Eric P. Visser

FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging: version 1.0

The aim of this guideline is to provide a minimum standard for the acquisition and interpretation of PET and PET/CT scans with [18F]-fluorodeoxyglucose (FDG). This guideline will therefore address general information about [18F]-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) and is provided to help the physician and physicist to assist to carrying out, interpret, and document quantitative FDG PET/CT examinations, but will concentrate on the optimisation of diagnostic quality and quantitative information.

FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0

The purpose of these guidelines is to assist physicians in recommending, performing, interpreting and reporting the results of FDG PET/CT for oncological imaging of adult patients. PET is a quantitative imaging technique and therefore requires a common quality control (QC)/quality assurance (QA) procedure to maintain the accuracy and precision of quantitation. Repeatability and reproducibility are two essential requirements for any quantitative measurement and/or imaging biomarker. Repeatability relates to the uncertainty in obtaining the same result in the same patient when he or she is examined more than once on the same system. However, imaging biomarkers should also have adequate reproducibility, i.e. the ability to yield the same result in the same patient when that patient is examined on different systems and at different imaging sites. Adequate repeatability and reproducibility are essential for the clinical management of patients and the use of FDG PET/CT within multicentre trials. A common standardised imaging procedure will help promote the appropriate use of FDG PET/CT imaging and increase the value of publications and, therefore, their contribution to evidence-based medicine. Moreover, consistency in numerical values between platforms and institutes that acquire the data will potentially enhance the role of semiquantitative and quantitative image interpretation. Precision and accuracy are additionally important as FDG PET/CT is used to evaluate tumour response as well as for diagnosis, prognosis and staging. Therefore both the previous and these new guidelines specifically aim to achieve standardised uptake value harmonisation in multicentre settings.

The Netherlands protocol for standardisation and quantification of FDG whole body PET studies in multi-centre trials.

IntroductionSeveral studies have shown the usefulness of positron emission tomography (PET) quantification using standardised uptake values (SUV) for diagnosis and staging, prognosis and response monitoring. Many factors affect SUV, such as patient preparation procedures, scan acquisition, image reconstruction and data analysis settings, and the variability in methodology across centres prohibits exchange of SUV data. Therefore, standardisation of 2-[18F] fluoro-2-deoxy-D-glucose (FDG) PET whole body procedures is required in multi-centre trials.MethodsA protocol for standardisation of quantitative FDG whole body PET studies in the Netherlands (NL) was defined. This protocol is based on standardisation of: (1) patient preparation; (2) matching of scan statistics by prescribing dosage as function of patient weight, scan time per bed position, percentage of bed overlap and image acquisition mode (2D or 3D); (3) matching of image resolution by prescribing reconstruction settings for each type of scanner; (4) matching of data analysis procedure by defining volume of interest methods and SUV calculations and; (5) finally, a multi-centre QC procedure is defined using a 20-cm diameter phantom for verification of scanner calibration and the NEMA NU 2 2001 Image Quality phantom for verification of activity concentration recoveries (i.e., verification of image resolution and reconstruction convergence).DiscussionThis paper describes a protocol for standardization of quantitative FDG whole body multi-centre PET studies.ConclusionThe protocol was successfully implemented in the Netherlands and has been approved by the Netherlands Society of Nuclear Medicine.

Spatial Resolution and Sensitivity of the Inveon Small-Animal PET Scanner

The Inveon small-animal PET scanner is characterized by a large, 127-mm axial length and a 161-mm crystal ring diameter. The associated high sensitivity is obtained by using all lines of response (LORs) up to the maximum ring difference (MRD) of 79, for which the most oblique LORs form acceptance angles of 38.3° with transaxial planes. The result is 2 phenomena that are normally not encountered in PET scanners: a parallax or depth-of-interaction effect in the axial direction and the breakdown of Fourier rebinning (FORE). Both effects cause a deterioration of axial spatial resolution. Limiting the MRD to smaller values reduces this axial blurring at the cost of sensitivity. Alternatively, 3-dimensional (3D) reconstruction techniques can be used in which the rebinning step is absent. The aim of this study was to experimentally determine the spatial resolution and sensitivity of the Inveon for its whole field of view (FOV). Methods: Spatial resolution and sensitivity were measured using filtered backprojection (FBP) with FORE, FBP with LOR angle-weighted adapted FORE (AFORE), and 3D ordered-subset expectation maximization followed by maximum a posteriori reconstruction (OSEM3D/MAP). Results: Tangential and radial full width at half maximum (FWHM) showed almost no dependence on the MRD using FORE and FBP. Tangential FWHMs were 1.5 mm in the center of the FOV (CFOV) and 1.8 mm at the edge of the FOV (EFOV). Radial FWHMs were 1.5 and 3.0 mm in the CFOV and EFOV, respectively. In contrast, axial FWHMs increased with the MRD and ranged between 1.1 and 2.0 mm in the CFOV and between 1.5 and 2.7 mm in the EFOV for a MRD between 1 and 79. AFORE improved the axial resolution for a large part of the FOV, but image noise increased. OSEM3D/MAP yielded uniform spatial resolution in all directions, with an average FWHM of 1.65 ± 0.06 mm. Sensitivity in the CFOV for the default energy and coincidence time window was 0.068; peak sensitivity was 0.111. Conclusion: The Inveon showed high spatial resolution and high sensitivity, both of which can be maintained using OSEM3D/MAP reconstruction instead of rebinning and 2D algorithms.

