U Simoncic

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′-[18F]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 (SUVmean) 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.” Clin Cancer Res; 17(24); 7634–44. ©2011 AACR.

Comparison of NaF and FDG PET/CT for Assessment of Treatment Response in Castration-Resistant Prostate Cancers With Osseous Metastases

BACKGROUNDnAssessment 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.nnnMATERIALS AND METHODSnPatients 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).nnnRESULTSnCorrelations 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%.nnnCONCLUSIONnThis 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.

Image-derived input function with factor analysis and a-priori information.

Background Quantitative PET studies often require the cumbersome and invasive procedure of arterial cannulation to measure the input function. This study sought to minimize the number of necessary blood samples by developing a factor-analysis-based image-derived input function (IDIF) methodology for dynamic PET brain studies. Materials and methods IDIF estimation was performed as follows: (a) carotid and background regions were segmented manually on an early PET time frame; (b) blood-weighted and tissue-weighted time–activity curves (TACs) were extracted with factor analysis; (c) factor analysis results were denoised and scaled using the voxels with the highest blood signal; (d) using population data and one blood sample at 40u2009min, whole-blood TAC was estimated from postprocessed factor analysis results; and (e) the parent concentration was finally estimated by correcting the whole-blood curve with measured radiometabolite concentrations. The methodology was tested using data from 10 healthy individuals imaged with [11C](R)-rolipram. The accuracy of IDIFs was assessed against full arterial sampling by comparing the area under the curve of the input functions and by calculating the total distribution volume (VT). Results The shape of the image-derived whole-blood TAC matched the reference arterial curves well, and the whole-blood area under the curves were accurately estimated (mean error 1.0±4.3%). The relative Logan-VT error was −4.1±6.4%. Compartmental modeling and spectral analysis gave less accurate VT results compared with Logan. Conclusion A factor-analysis-based IDIF for [11C](R)-rolipram brain PET studies that relies on a single blood sample and population data can be used for accurate quantification of Logan-VT values.

Cumulative Input Function Method for Linear Compartmental Models and Spectral Analysis in PET

Compartmental modeling and spectral analysis are often used for tracer kinetic modeling in positron emission tomography (PET). The concentrations in kinetic equations are usually considered to be instantaneous, whereas PET data are inherently integrated over time, which leads to uncertainties in the results. A new formalism for kinetic analysis that uses cumulative tracer concentrations and avoids approximating the image-derived input function and PET measurements with midframe instantanous values was developed. We assessed the improvements of the new formalism over the midframe approximation methods for three commonly used radiopharmaceuticals: [11C]raclopride, 2′-deoxy-2′-[18F]fluoro-d-glucose (FDG), and 3′-deoxy-3′-[18F]fluoro-thymidine (FLT). We found that improvements are case dependent and often not negligible. Improvements for determination of binding potential for [11C]raclopride ranged from 5% to 25%. Improvements in estimation accuracy of FDG and FLT microparameters ranged up to 25%. On the other hand, estimation of macroparameter K i = K1k3/(k2 + k3) for FDG or FLT did not show significant benefit with the new method; only modest improvement up to 2% was observed. Assessment of the benefits of using new method is far from being exhaustive, but possibly significant improvement was demonstrated. Therefore, we consider the proposed algorithm a necessary component of any kinetic analysis software.

