PET/CT in lung cancer: Influence of contrast medium on quantitative and clinical assessment

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1 DOI /s ONCOLOGY PET/CT in lung cancer: Influence of contrast medium on quantitative and clinical assessment Florian F. Behrendt Yavuz Temur Frederik A. Verburg Moritz Palmowski Thomas Krohn Hubertus Pietsch Christiane K. Kuhl Felix M. Mottaghy Received: 22 March 2012 /Revised: 17 April 2012 /Accepted: 27 April 2012 # European Society of Radiology 2012 Abstract Objectives To evaluate the influence of intravenous contrast medium and different contrast medium phases on attenuation correction, PET image quality and clinical staging in combined PET/CT in patients with a suspicion of lung cancer. Methods Sixty patients with a suspicion of lung cancer were prospectively enrolled for combined 18 F-FDG-PET/CT examination. PET images were reconstructed with non-enhanced Y. Temur : F. A. Verburg : M. Palmowski : T. Krohn : F. M. Mottaghy Department of Nuclear Medicine, RWTH Aachen University, Aachen, Germany F. A. Verburg : F. M. Mottaghy Department of Nuclear Medicine, Maastricht University Medical Center, Maastricht, The Netherlands M. Palmowski : C. K. Kuhl Department of Radiology, RWTH Aachen University, Aachen, Germany M. Palmowski Department of Experimental Molecular Imaging, RWTH Aachen University, Aachen, Germany H. Pietsch Contrast Media Research, Bayer Healthcare AG, Berlin, Germany F. F. Behrendt (*) Department of Nuclear Medicine, University Hospital, RWTH-Aachen University, Pauwelsstrasse 30, Aachen, Germany fbehrendt@ukaachen.de and arterial and venous phase contrast CT. Maximum and mean standardised uptake values (SUVmax and SUVmean) and contrast enhancement (HU) were determined in the subclavian vein, ascending aorta, abdominal aorta, inferior vena cava, portal vein, liver and kidney and lung tumour. PET data were evaluated visually for clinical staging and image quality. Results SUVmax was significantly increased between contrast and non-contrast PET/CT at all anatomic sites (all P< 0.001). SUVmax was significantly increased for arterial PET/ CT compared to venous PET/CT in the arteries (all P<0.001). Venous PET/CT resulted in significantly higher SUVmax values compared to arterial PET/CT in the parenchymatous organs (all P<0.05). Visual clinical evaluation of malignant lesions showed no differences between contrast and noncontrast PET/CT (P01.0). Conclusions Contrast enhanced CT is suitable for attenuation correction in combined PET/CT in lung cancer; it affects neither the clinical assessment nor image quality of the PET images. Key Points Positron emission tomography combined with computed tomography is now a mainstream investigation There has been debate about whether CT contrast agents affect PET results Contrast-enhanced CT is satisfactory for attenuation correction in lung cancer PET/CT Multiphase CT does not affect PET; additional unenhanced CT is unnecessary For quantitative follow-up PET analysis, an identical PET/ CT protocol is required Keywords PET/CT. Attenuation correction. Contrast medium. Lung cancer. SUV

2 Introduction Combined positron emission tomography (PET) and computed tomography (CT) (PET/CT) are widely used imaging procedures for the diagnosis, staging and follow-up of cancer patients. Many studies have shown the superiority of PET/CT compared to PET or CT alone, and consequently, PET/CT is now considered a standard of care [1 4]. Especially in lung cancer the benefit in terms of greater diagnostic accuracy of combined PET/CT imaging for detecting primary tumour, lymph node and distant metastases in comparison with CT or PET alone has been firmly established [5, 6]. In order to obtain a diagnostically adequate CT, the application of intravenous contrast media may be required during the CT acquisition phase of PET/CT. However, no consensus for the use of intravenous contrast media exists and injection protocols vary considerably between different institutions [7 9]. Furthermore, an influence on PET data resulting from the use of a contrast-enhanced CT for attenuation correction cannot be ruled out. Previous studies have suggested a potential overcorrection of PET data caused by the higher attenuation coefficients of the contrast-enhanced CT [10, 11]. As this might result in artefacts and inaccuracies in PET, some institutions obtain an unenhanced low-dose CT data acquisition for attenuation correction of the PET data in addition to the diagnostic CT or do not use intravenous contrast medium at all, thereby losing potentially useful diagnostic information. On the other hand, several studies have documented that the clinical impact of such attenuation correction differences seems to be small [12 15] if the venous contrast medium phase of the CT is used for attenuation correction. The aim of the present study was to compare both quantitatively and clinically the use of CT without intravenous contrast medium, CT acquired in the venous contrast medium phase and CT in the arterial contrast medium