, we assessed the value of HSI in quantifying perfusion changes during interventions in clinical oncology through a systematic review of the literature. MATERIALS AND METHODS: The PubMed and Web of Science electronic databases were searched using the terms "hyperspectral imaging perfusion cancer" and "hyperspectral imaging resection cancer". The inclusion criterion was the use of HSI in clinical oncology, meaning that all animal, phantom, ex vivo, experimental, research and development, and purely methodological studies were excluded. RESULTS: Twenty articles met the inclusion criteria. The anatomic locations of the neoplasms in the selected articles were as follows: kidneys (1 article), breasts (2 articles), eye (1 article), brain (4 articles), entire gastrointestinal (GI) tract (1 article), upper GI tract (5 articles), and lower GI tract (6 articles). CONCLUSIONS: HSI is a potentially attractive imaging modality for clinical application in oncology, with assessment of mastectomy skin flap perfusion after reconstructive breast surgery and anastomotic perfusion during reconstruction of gastrointenstinal conduit as the most promising at present.

The dose accumulation and the impact of deformable image registration on dose reporting parameters in a moving patient undergoing proton radiotherapy.

INTRODUCTION: Potential changes in patient anatomy during proton radiotherapy may lead to a deviation of the delivered dose. A dose estimate can be computed through a deformable image registration (DIR) driven dose accumulation. The present study evaluates the accumulated dose uncertainties in a patient subject to an inadvertent breathing associated motion. MATERIALS AND METHODS: A virtual lung tumour was inserted into a pair of single participant landmark annotated computed tomography images depicting opposite breathing phases, with the deep inspiration breath-hold the planning reference and the exhale the off-reference geometry. A novel Monte Carlo N-Particle, Version 6 (MCNP6) dose engine was developed, validated and used in treatment plan optimization. Three DIR methods were compared and used to transfer the exhale simulated dose to the reference geometry. Dose conformity and homogeneity measures from International Committee on Radioactivity Units and Measurements (ICRU) reports 78 and 83 were evaluated on simulated dose distributions registered with different DIR algorithms. RESULTS: The MCNP6 dose engine handled patient-like geometries in reasonable dose calculation times. All registration methods were able to align image associated landmarks to distances, comparable to voxel sizes. A moderate deterioration of ICRU measures was encountered in comparing doses in on and off-reference anatomy. There were statistically significant DIR driven differences in ICRU measures, particularly a 10% difference in the relative D98% for planning tumour volume and in the 3 mm/3% gamma passing rate. CONCLUSIONS: T he dose accumulation over two anatomies resulted in a DIR driven uncertainty, important in reporting the associated ICRU measures for quality assurance.

Selection of the First 99mTc-Labelled Somatostatin Receptor Subtype 2 Antagonist for Clinical Translation-Preclinical Assessment of Two Optimized Candidates.

Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project "TECANT" two 99mTc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical translation. Receptor-affinity, internalization and dissociation studies were performed in human embryonic kidney-293 (HEK293) cells transfected with the human SST2 (HEK-SST2). Log D, protein binding and stability in human serum were assessed. Biodistribution and SPECT/CT studies were carried out in nude mice bearing HEK-SST2 xenografts, together with dosimetric estimations from mouse-to-man. [99mTc]Tc-TECANT-1 showed higher hydrophilicity and lower protein binding than [99mTc]-TECANT-2, while stability was comparable. Both radiotracers revealed similar binding affinity, while [99mTc]Tc-TECANT-1 had higher cellular uptake (>50%, at 2 h/37 °C) and lower dissociation rate (<30%, at 2 h/37 °C). In vivo, [99mTc]Tc-TECANT-1 showed lower blood values, kidney and muscles uptake, whereas tumour uptake was comparable to [99mTc]Tc-TECANT-2. SPECT/CT imaging confirmed the biodistribution results, providing the best tumour-to-background image contrast for [99mTc]Tc-TECANT-1 at 4 h post-injection (p.i.). The estimated radiation dose amounted to approximately 6 µSv/MBq for both radiotracers. This preclinical study provided the basis of selection of [99mTc]Tc-TECANT-1 for clinical translation of the first 99mTc-based SST2 antagonist.

[18F]FDG PET immunotherapy radiomics signature (iRADIOMICS) predicts response of non-small-cell lung cancer patients treated with pembrolizumab.