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

BackgroundPET/computed tomography (CT) imaging with the sodium-(18F)-fluoride/2-(18F)-fluoro-2-deoxy-D-glucose (18F-NaF/18F-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 methodsThe study was carried out on six patients with mCRPC, with a total of 26 analyzed lesions. The patients were injected with 18F-NaF and 18F-FDG at separate time points. Dynamic PET/CT imaging recorded the uptake time course for both the tracers into osseous metastases. 18F-NaF and 18F-FDG uptakes were decoupled by kinetic analysis, which enabled calculation of 18F-NaF and 18F-FDG standardized uptake values (SUVs) images. Peak, mean, and total SUVs were evaluated for both tracers and all visible lesions. The 18F-NaF/18F-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 18F-NaF and 18F-FDG were generated for cocktail compositions with an 18F-NaFu2009:u200918F-FDG ratio varying from 1u2009:u20098 to 1u2009:u20092. ResultsThe 18F-NaF peak and mean SUVs were on average four to five times higher than the 18F-FDG peak and mean SUVs, with an interlesion coefficient of variations of 20%. The total SUV for 18F-NaF was on average seven times higher than that for 18F-FDG. When the 18F-NaFu2009:u200918F-FDG ratio changed from 1u2009:u20098 to 1u2009:u20092, the typical SUV on the generated PET images increased by 50%, whereas the change in the uptake visual pattern was hardly noticeable. Conclusion18F-NaF and 18F-FDG in the cocktail contribute equally to image formation when the 18F-NaFu2009:u200918F-FDG ratio is 1u2009:u20095. Therefore, we propose this ratio as the optimal cocktail composition for mCRPC patients. We also urge to strictly control the cocktail composition during any 18F-NaF/18F-FDG cocktail PET/CT examination.

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 90u2009min 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(30-50u2009min) 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 30-50u2009min 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 30-50u2009min for our patients. Additionally, kinetic analysis should be used when low FLT avidity is expected. Low SUVs should be treated with great caution.

TU‐G‐211‐07: Combined NaF PET and FDG PET Based Assesment of Bone Metastasis Response after Chemotherapy Using Kinetic Analysis

Purpose: The differentiation between the residual tumor activity and the osseous reaction to the tumor is essential for therapy assessment of bone metastases. The 18‐F‐Sodium Fluoride (NaF) uptake reflects the osteoblastic process, while the FDG uptake reflects the tumor metabolism. The purpose of this study was to evaluate the assessment of treatment response with the kinetic analysis of concurrent NaF/FDG PET/CT images for specific clinical cases. Methods: Three prostate adenocarcinomas were treated with chemotherapy and imaged twice with NaF/FDG PET/CT: a baseline scan and a second scan after four weeks of chemotherapy. The NaF/FDG PET/CT imaging started with NaF injection, followed by 100 min dynamic PETimaging. Next, FDG was injected and followed by an additional 45 min of dynamic PETimaging. Macroparameters K_NaF and K_FDG (defined as K=K1×k3/(k2+k3)) were obtained by compartmental kinetic analysis. The accuracy of the kinetic parameter estimations was evaluated with simulations. Bone metastases were segmented (29 total). The ratio of mid‐therapy to pre‐therapy mean K_FDG and K_NaF parameters, which measured the response to therapy, was calculated for each metastasis. Results: The simulations revealed that the K_NaF and K_FDG estimations are highly correlated to the simulated value (r=0.9) while an estimated error is 50%. The K_FDG response and the K_NaF response are moderately correlated (r=0.7), but the mean K_FDG response over all the metastases is 0.7 while the mean K_NaF response is 0.9. The patterns in K_FDG and K_NaF parametric images are similar, but displaced and slightly distorted. Conclusions: Tumor metabolism and bone repair process can be imaged separately at the same time point using the presented imaging protocol, which was validated with simulations. The addition of FDG PETimaging to the osseous NaF PETimaging provides additional information to treatment response and has the potential to improve the assessment of bone metastasis in therapy.

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%, Pu2009u2009=u2009u20090.07), K 1 (median -39%, Pu2009u2009<u2009u20090.01), and K i (median -37%, Pu2009u2009<u2009u20090.01), 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 (medianu2009u2009+42%, Pu2009u2009<u2009u20090.01), K 1 (medianu2009u2009+46%, Pu2009u2009<u2009u20090.01), and K i (medianu2009u2009+39%, Pu2009u2009<u2009u20090.01) that is suggestive of an optimal time to schedule synergistic chemotherapy. Significant negative correlations (rhou2009u2009⩽u2009u2009-0.70, Pu2009u2009<u2009u20090.01) 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.