phase in patients with a suspicion of lung cancer. Materials and methods Patient population Sixty consecutive patients (47 men, 13 women; mean age 64±11 years, range: years) with a suspicion of lung cancer who were scheduled for PET/CT were prospectively enrolled in this study. The study was approved by the institutional review board and all patients gave informed consent. All patients underwent combined PET/CT including a diagnostic contrast-enhanced CT. Mean body weight was 76±13 kg, mean height was 173±8 cm and mean BMI was 25.3±3.3 kg/m2. Final diagnoses were obtained from histopathological evaluation of biopsies and clinical followup in all cases. Lung cancer was confirmed in 54 patients, 2 patients had metastases of other carcinomas, 2 were diagnosed with sarcoidosis and 2 with infectious infiltration, and 1 had a calcified nodule without further identified cause. PET/CT protocol All patients fasted for at least 6 h before the examination, and the blood glucose level was confirmed to be lower than 160 mg/dl. Patients received 3 MBq/kg body weight 18 F- FDG and were examined 60 min after injection. PET/CT acquisition was performed on a Philips Gemini TF 16 PET/CT (Philips Medical Systems, Best, The Netherlands) [16]. This system is time-of-flight (TOF) capable, and has fully three-dimensional (3D) PET capabilities together with a 16-slice Brilliance-CT. Patients were examined in cranio-caudal orientation with their arms raised to decrease beam-hardening artefacts. First a low-dose whole body CT from the base of the skull to the upper thigh was performed without contrast medium for attenuation correction purposes. Then a contrast-enhanced diagnostic CT was performed including an arterial phase of the chest and the upper abdomen and a venous phase from the base of the skull to the upper thigh. For contrast enhancement patients received 120 ml contrast medium with a high iodine concentration of 370 mg iodine/ml (Ultravist 370, Bayer Schering Pharma, Berlin, Germany). Contrast medium was administered intravenously at a flow rate of 3.5 ml/s into an antecubital vein via a 20-gauge catheter using a power injector. Injection of contrast media was followed by a saline chaser (30 ml of 0.9 % sodium chloride solution) administered at the same flow rate. For bolus tracking, the region of interest was placed in the ascending aorta as the examination was performed within a combined CT of chest and abdomen. The threshold for initiation of the CT data acquisition was set at 140 Hounsfield units (HU). A whole-body portal venous phase CT acquisition was started 70 s after the beginning of the contrast media injection. CT parameters for the low-dose unenhanced CT were: collimation, mm; pitch 0.812; rotation time, 0.4 s; effective tube current-time product of 30 mas; tube voltage of 120 kvp. CT parameters for the diagnostic contrast enhanced CT was: collimation, mm; pitch 0.813; rotation time, 0.75 s; effective tube current-time product of 200 mas; tube voltage of 120 kvp. Image reconstruction was performed with a medium-smooth soft-tissue kernel (window center 60; window wide 450) at a slice thickness of 5 mm with an overlapping increment of 3.5 mm. Patients were asked to stop breathing at the end of normal expiration. Immediately after the CT examination, PET was performed. The PET system has 28 flat modules of a array of mm lutetium-yttrium oxyorthosilicate (LYSO) crystals placed in a full ring. The patient bore has

3 a diameter of 71.7 cm with active transverse and axial field of views (FOVs) of 57.6 and 18 cm, respectively. The examined anatomical volumes (coaxial imaging range) of the whole-body PET and the unenhanced and the portal venous contrast-enhanced CT examinations were identical. The arterial CT covered a reduced anatomical volume from the top of the chest down to the middle of the abdomen. When using the arterial contrast-enhanced CT for PET reconstruction, the resulting PET data set therefore contained a reduced imaging range matching the arterial CT anatomical volume. Data were collected in list mode for all coincident events along with their time stamps over multiple time points. PET acquisition time was 1.5 min per bed position using the TOF- PET technique, which provides a reasonably short acquisition time [17]. Slices of 4 mm thickness (pixel size mm²) were reconstructed using the iterative LOR-TF-RAMLA ( Blob-OS-TF ) algorithm (number of iterations 0 3, number of subsets 0 33) [8, 16]. Data sets were fully corrected for random coincidences, scatter radiation and attenuation. Noncontrast low-dose CT, arterial phase CT and venous phase CT data sets were used for the attenuation correction resulting in three PET image data sets based on the same set of raw emission data. Quantitative analysis For quantification of the PET data, maximum and mean standardised uptake values (SUVmean and SUVmax) were measured in all reconstructions by placing a circular region of interest (ROI) at each anatomical landmark site. Attenuation was assessed in the following regions: subclavian vein at the side of the contrast medium injection ascending aorta abdominal aorta at the level of (1) the coeliac trunk and (2) immediately before the aortic bifurcation inferior vena cava at the level of the origin of the renal arteries main portal vein liver: segment II and segment VI kidney: in the renal cortex at the upper pole of the right kidney. Contrast enhancement (HU) of the CT images was measured by placing ROIs in identical positions as in the PET reconstructions. For parenchymal measurements, visible blood vessels, bile ducts and artefacts were excluded from the measurement. At all anatomical sites, an attempt was made to maintain a constant size of the region of interest (ROI) of approximately 1.0 cm 2. Measurements were performed for the unenhanced, arterial and portal venous enhanced CT images. Data were analysed on an Imalytics workstation (Philips Medical Systems, Best, The Netherlands). In patients (n054) with histopathologically proven lung cancer, additional quantitative analysis of the primary tumour was obtained for PET (SUVmean and SUVmax) and CT (HU) data as described above for the reference sites. The mean diameter (measured in CT) of the lung tumours was 46.2 mm±24.8 (range mm) 35.2 mm±18.8 (range mm). Qualitative analysis Image quality and clinical interpretation of all three PET data sets (reconstruction with the unenhanced, arterial and venous CT) independently from the according CT images were assessed by a PET/CT-experienced board-certified nuclear medicine physician and a PET/CT-experienced boardcertified radiologist. The observers were blinded to clinical data and reconstruction parameters. Images of each data set were visually assessed for the presence of a malignant lung tumour, lymph node metastasis and other metastasis. In a second analysis, PET images of the data sets reconstructed with arterial or venous CT were compared directly to the PET images reconstructed with the unenhanced CT as reference standard. The comparison was scored on a fourpoint scale (0 0 image visually fully comparable, 1 0 image visually slightly different but without clinical significance, 2 0 image visually different with clinical significance, 3 0 image quality not sufficient for diagnostic interpretation). Statistical analysis Mean attenuation of all CT data sets (HU) and SUVmean and SUVmax of all PET reconstructions were summarised by the arithmetic mean and corresponding standard deviation (SD) and relative differences of SUVmean and SUVmax were calculated. Paired t-tests were conducted with a significance level of α05 % for comparison of contrast enhancement, SUV mean and SUV max between the different CT and PET data. The two-sided nonparametric paired Wilcoxon test was used to compare the results of staging and qualitative grading between the different PET reconstructions. Interobserver agreement for each reconstruction was evaluated using Cohen s kappa (poor agreement, κ00; slight agreement, κ ; fair agreement, κ ; moderate agreement, κ ; good agreement, κ ; excellent agreement κ ). All statistical analyses were performed in an explorative manner; thus P values of P 0.05 can be interpreted as statistically significant. All statistical analyses were conducted using SPSS 19 (IBM, Somers, USA).

4 Results Quantitative analysis Injection of contrast medium resulted in significantly increased attenuation values in the arterial and venous phase compared to the unenhanced CT at all anatomical sites (all P< 0.001) (Table 1). In the arterial phase contrast enhancement was significantly higher than in the venous phase in the subclavian vein, the ascending aorta and the abdominal aorta at the level of the celiac trunk and aortic bifurcation (all P< 0.001). The enhancement values in the venous phase were significantly higher than those in the arterial phase in the inferior vena cava (P<0.001), the main portal vein (P ), the liver segment II (P<0.001) and VI (P<0.001), and the kidney (P00.001) (Table 1). Results of the SUVmean and SUVmax measurements for the different PET reconstructions are given in Table 2. SUVmean and SUVmax values were significantly higher for both the PET data reconstructed with the arterial and with the venous CT compared to the reconstruction with the unenhanced CT at all anatomical sites (all P<0.001). PET values were significantly higher using the arterial CT compared to the venous CT in the subclavian vein, the ascending aorta and the abdominal aorta at the level of the celiac trunk as well as the aortic bifurcation (all P<0.001). SUVmean and SUVmax values were significantly higher using the venous CT for attenuation correction compared to the arterial one in the inferior vena cava (both P00.007), the main portal vein (SUVmean P00.011, SUVmax P00.021, respectively), liver segment II (P and P00.019, respectively) and VI (P00.04 and P00.005, respectively), and the kidney (P and P00.011, respectively). Additional analysis of the histopathologically proven lung cancer in 54 patients revealed significant increases in attenuation values