Background Immune checkpoint inhibitors have changed the paradigm of cancer treatment; however, non-invasive biomarkers of response are still needed to identify candidates for non-responders. We aimed to investigate whether immunotherapy [18F]FDG PET radiomics signature (iRADIOMICS) predicts response of metastatic non-small-cell lung cancer (NSCLC) patients to pembrolizumab better than the current clinical standards. Patients and methods Thirty patients receiving pembrolizumab were scanned with [18F]FDG PET/CT at baseline, month 1 and 4. Associations of six robust primary tumour radiomics features with overall survival were analysed with Mann-Whitney U-test (MWU), Cox proportional hazards regression analysis, and ROC curve analysis. iRADIOMICS was constructed using univariate and multivariate logistic models of the most promising feature(s). Its predictive power was compared to PD-L1 tumour proportion score (TPS) and iRECIST using ROC curve analysis. Prediction accuracies were assessed with 5-fold cross validation. Results The most predictive were baseline radiomics features, e.g. Small Run Emphasis (MWU, p = 0.001; hazard ratio = 0.46, p = 0.007; AUC = 0.85 (95% CI 0.69-1.00)). Multivariate iRADIOMICS was found superior to the current standards in terms of predictive power and timewise with the following AUC (95% CI) and accuracy (standard deviation): iRADIOMICS (baseline), 0.90 (0.78-1.00), 78% (18%); PD-L1 TPS (baseline), 0.60 (0.37-0.83), 53% (18%); iRECIST (month 1), 0.79 (0.62-0.95), 76% (16%); iRECIST (month 4), 0.86 (0.72-1.00), 76% (17%). Conclusions Multivariate iRADIOMICS was identified as a promising imaging biomarker, which could improve management of metastatic NSCLC patients treated with pembrolizumab. The predicted non-responders could be offered other treatment options to improve their overall survival.

Computational modelling of resistance and associated treatment response heterogeneity in metastatic cancers.

Metastatic cancer patients invariably develop treatment resistance. Different levels of resistance lead to observed heterogeneity in treatment response. The main goal was to evaluate treatment response heterogeneity with a computation model simulating the dynamics of drug-sensitive and drug-resistant cells. Model parameters included proliferation, drug-induced death, transition and proportion of intrinsically resistant cells. The model was benchmarked with imaging metrics extracted from 39 metastatic prostate cancer patients who had 18F-NaF-PET/CT scans performed at baseline and at three cycles into chemotherapy or hormonal therapy. Two initial model assumptions were evaluated: considering only inter-patient heterogeneity and both inter-patient and intra-patient heterogeneity in the proportion of intrinsically resistant cells. The correlation between the median proportion of intrinsically resistant cells and baseline patient-level imaging metrics was assessed with Spearman's rank correlation coefficient. The impact of model parameters on simulated treatment response was evaluated with a sensitivity study. Treatment response after periods of six, nine, and 12 months was predicted with the model. The median predicted range of response for patients treated with both therapies was compared with a Wilcoxon rank sum test. For each patient, the time was calculated when the proportion of disease with a non-favourable response outperformed a favourable response. By taking into account inter-patient and intra-patient heterogeneity in the proportion of intrinsically resistant cells, the model performed significantly better ([Formula: see text]) than by taking into account only inter-patient heterogeneity ([Formula: see text]). The median proportion of intrinsically resistant cells showed a moderate correlation (ρ = 0.55) with mean patient-level uptake, and a low correlation (ρ = 0.36) with the dispersion of mean metastasis-level uptake in a patient. The sensitivity study showed a strong impact of the proportion of intrinsically resistant cells on model behaviour after three cycles of therapy. The difference in the median range of response (MRR) was not significant between cohorts at any time point (p  > 0.15). The median time when the proportion of disease with a non-favourable response outperformed the favourable response was eight months, for both cohorts. The model provides an insight into inter-patient and intra-patient heterogeneity in the evolution of treatment resistance.

Predicting tumour response to anti-PD-1 immunotherapy with computational modelling.