MO-AB-BRA-06: Dynamic FLT PET for Investigating Potential Synergistic Therapeutic Targets During Anti-Angiogenic Treatment

PURPOSEnNovel treatment strategies for metastatic cancer patients involve synergistically combining treatments with the hope of improving outcomes. This study investigated changes in tumor proliferative and vascular characteristics derived from dynamic [F-18]FLT PET during antiangiogenic treatment with the goal of identifying synergistic treatment opportunities.nnnMETHODSnPatients with various solid cancers underwent continuous three-week cycles of anti-angiogenic treatment with intermittent dosing (two-weeks-on/one-week-off). Patients received up to six dynamic FLT PET/CT scans (days 0, 14, and 21 of cycle 1 (C1) and cycle 3 (C3)). Tumor proliferative (Kflt, net uptake rate) and vascular parameters (K1 blood-to-tissue transfer; Vb, vascular fraction) were calculated using a two-tissue compartment four-rate parameter kinetic model. Relative changes in these parameters, from day 0 to 14 (TxResp) and day 14 to 21 (offTxResp), were calculated. Significant differences were tested using Wilcoxon signed-rank test and significant correlations were tested using Spearman correlation.nnnRESULTSnThirty patients were evaluable for C1 offTxResp with median values for Kflt, K1, and Vb of +30%, +35% and +30%, respectively. The fractions of patients with positive C1 offTxResp were: 21/30 for Ki, 24/30 for K1, 21/30 for Vb, and 12/30 had positive offTxResp for all three kinetic parameters. The offTxResp in C3 was not significantly different from C1 for any of the kinetic parameters. Significant correlations were found between TxResp and offTxResp in C1 for Kflt (ρ=-0.52, p=0.014), K1 (ρ=-0.61, p=0.003) and Vb (ρ=-0.80, p<0.001). Similar correlations were found for Kflt (ρ=-1, p=0.017) and K1 (ρ=-1, p=0.017) for the five patients evaluable in C3.nnnCONCLUSIONnDynamic FLT PET showed evidence of distinct vascular and proliferative increases during off treatment weeks that could potentially be targeted with synergistic therapy. Early changes in kinetic parameters were correlated with later changes suggesting potential for early prediction of vascular and proliferative changes during off treatment weeks.

WE-H-207A-05: Spatial Co-Localization of F-18 NaF Vs. F-18 FDG Defined Disease Volumes

PURPOSEnBoth [F-18]NaF and [F-18]FDG show promise for quantitative PET/CT assessment in metastatic prostate cancer to bone. Broad agreement between the tracers has been shown but voxel-wise correspondence has not been explored in depth. This study evaluates the spatial co-localization of [F-18]NaF PET and [F-18]FDG PET in bone lesions.nnnMETHODSnSeventy-three lesion contours were identified in six patients receiving dynamic NaF PET/CT and FDG PET/CT scans two hours apart using identical fields-of-view. Tracer uptake (SUV) reflecting 60 minutes post-injection was modeled from kinetic parameters. Lesions were segmented by a physician separately on NaF PET and FDG PET. PET images were rigidly aligned using skeletal references on CT images. Lesion size, degree of overlap, voxel-wise tracer uptake values (SUV), and CT density distributions were compared using Dice coefficient, Positive Predictive Value (PPV), and Spearman rank correlation tests.nnnRESULTSnAcross all patients, 42 lesions were identified on NaF PET (median 1.4 cm3 , range <1-204 cm3 ) compared to 31 using FDG PET (median 1.8 cm3 , range <1-244 cm3 ). Spatial cooccurrence was found in 25 lesion pairs. Lesions on NaF PET had PPV of 0.91 and on FDG a PPV of 0.65. Overall, NaF-defined lesions were 47% (±24%) larger by volume with moderate overlap to FDG, resulting in mean Dice coefficient of 34% (±22%). In areas of overlap, voxel-wise correlation of NaF and FDG SUV was moderate (ρ=0.56). Expanding to regions of non-spatial overlap, voxels contained in FDG-only contours were almost exclusively low HU (median 118), compared to dense regions of NaF-only voxels (median 250). In sclerotic sub-volumes (HU > 300) NaF-defined contours encompassed 83% of total FDG volume.nnnCONCLUSIONnModerate voxel-wise correlation of FDG and NaF PET/CT uptake was observed. Spatial discrepancies in FDG and NaF PET/CT imaging of boney metastases could be influenced by poor sensitivity of FDG PET/CT in sclerotic regions. Funded by Prostate Cancer Foundation.