Chemotherapy Response Evaluation with 18F-FDG PET in Patients with Non-Small Cell Lung Cancer

The aim of this prospective study was to evaluate the value of 18F-FDG PET for the assessment of chemotherapy response in patients with non–small cell lung cancer. Furthermore, part of the objective of this study was to compare 2 methods to quantify changes in glucose metabolism. Methods: In 51 patients, dynamic 18F-FDG PET was performed before and at 5–8 wk into treatment. Simplified methods to measure glucose metabolism (standardized uptake value [SUV]) and quantitative measures (metabolic rate of glucose [MRGlu]), derived from Patlak analysis, were evaluated. The overall survival and progression-free survival with respect to MRGlu and SUV were calculated using Kaplan–Meier estimates. Fractional changes in tumor glucose use were stratified by the median value and also the predefined EORTC (European Organization for Research and Treatment of Cancer) metabolic response criteria, and criteria applying cutoff levels similar to those of RECIST (Response Evaluation Criteria in Solid Tumors) were evaluated. Results: When stratifying at the median value of ΔMRGlu and ΔSUV, the difference in overall survival (P = 0.017 for ΔMRGlu, P = 0.018 for ΔSUV) and progression-free survival (P = 0.002 for ΔMRGlu, P = 0.0009 for ΔSUV) was highly significant. When applying the predefined criteria for metabolic response, the cutoff levels as also used for size measurement (RECIST) showed significant differences for ΔSUV between response categories in progression-free survival (P = 0.0003) as well as overall survival (P = 0.027). Conclusion: The degree of chemotherapy-induced changes in tumor glucose metabolism as determined by 18F-FDG PET is highly predictive for patient outcome, stratifying patients into groups with widely differing overall survival and progression-free survival probabilities. The use of 18F-FDG PET for therapy monitoring seems clinically feasible, because simplified methods to measure tumor glucose use (SUV) are sufficiently reliable and can replace more complex, quantitative measures (MRGlu) in this patient population.

Image-quality assessment for several positron emitters using the NEMA NU 4-2008 standards in the Siemens Inveon small-animal PET scanner.

The positron emitters 18F, 68Ga, 124I, and 89Zr are all relevant in small-animal PET. Each of these radionuclides has different positron energies and ranges and a different fraction of single photons emitted. Average positron ranges larger than the intrinsic spatial resolution of the scanner (for 124I and 68Ga) will deteriorate the effective spatial resolution and activity recovery coefficient (RC) for small lesions or phantom structures. The presence of single photons (for 124I and 89Zr) could increase image noise and spillover ratios (SORs). Methods: Image noise, expressed as percentage SD in a uniform region (%SD), RC, and SOR (in air and water) were determined using the NEMA NU 4 small-animal image-quality phantom filled with 3.7 MBq of total activity of 18F, 68Ga, 124I, or 89Zr. Filtered backprojection (FBP), ordered-subset expectation maximization in 2 dimensions, and maximum a posteriori (MAP) reconstructions were compared. In addition to the NEMA NU 4 image-quality parameters, spatial resolutions were determined using small glass capillaries filled with these radionuclides in a water environment. Results: The %SD for 18F, 68Ga, 124I, and 89Zr using FBP was 6.27, 6.40, 6.74, and 5.83, respectively. The respective RCs were 0.21, 0.11, 0.12, and 0.19 for the 1-mm-diameter rod and 0.97, 0.65, 0.64, and 0.88 for the 5-mm-diameter rod. SORs in air were 0.01, 0.03, 0.04, and 0.01, respectively, and in water 0.02, 0.10, 0.13, and 0.02. Other reconstruction algorithms gave similar differences between the radionuclides. MAP produced the highest RCs. For the glass capillaries using FBP, the full widths at half maximum for 18F, 68Ga, 124I, and 89Zr were 1.81, 2.46, 2.38, and 1.99 mm, respectively. The corresponding full widths at tenth maximum were 3.57, 6.52, 5.87, and 4.01 mm. Conclusion: With the intrinsic spatial resolution (≈1.5 mm) of this latest-generation small-animal PET scanner, the finite positron range has become the limiting factor for the overall spatial resolution and activity recovery in small structures imaged with 124I and 68Ga. The presence of single photons had only a limited effect on the image noise. MAP, as compared with the other reconstruction algorithms, increased RC and decreased %SD and SOR.