Cancer immunotherapy is a rapidly developing field, with numerous drugs and therapy combinations waiting to be tested in pre-clinical and clinical settings. However, the costly and time-consuming trial-and-error approach to development of new treatment paradigms creates a research bottleneck, motivating the development of complementary approaches. Computational modelling is a compelling candidate for this task, however, difficulties associated with the validation of such models limit their use in pre-clinical and clinical settings. Here we propose a bottom-up deterministic computational model to simulate tumour response to treatment with anti-programmed-death-1 antibodies (anti-PD-1). The model was built with validation in mind, and so contains minimum number of parameters, and only four free parameters. Moreover, all model parameters can be measured experimentally. Free parameters were tuned by fitting the model to experimental data from the literature, using B16-F10 murine melanoma implanted into wild type (C57BL/6), as well as into immunodeficient (NSG) mice strains, and treated with anti-PD-1 antibodies. The model's predictive ability was verified on two independent datasets from literature with different but well-known inputs. To identify possible biomarkers of response to anti-PD-1 immunotherapy, sensitivity study of key model parameters was performed. Good agreement between the simulated tumour growth curves and the experimental data was achieved, with mean relative deviations in the range of 13%-20%. Our sensitivity study demonstrated that major histocompatibility complex (MHC) class I expression was the only parameter able to clearly discriminate responders from non-responders to anti-PD-1 therapy. Additionally, the results of sensitivity studies suggest that MHC class I expression might affect the predictive ability of other biomarkers that are currently used in the clinics, such as PD-1 ligand (PD-L1) expression. Interestingly, our model predicts the best response to anti-PD-1 therapy for subjects with moderate PD-L1 values. Such computational models show promise to support, guide and accelerate future immunotherapy research.

Dynamic 18F-FLT PET imaging of spatiotemporal changes in tumor cell proliferation and vasculature reveals the mechanistic actions of anti-angiogenic therapy.

Anti-angiogenic therapies target tumor vasculature and tumor cells, thus a concurrent assessment of these targets would lead to a greater understanding of therapeutic resistance and facilitate development of improved therapeutic strategies. We utilize dynamic 3'-deoxy-3'-18F-fluorothymidine positron emission tomography (18F-FLT PET) scanning to concurrently assess changes in tumor cell proliferation and vasculature during anti-angiogenic therapy, providing insight into how these therapies may be used effectively with combination chemotherapy. Thirty-three patients with advanced solid malignancies underwent treatment with vascular endothelial growth factor receptor inhibitor (VEGFR-TKI) axitinib on an intermittent schedule (two-weeks-on/one-week-off). Patients had up to three dynamic 18F-FLT PET/CT scans: at baseline, after two weeks of continuous VEGFR-TKI treatment, and following a one week treatment break. 18F-FLT kinetics were analyzed using a two-tissue compartment kinetic model. Kinetic parameters V b and K 1 were extracted to quantify changes in tumor vasculature and the 18F-FLT flux constant K i was calculated to quantify changes in tumor cell proliferation. Two weeks of continuous axitinib exposure led to decreases in V b (median -21%, P = 0.07), K 1 (median -39%, P < 0.01), and K i (median -37%, P < 0.01), corresponding to diminished tumor vasculature and cell proliferation that may antagonize treatment with concurrent chemotherapy. Axitinib treatment breaks led to significant increases in V b (median +42%, P < 0.01), K 1 (median +46%, P < 0.01), and K i (median +39%, P < 0.01) that is suggestive of an optimal time to schedule synergistic chemotherapy. Significant negative correlations (rho ⩽ -0.70, P < 0.01) were found between changes in tumor vasculature during axitinib exposure weeks and changes in tumor vasculature during treatment breaks. Imaging with dynamic 18F-FLT PET revealed new insights relating to the interplay of vascular and proliferative pharmacodynamics of axitinib therapy, facilitating a greater understanding of the mechanistic actions of VEGFR-TKIs. Increases in tumor vasculature and cell proliferation during VEGFR-TKI treatment breaks, suggests this period is an optimal time to schedule synergistic chemotherapy and warrants further investigation.

Comparison of DCE-MRI kinetic parameters and FMISO-PET uptake parameters in head and neck cancer patients.

