- Email: [email protected]
Imaging Hepatocellular Carcinoma with Dynamic CT Before and After Transarterial Chemoembolization
Imaging Hepatocellular Carcinoma with Dynamic CT Before and After Transarterial Chemoembolization: Optimal Scan Timing of Arterial Phase Marc Saake, MD, Michael M. Lell, MD, Achim Eller, MD, Wolfgang Wuest, MD, Marco Heinz, MD, Michael Uder, MD, Axel Schmid, MD Rationale and Objectives: The aim of this study was to determine the optimal arterial phase delay for computed tomography imaging of hepatocellular carcinoma (HCC) before and after transarterial chemoembolization (TACE) using a low iodine dose protocol. Materials and Methods: A total of 39 patients with known HCC were imaged with dynamic computed tomography of the liver (40-second scan duration, 60 mL of contrast medium), both on the same day before TACE and 1 day after TACE. Time attenuation curves of vessels, nonmalignant liver parenchyma, and 62 HCCs were normalized to a uniform aortic contrast arrival and analyzed. Results: Maximal arterial phase HCC to liver contrast was reached between 13 and 17 seconds after aortic contrast arrival, both before and after TACE. Conclusions: Using our low iodine dose protocol, arterial phase imaging of HCC should be performed between 13 and 17 seconds after aortic contrast arrival, both before and after TACE. Key Words: Hepatocellular carcinoma; computed tomography; contrast media; scan delay; transarterial chemoembolization. ªAUR, 2015
INTRODUCTION
T
ransarterial chemoembolization (TACE) is the recommended first-line therapy for hepatocellular carcinoma (HCC) in intermediate stage of the disease (Barcelona Clinic Liver Cancer scoring system stage B) (1). It is the most common first-line treatment for HCC worldwide, and currently almost half of all TACE treatments are performed in Barcelona Clinic Liver Cancer stage C (2). Classic anatomic tumor response criteria are insufficient for treatment monitoring after TACE as they do not take into account tumor necrosis induced by treatment (3). Therefore, modified Response Evaluation Criteria in Solid Tumors (mRECIST) are generally applied for HCC today, using the reduction in viable tumor mass to assess treatment response. Viable tumor is defined as uptake
Acad Radiol 2015; 22:1516–1521 From the Department of Radiology, University of Erlangen-Nuremberg, Erlangen, Germany. Received June 2, 2015; accepted August 23, 2015. Marc Saake and Michael M Lell contributed equally to this work. Address correspondence to: M.S. e-mail: [email protected] ªAUR, 2015 http://dx.doi.org/10.1016/j.acra.2015.08.021
1516
of contrast agent in the arterial phase of computed tomography (CT) or magnetic resonance imaging (4,5). Most HCCs show increased enhancement in the arterial phase (6,7). Absence of contrast uptake after TACE indicates therapy-induced tumor devascularization. However, complete devascularization is not always achieved and the amount of contrast enhancement in viable tumors can vary (8). Therefore, optimization of arterial contrast should be aimed at. Beside the contrast injection protocol, the scan timing is the essential parameter for the resulting tumor to liver contrast (TLC). Liver dynamic CT (dCT) is a special mode available on modern CT scanners, repeatedly scanning the complete or a part of the liver when a contrast bolus flows through the vessels and liver parenchyma (9,10). We used the resulting four-dimensional (4D) data set (consisting of multiple sequential 3D spiral scans) to analyze the HCC enhancement over time. Recently, Kagawa et al. (11) investigated the optimal scan time for hepatic arterial-phase imaging of HCC. However, they used a higher amount of contrast medium (CM), a longer injection time, and evaluated only the highest density area of the tumor on transversal CT images (2D regions of interest
Academic Radiology, Vol 22, No 12, December 2015
[ROIs]). We assumed 3D volumes of interest (VOIs) could better reflect the 3D properties of HCCs and segmented the entire tumors in volume data sets. The aim of this study was to determine the optimal arterial phase delay for maximal HCC to liver contrast before and after TACE using a low iodine dose protocol. MATERIALS AND METHODS Study Population