Methodological considerations in quantification of oncological FDG PET studies.

PurposeThis review aims to provide insight into the factors that influence quantification of glucose metabolism by FDG PET images in oncology as well as their influence on repeated measures studies (i.e. treatment response assessment), offering improved understanding both for clinical practice and research.MethodsStructural PubMed searches have been performed for the many factors affecting quantification of glucose metabolism by FDG PET. Review articles and references lists have been used to supplement the search findings.ResultsBiological factors such as fasting blood glucose level, FDG uptake period, FDG distribution and clearance, patient motion (breathing) and patient discomfort (stress) all influence quantification. Acquisition parameters should be adjusted to maximize the signal to noise ratio without exposing the patient to a higher than strictly necessary radiation dose. This is especially challenging in pharmacokinetic analysis, where the temporal resolution is of significant importance. The literature is reviewed on the influence of attenuation correction on parameters for glucose metabolism, the effect of motion, metal artefacts and contrast agents on quantification of CT attenuation-corrected images. Reconstruction settings (analytical versus iterative reconstruction, post-reconstruction filtering and image matrix size) all potentially influence quantification due to artefacts, noise levels and lesion size dependency. Many region of interest definitions are available, but increased complexity does not necessarily result in improved performance. Different methods for the quantification of the tissue of interest can introduce systematic and random inaccuracy.ConclusionsThis review provides an up-to-date overview of the many factors that influence quantification of glucose metabolism by FDG PET.

A Curve-Fitting Approach to Estimate the Arterial Plasma Input Function for the Assessment of Glucose Metabolic Rate and Response to Treatment

For the quantification of dynamic 18F-FDG PET studies, the arterial plasma time–activity concentration curve (APTAC) needs to be available. This can be obtained using serial sampling of arterial blood or an image-derived input function (IDIF). Arterial sampling is invasive and often not feasible in practice; IDIFs are biased because of partial-volume effects and cannot be used when no large arterial blood pool is in the field of view. We propose a mathematic function, consisting of an initial linear rising activity concentration followed by a triexponential decay, to describe the APTAC. This function was fitted to 80 oncologic patients and verified for 40 different oncologic patients by area-under-the-curve (AUC) comparison, Patlak glucose metabolic rate (MRglc) estimation, and therapy response monitoring (ΔMRglc). The proposed function was compared with the gold standard (serial arterial sampling) and the IDIF. Methods: To determine the free parameters of the function, plasma time–activity curves based on arterial samples in 80 patients were fitted after normalization for administered activity (AA) and initial distribution volume (iDV) of 18F-FDG. The medians of these free parameters were used for the model. In 40 other patients (20 baseline and 20 follow-up dynamic 18F-FDG PET scans), this model was validated. The population-based curve, individually calibrated by AA and iDV (APTACAA/iDV), by 1 late arterial sample (APTAC1sample), and by the individual IDIF (APTACIDIF), was compared with the gold standard of serial arterial sampling (APTACsampled) using the AUC. Additionally, these 3 methods of APTAC determination were evaluated with Patlak MRglc estimation and with ΔMRglc for therapy effects using serial sampling as the gold standard. Results: Excellent individual fits to the function were derived with significantly different decay constants (P < 0.001). Correlations between AUC from APTACAA/iDV, APTAC1sample, and APTACIDIF with the gold standard (APTACsampled) were 0.880, 0.994, and 0.856, respectively. For MRglc, these correlations were 0.963, 0.994, and 0.966, respectively. In response monitoring, these correlations were 0.947, 0.982, and 0.949, respectively. Additional scaling by 1 late arterial sample showed a significant improvement (P < 0.001). Conclusion: The fitted input function calibrated for AA and iDV performed similarly to IDIF. Performance improved significantly using 1 late arterial sample. The proposed model can be used when an IDIF is not available or when serial arterial sampling is not feasible.