PURPOSE: Tumor hypoxia is a major cause of radiation resistance, often present in various solid tumors. Dynamic [18 F]-fluoromisonidazole (FMISO) PET imaging is able to reliably assess tumor hypoxia. Comprehensive characterization of tumor microenvironment through FMISO-PET and dynamic contrast enhanced (DCE) MR multimodality imaging might be a valuable alternative to the dynamic FMISO-PET acquisition. The aim of this work was to explore the correlation between the FMISO-PET and DCE-MRI kinetic parameters. METHODS: This study was done on head and neck cancer patients (N = 6), who were imaged dynamically with FMISO-PET and DCE-MRI on the same day. Images were registered and analyzed for kinetics on a voxel basis. FMISO-PET images were analyzed with the two-tissue compartment three rate-constant model. Additionally, tumor-to-muscle ratio (TMR) maps were evaluated. DCE-MRI was analyzed with the extended Tofts model. Voxel-wise Pearson's coefficients were calculated for each patient to assess pairwise parameter correlations. RESULTS: Median correlations between FMISO uptake parameters and DCE-MRI kinetic parameters varied across the parameter pairs in the range from -0.05 to 0.71. The highest median correlation of r = 0.71 was observed for the pair Vb -vp , while the K1 -Ktrans median correlation was r = 0.45. Median correlation coefficients for the K1 -vp and the Ki -Ktrans pairs were r = 0.42 and r = 0.32, respectively. Correlations between FMISO uptake rate parameter Ki and DCE-MRI kinetic parameters varied substantially across the patients, whereas correlations between the FMISO and DCE-MRI vascular parameters were consistently high. Median TMR-K1 and TMR-Ktrans correlations were r = 0.52 and r = 0.46, respectively, but varied substantially across the patients. CONCLUSIONS: Based on this clinical evidence, we can conclude that the vascular fraction parameters obtained through DCE-MRI kinetic analysis or FMISO kinetic analysis measure the same biological property, while other kinetic parameters are unrelated. These results might be useful in the design of future clinical trials involving FMISO-PET/DCE-MR multimodality imaging for the assessment of tumor microenvironment.

Molecular Imaging to Plan Radiotherapy and Evaluate Its Efficacy.

Molecular imaging plays a central role in the management of radiation oncology patients. Specific uses of imaging, particularly to plan radiotherapy and assess its efficacy, require an additional level of reproducibility and image quality beyond what is required for diagnostic imaging. Specific requirements include proper patient preparation, adequate technologist training, careful imaging protocol design, reliable scanner technology, reproducible software algorithms, and reliable data analysis methods. As uncertainty in target definition is arguably the greatest challenge facing radiation oncology, the greatest impact that molecular imaging can have may be in the reduction of interobserver variability in target volume delineation and in providing greater conformity between target volume boundaries and true tumor boundaries. Several automatic and semiautomatic contouring methods based on molecular imaging are available but still need sufficient validation to be widely adopted. Biologically conformal radiotherapy (dose painting) based on molecular imaging-assessed tumor heterogeneity is being investigated, but many challenges remain to fully exploring its potential. Molecular imaging also plays increasingly important roles in both early (during treatment) and late (after treatment) response assessment as both a predictive and a prognostic tool. Because of potentially confounding effects of radiation-induced inflammation, treatment response assessment requires careful interpretation. Although molecular imaging is already strongly embedded in radiotherapy, the path to widespread and all-inclusive use is still long. The lack of solid clinical evidence is the main impediment to broader use. Recommendations for practicing physicians are still rather scarce. (18)F-FDG PET/CT remains the main molecular imaging modality in radiation oncology applications. Although other molecular imaging options (e.g., proliferation imaging) are becoming more common, their widespread use is limited by lack of tracer availability and inadequate reimbursement models. With the increasing presence of molecular imaging in radiation oncology, special emphasis should be placed on adequate training of radiation oncology personnel to understand the potential, and particularly the limitations, of quantitative molecular imaging applications. Similarly, radiologists and nuclear medicine specialists should be sensitized to the special need of the radiation oncologist in terms of quantification and reproducibility. Furthermore, strong collaboration between radiation oncology, nuclear medicine/radiology, and medical physics teams is necessary, as optimal and safe use of molecular imaging can be ensured only within appropriate interdisciplinary teams.

Optimizing an 18F-NaF and 18F-FDG cocktail for PET assessment of metastatic castration-resistant prostate cancer.