in the arterial and venous phases compared to the unenhanced CT (both P<0.001) (Table 1). In the venous phase contrast enhancement was significantly higher than in the arterial phase (P<0.001). SUVmean and SUVmax values were significantly higher in the PET reconstructions based on the arterial as well as the venous CT compared to the one based on the unenhanced CT (SUVmean: P and P00.002; SUVmax: P and P00.004, respectively). There was no significant difference between the SUVmean or SUVmax in PET reconstructions based on the arterial CT or those reconstructed based on the venous CT (P00.32 and P00.46, respectively). Qualitative analysis Visual assessment of the PET data revealed no difference among the three differently reconstructed PET images (unenhanced, arterial, venous) within each observer (all P01.0) for the classification of the primary tumour and the presence of lymph node or distant metastases (Fig. 1). Neither observer found any disparate lesions comparing the three PET data sets. Observers 1 and 2 found positive (suspicious) lesions for a malignant lung tumour in 55 and 54 cases, for lymph node metastasis in 33 and 27 cases, and for other metastasis in 15 and 15 cases, respectively. Interobserver agreement was excellent for a malignant lung tumour (κ00.90) and other metastasis (κ01.0). For lymph node metastasis interobserver agreement was good with a kappa value of In the assessment of the visual differences between PET data sets reconstructed with unenhanced, arterial and venous CT on a four-point scale, both observers scored 0 points in 59 of the 60 cases, indicating no discernable visual differences between the various PET reconstructions. In one case both observers scored one point, indicating discernable visual differences without influence on the clinical assessment between the PET data reconstructed with the contrastenhanced (both arterial and venous) and unenhanced CT. In this case, a slightly decreased FDG uptake of the distal oesophagus was found in the PET reconstructed with the arterial and venous phase in comparison with the unenhanced CT. Interobserver agreement in visual scoring was excellent with a kappa value of 1.0. Table 1 CT contrast enhancement (HU, mean ± SD) Region/vessel Unenhanced Arterial phase Venous phase Subclavian vein 33±10 2,250± ±34 Ascending aorta 39±6 262±60 169±29 Aorta: coeliac trunk 38±5 286±55 149±21 Aorta: aortic bifurcation 41±6 320±68 154±22 Inferior vena cava 35±5 90±31 112±21 Portal vein 33±5 147±32 155±24 Liver: segment II 49±8 87±19 110±20 Liver: segment VI 46±6 93±18 113±20 Kidney 25±5 167±42 187±38 Lung cancer 24±10 59±23 73±33

5 Table 2 SUVmax and SUVmean (mean ± SD) and relative differences (%, mean ± SD) in comparison to the unenhanced PET/CT Region/vessel Unenhanced Arterial phase Venous phase Arterial phase (%) Venous phase (%) SUVmean SUVmax SUVmean SUVmax SUVmean SUVmax SUVmean SUVmax SUVmean SUVmax Subclavian vein 1.2± ± ± ± ± ± ± ± ± ±10.1 Ascending aorta 1.4± ± ± ± ± ± ± ± ± ±5.0 Aorta: coeliac trunk 1.5± ± ± ± ± ± ± ± ± ±10.1 Aorta: aortic bifurcation 1.5± ± ± ± ± ± ± ± ± ±9.8 Inferior vena cava 1.3± ± ± ± ± ± ± ± ± ±11.8 Portal vein 1.3± ± ± ± ± ± ± ± ± ±9.4 Liver: segment II 2.1± ± ± ± ± ± ± ± ± ±10.6 Liver: segment VI 2.0± ± ± ± ± ± ± ± ± ±7.0 Kidney 2.2± ± ± ± ± ± ± ± ± ±11.2 Lung Cancer 6.4± ± ± ± ± ± ± ± ± ±12.1 Fig. 1 Maximum intensity projection (MIP) whole body images (a-d), axial PET/CT (e-g) and axial CT images (h-j) of a patient with lung cancer. Attenuation correction performed using unenhanced (a, e, h), arterial phase (b, f, i) and venous phase (c, g, j) contrast-enhanced CT. Non-attenuation-corrected projection is given in image d. Qualitative analysis revealed no clinically relevant differences between the different PET reconstructions in spite of significantly increased of SUV values in the quantitative evaluation. The SUVmax values of the clearly recognisable lung tumour in a, b, c and e, f, g were 6.8, 7.2 and 7.3 for the reconstruction with the unenhanced CT, arterial and venous CT, respectively

6 Discussion Some recent studies have already demonstrated that, like the results in the present study, the clinical significance of the effect of contrast medium on the PET data is marginal [12 14, 18, 19]. However, these studies concerned relatively small numbers of patients or the effect of multiphase CT was not evaluated. The present study prospectively analysed the influence of different contrast medium phases on attenuation correction, PET image quality and clinical staging in a group of 60 patients referred for the same indication. The distribution of the contrast medium is completely different between the contrast media phases [20]. The different enhancement patterns result in significant differences in attenuation values in CT with a possible influence on the attenuation correction of the PET data. Indeed the present study shows that, in concordance with previous studies, the application of contrast medium leads to a significantly higher estimate of tracer uptake compared