Comparison of Tumor Volumes Derived from Glucose Metabolic Rate Maps and SUV Maps in Dynamic 18F-FDG PET

Tumor delineation using noninvasive medical imaging modalities is important to determine the target volume in radiation treatment planning and to evaluate treatment response. It is expected that combined use of CT and functional information from 18F-FDG PET will improve tumor delineation. However, until now, tumor delineation using PET has been based on static images of 18F-FDG standardized uptake values (SUVs). 18F-FDG uptake depends not only on tumor physiology but also on blood supply, distribution volume, and competitive uptake processes in other tissues. Moreover, 18F-FDG uptake in tumor tissue and in surrounding healthy tissue depends on the time after injection. Therefore, it is expected that the glucose metabolic rate (MRglu) derived from dynamic PET scans gives a better representation of the tumor activity than does SUV. The aim of this study was to determine tumor volumes in MRglu maps and to compare them with the values from SUV maps. Methods: Twenty-nine lesions in 16 dynamic 18F-FDG PET scans in 13 patients with non–small cell lung carcinoma were analyzed. MRglu values were calculated on a voxel-by-voxel basis using the standard 2-compartment 18F-FDG model with trapping in the linear approximation (Patlak analysis). The blood input function was obtained by arterial sampling. Tumor volumes were determined in SUV maps of the last time frame and in MRglu maps using 3-dimensional isocontours at 50% of the maximum SUV and the maximum MRglu, respectively. Results: Tumor volumes based on SUV contouring ranged from 1.31 to 52.16 cm3, with a median of 8.57 cm3. Volumes based on MRglu ranged from 0.95 to 37.29 cm3, with a median of 3.14 cm3. For all lesions, the MRglu volumes were significantly smaller than the SUV volumes. The percentage differences (defined as 100% × (VMRglu − VSUV)/VSUV, where V is volume) ranged from −12.8% to −84.8%, with a median of −32.8%. Conclusion: Tumor volumes from MRglu maps were significantly smaller than SUV-based volumes. These findings can be of importance for PET-based radiotherapy planning and therapy response monitoring.

Glucose Metabolism in NSCLC Is Histology-Specific and Diverges the Prognostic Potential of 18FDG-PET for Adenocarcinoma and Squamous Cell Carcinoma

Introduction: Biological features of non–small-cell lung carcinomas (NSCLCs) are important determinants for prognosis. In this study, differences in glucose metabolism between adeno- and squamous cell NSCLCs were quantified using the hypoxia and glycolysis-related markers glucose transporter 1 (GLUT1), carbonic anhydrase IX (CAIX), monocarboxylate transporter 1 (MCT1) and 4 (MCT4) vasculature, and 18-fluoro-2-deoxyglucose (18FDG)-uptake. Relevance of these markers for disease-free survival (DFS) was analyzed. Methods: Patients with curatively resected stage I to II and resectable stage IIIA, cN0-1 adeno- or squamous cell NSCLC, of whom fresh-frozen lung resection biopsies and pretreatment 18FDG-positron emission tomography (PET) scans were available, were included in this study (n = 108). 18FDG-uptake was quantified by calculating total lesion glycolysis (TLG). Metabolic marker expression was measured by immunofluorescent staining (protein) and quantitative polymerase chain reaction (messenger ribonucleic acid [mRNA]). Patients were retrospectively evaluated for DFS. Results: mRNA and protein expression of metabolic markers, with the exception of MCT4, and TLG were higher in squamous cell carcinomas than in adenocarcinomas, whereas adenocarcinomas were better vascularized. Adenocarcinomas had a worse DFS compared with squamous cell carcinomas (p = 0.016) based on the potential to metastasize. High TLG was associated with a worse DFS only in adenocarcinomas. Conclusion: Our findings suggest that the adenocarcinomas exhibit glycolysis under normoxic conditions, whereas squamous cell carcinomas are exposed to diffusion-limited hypoxia resulting in a very high anaerobic glycolytic rate. Although squamous cell carcinomas have a higher 18FDG-uptake, in general regarded as a poor prognostic factor, adenocarcinomas have a higher metastatic potential and a worse DFS. These findings show that 18FDG-PET should be interpreted in relation to histology. This may improve the prognostic potential of 18FDG-PET and may aid in exploiting 18FDG-PET in treatment strategies allied to histology.