BACKGROUND: PET/computed tomography (CT) imaging with the sodium-(F)-fluoride/2-(F)-fluoro-2-deoxy-D-glucose (F-NaF/F-FDG) cocktail has been proposed for patients with osseous metastases. This work aimed to optimize the cocktail composition for patients with metastatic castration-resistant prostate cancer (mCRPC). MATERIALS AND METHODS: The study was carried out on six patients with mCRPC, with a total of 26 analyzed lesions. The patients were injected with F-NaF and F-FDG at separate time points. Dynamic PET/CT imaging recorded the uptake time course for both the tracers into osseous metastases. F-NaF and F-FDG uptakes were decoupled by kinetic analysis, which enabled calculation of F-NaF and F-FDG standardized uptake values (SUVs) images. Peak, mean, and total SUVs were evaluated for both tracers and all visible lesions. The F-NaF/F-FDG cocktail was optimized under the assumption that the contribution of both tracers to image formation is equal. SUV images from PET/CT imaging with a combination of F-NaF and F-FDG were generated for cocktail compositions with an F-NaF : F-FDG ratio varying from 1 : 8 to 1 : 2. RESULTS: The F-NaF peak and mean SUVs were on average four to five times higher than the F-FDG peak and mean SUVs, with an interlesion coefficient of variations of 20%. The total SUV for F-NaF was on average seven times higher than that for F-FDG. When the F-NaF : F-FDG ratio changed from 1 : 8 to 1 : 2, the typical SUV on the generated PET images increased by 50%, whereas the change in the uptake visual pattern was hardly noticeable. CONCLUSION: F-NaF and F-FDG in the cocktail contribute equally to image formation when the F-NaF : F-FDG ratio is 1 : 5. Therefore, we propose this ratio as the optimal cocktail composition for mCRPC patients. We also urge to strictly control the cocktail composition during any F-NaF/F-FDG cocktail PET/CT examination.

Comparison of NaF and FDG PET/CT for assessment of treatment response in castration-resistant prostate cancers with osseous metastases.

BACKGROUND: Assessment of skeletal metastases' response to therapy is a highly relevant but unresolved clinical problem. The main goal of this work was to compare pharmacodynamic responses to therapy assessed with positron emission tomography-computed tomography (PET/CT) using fluorine-18 sodium fluoride (NaF) and fluorine-18 fluorodeoxyglucose (FDG) as the tracers. MATERIALS AND METHODS: Patients with prostate cancer with known osseous metastases were treated with zibotentan (ZD4054) and imaged with combined dynamic NaF/FDG PET/CT before therapy (baseline), after 4 weeks of therapy (week 4), and after 2 weeks of treatment break (week 6). Kinetic analysis allowed comparison of the voxel-based tracer uptake rate parameter Ki, the vasculature parameters K1 (measuring perfusion/permeability) and Vb (measuring vasculature fraction in the tissue), and the standardized uptake values (SUVs). RESULTS: Correlations were high for the NaF and FDG peak uptake parameters (Ki and SUV correlations ranged from 0.57 to 0.88) and for vasculature parameters (K1 and Vb correlations ranged from 0.61 to 0.81). Correlation was low between the NaF and FDG week 4 Ki responses (ρ = 0.35; P = .084) but was higher for NaF and FDG week 6 Ki responses (ρ = 0.72; P < .0001). Correlations for vasculature responses were always low (ρ < 0.35). NaF and FDG uptakes in the osseous metastases were spatially dislocated, with overlap in the range from 0% to 80%. CONCLUSION: This study found that late NaF and FDG uptake responses are consistently correlated but that earlier uptake responses and all vasculature responses can be unrelated. This study also confirmed that FDG and NaF uptakes are spatially dislocated. Although treatment responses assessed with NaF and FDG may be correlated, using both tracers provides additional information.

Optimal scan time for evaluation of parathyroid adenoma with [(18)F]-fluorocholine PET/CT.

BACKGROUND: Parathyroid adenomas, the most common cause of primary hyperparathyroidism, are benign tumours which autonomously produce and secrete parathyroid hormone. [(18)F]-fluorocholine (FCH), PET marker of cellular proliferation, was recently demonstrated to accumulate in lesions representing enlarged parathyroid tissue; however, the optimal time to perform FCH PET/CT after FCH administration is not known. The aim of this study was to determine the optimal scan time of FCH PET/CT in patients with primary hyperparathyroidism. PATIENTS AND METHODS: 43 patients with primary hyperparathyroidism were enrolled in this study. A triple-phase PET/CT imaging was performed five minutes, one and two hours after the administration of FCH. Regions of interest (ROI) were placed in lesions representing enlarged parathyroid tissue and thyroid tissue. Standardized uptake value (SUVmean), retention index and lesion contrast for parathyroid and thyroid tissue were calculated. RESULTS: Accumulation of FCH was higher in lesions representing enlarged parathyroid tissue in comparison to the thyroid tissue with significantly higher SUVmean in the second and in the third phase (p < 0.0001). Average retention index decreased significantly between the first and the second phase and increased significantly between the second and the third phase in lesions representing enlarged parathyroid tissue and decreased significantly over all three phases in thyroid tissue (p< 0.0001). The lesion contrast of lesions representing enlarged parathyroid tissue and thyroid tissue was significantly better in the second and the third phase compared to the first phase (p < 0.05). CONCLUSIONS: According to the results the optimal scan time of FCH PET/CT for localization of lesions representing enlarged parathyroid tissue is one hour after administration of the FCH.