to PET data reconstructed with unenhanced CT [12, 13, 18]. Furthermore, this study demonstrates that different contrast medium phases have a significantly different influence on the attenuation correction of the PET data: the arterial phase causes a significant increase in the estimated tracer uptake in arteries compared to the venous phase. Conversely, the use of the venous CT resulted in a significantly higher tracer uptake estimate in the parenchymatous organs compared to use of arterial phase CT. The pattern of these findings is directly correlated to those of the CT enhancement values, which also show significantly higher HU values in the arterial phase in the arteries and in the venous phase in the solid organs. These differences in the PET values, especially of the tumour between arterial, venous and unenhanced PET/CT, will influence the comparability of quantitative measurements in the follow-up when the tracer uptake is analysed in the context of response to therapy. For reliable comparisons it necessary and very important that baseline and follow-up PET/CTs be obtained with an identical examination and reconstruction protocol. In spite of the sometimes considerable quantitative differences, the visual assessment was hardly affected by the different contrast medium phases: the intraobserver staging concerning the presence of a malignant lung tumour and the presence of metastases did not change between phases. As opposed to previously reported findings in the literature [21], we did not find any artefacts in PET images in the vicinity of the subclavian vein, even though the concentration of the contrast medium in the subclavian vein during the arterial phase is very high, with a mean corresponding attenuation value in CT as high as +2,250 HU. Another concern in studies employing multiple consecutive CT data acquisitions is the precise alignment of the inspiratory volume; minor differences are almost unavoidable. Especially at the base of the lungs/upper abdomen, minor differences in chest inspiration volume between the different CT examinations might cause a misalignment of the anatomical structures, which may potentially influence SUV measurements and the clinical assessment. Fortunately these potential influences hardly materialised in the present study: in only one case was a minor difference in FDG uptake in the distal oesophagus found between the various PET reconstructions, which was most likely caused by a minor misalignment. This did not influence the clinical assessment. In general, the application of intravenous contrast medium in combined PET/CT yields improved diagnostic accuracy compared to low-dose unenhanced PET/CT as vascular and parenchymatous organs can be identified and separated more precisely from surrounding tissue. A typical example in patients with lung cancer is the hilum where vessels, lymph nodes and central lung cancers are often difficult to differentiate. A previous study by Pfannenberg et al. [2] already demonstrated the advantages of the acquisition of a diagnostic contrast-enhanced CT within staging of lung cancer leading to a more precisely defined tumour extent in 63 % of patients and in an altered therapy regime. Therefore, a contrast-enhanced CT should be a fixed part of a standard combined PET/CT protocol; a separate diagnostic CT had already been acquired shortly before. A potential limitation of this study is that not all suspicious lesions such as lymph node metastases could be correlated histopathologically. But this was not the topic of this study because the aim was to evaluate the effect of contrast-related attenuation changes. Furthermore it is questionable whether the quantitative results of the present study are directly applicable to PET-CT systems from other manufacturers, as these depend on the attenuation correction map, which is software generated based on the CT data using manufacturer-specific software and algorithms. Further research on other manufacturers systems may be required here. The clinical implication of our results is that, in spite of the quantitative differences, a contrast-enhanced CT acquired during combined PET/CT is suitable for attenuation correction in patients with suspected lung cancer as the contrast medium does not affect clinical assessment. Although in selected patients, such as in the case of renal imaging [22, 23], an unenhanced CT can usually not be omitted, in the majority of patients the separate acquisition of an unenhanced low-dose CT acquisition specifically for attenuation correction purposes may be unnecessary, thereby decreasing the whole-body radiation exposure by approximately 2-4 msv depending on the type of PET/CT equipment [24]. In summary, in PET/CT, different contrast medium phases do not significantly affect image quality and clinical assessment, although quantitative analysis does show statistically significant differences in attenuation values and tracer uptake estimates. Contrast-enhanced CT is suitable for

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