Heterogeneity in stabilization phenomena in FLT PET images of canines.

3'-((18)F)fluoro-3'-deoxy-L-thymidine (FLT) is a PET marker of cellular proliferation. Its tissue uptake rate is often quantified with a Standardized Uptake Value (SUV), although kinetic analysis provides a more accurate quantification. The purpose of this study is to investigate the heterogeneity in FLT stabilization phenomena. The study was done on 15 canines with spontaneously occurring sinonasal tumours. They were imaged dynamically for 90 min with FLT PET/CT twice; before and during the radiotherapy. Images were analyzed for kinetics on a voxel basis through compartmental analysis. Stabilization curves were calculated as a time-dependant correlation between the time-dependant SUV and the kinetic parameters (voxel values within the tumour were correlated). Stabilization curves were analyzed for stabilization speed, maximal correlation and correlation decrease following the maximal correlation. These stabilization parameters were correlated with the region-averaged kinetic parameters. The FLT SUV was highly correlated with vasculature fraction immediately post-injection, followed by maximum in correlation with the perfusion/permeability. At later times post-injection the FLT SUV was highly correlated (Pearson correlation coefficient above 0.95) with the FLT influx parameter for cases with tumour-averaged SUV(30-50 min) above 2, while others were indeterminate (correlation coefficients from 0.1 to 0.97). All cases with highly correlated SUV and FLT influx parameter had correlation coefficient within 0.5% of its maximum in the period of 30-50 min post-injection. Stabilization time was inversely proportional to the FLT influx rate. Correlation between the FLT SUV and FLT influx parameter dropped at later times post-injection with drop being proportional to the dephosphorylation rate. The FLT was found to be metabolically stable in canines. FLT PET imaging protocol should define minimal and maximal FLT uptake period, which would be 30-50 min for our patients. Additionally, kinetic analysis should be used when low FLT avidity is expected. Low SUVs should be treated with great caution.

Pharmacodynamic study using FLT PET/CT in patients with renal cell cancer and other solid malignancies treated with sunitinib malate.

PURPOSE: To characterize proliferative changes in tumors during the sunitinib malate exposure/withdrawal using 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) positron emission tomography (PET)/computed tomography (CT) imaging. PATIENTS AND METHODS: Patients with advanced solid malignancies and no prior anti-VEGF exposure were enrolled. All patients had metastatic lesions amenable to FLT PET/CT imaging. Sunitinib was initiated at the standard dose of 50 mg p.o. daily either on a 4/2 or 2/1 schedule. FLT PET/CT scans were obtained at baseline, during sunitinib exposure, and after sunitinib withdrawal within cycle #1 of therapy. VEGF levels and sunitinib pharmacokinetic (PK) data were assessed at the same time points. RESULTS: Sixteen patients (8 patients on 4/2 schedule and 8 patients on 2/1 schedule) completed all three planned FLT PET/CT scans and were evaluable for pharmacodynamic imaging evaluation. During sunitinib withdrawal (change from scans 2 to 3), median FLT PET standardized uptake value (SUV(mean)) increased +15% (range: -14% to 277%; P = 0.047) for the 4/2 schedule and +19% (range: -5.3% to 200%; P = 0.047) for the 2/1 schedule. Sunitinib PK and VEGF ligand levels increased during sunitinib exposure and returned toward baseline during the treatment withdrawal. CONCLUSIONS: The increase of cellular proliferation during sunitinib withdrawal in patients with renal cell carcinoma and other solid malignancies is consistent with a VEGF receptor (VEGFR) tyrosine kinase inhibitor (TKI) withdrawal flare. Univariate and multivariate analysis suggest that plasma VEGF is associated with this flare, with an exploratory analysis implying that patients who experience less clinical benefit have a larger withdrawal flare. This might suggest that patients with a robust compensatory response to VEGFR TKI therapy experience early "angiogenic escape."