Institutional review board approval was obtained before the commencement of this retrospective analysis. Informed consent of the patients was obtained. Sixty-three patients who had undergone dCT in our department between August 2010 and January 2013 were retrospectively screened for the study. All examinations had been performed because of clinical indication. Inclusion criteria were cirrhotic liver, performance of TACE, and dCT before and after TACE. Exclusion criteria were an age less than 18 years and incomplete or nonevaluable examinations (eg, because of massive artifacts). Diagnosis of HCC was based on histology or imaging criteria according to the 2011 guidelines on HCC by the American Association for the Study of Liver Diseases (12). In all patients multiphasic pre-TACE liver CTor magnetic resonance imaging had been performed and all available imaging data were considered for defining the HCC lesions. Twenty-five of the screened patients did not fulfill all inclusion and exclusion criteria. A total of 38 patients (31 male; mean age 69 years, range 49–90 years) were included in the final analysis. Histology had been performed in 18 patients (HCC differentiation—grade 1, n = 2; grade 2, n = 13; grade 3, n = 3). HCCs had not been previously treated in 25 patients. In eight patients previous TACE and in five patients previous radiofrequency ablation had been performed and follow-up imaging had demonstrated HCC recurrence. Transarterial Chemoembolization
Chemoembolization was performed using epirubicin-loaded drug-eluting beads (DC Bead, beads size 100–300 mm, maximum dose of epirubicin 50 mg; Biocompatibles UK Ltd, Surrey, UK) from superselective microcatheter positions under fluoroscopy until hemostasis was reached. If the amount of epirubicin-loaded beads was not sufficient to reach hemostasis, the procedure was continued using bland embolization (up to a maximum of two additional vials of 100–300 mm beads). Dynamic CT of the Liver
In all patients dCT scans were performed at the same day before the TACE procedure for TACE planning (preTACE) and were repeated on the following day after the TACE procedure to evaluate therapy success (post-TACE).
CT ARTERIAL PHASE TIMING IN HCC
All scans were performed on a 128-section CT scanner (Somatom Definition AS+; Siemens, Erlangen, Germany) using a standardized 4D spiral protocol with 20.7 cm coverage in z-axis. Ten consecutive spiral scans in craniocaudal scan direction were performed within 40 seconds, with one scan and the subsequent table reposition to the cranial start position lasting for 2 seconds each. Aortic bolus arrival time was measured using the test bolus method with an injection of 5 mL iodinated CM (iomeprol 350 mg iodine/mL, Imeron 350; Bracco Imaging, Konstanz, Germany) during breath hold in inspiration. Then, the dCT scan was performed during breath hold in inspiration with a scan start time of 8 seconds before the measured aortic test bolus peak. Sixty milliliters of CM, followed by 30 mL of saline flush, were injected at body temperature (37 C) via an 18-gauge cannula into a cubital vein at a rate of 6 mL/s using a double-piston power injector (Accutron CT2; Medtron, Saarbruecken, Germany). Analogous to other published works we used a fixed amount of CM (13). Scan parameters were tube voltage, 100 kV; tube currenttime product, 150 mAs; collimation, 128 0.6 mm; rotation time, 0.3 seconds; CT dose index volume, 71.02 mGy. The effective radiation dose of one complete dCT scan was calculated as 22.8 mSv, based on the dose-length product using the conversion coefficient for 100 kV tube voltage and 32 cm body phantom (0.0151 mSv/(mGy cm) (14)). Image reconstruction parameters were section thickness, 3 mm; increment, 2 mm; reconstruction kernel, B20f. Image Processing
Image processing was performed by a board-certified radiologist with 7 years of experience in abdominal imaging using dedicated body perfusion analysis software on a clinical multimodality postprocessing platform (syngo.via VA30, CT Body Perfusion; Siemens). Data preprocessing consisted of automated motion correction, bone removal, and vessel segmentation. ROIs were placed in the abdominal aorta at the level of the celiac artery, the portal vein, and the spleen parenchyma to differentiate between the arterial and portal venous perfusion of the liver. Color-coded liver perfusion parameter maps (arterial liver perfusion, portal venous liver perfusion, and hepatic perfusion index) were calculated and were used in evaluation of liver parenchyma and for detection of viable tumor remnants after TACE. ROI/VOI Placement
For evaluation of nontumorous liver parenchyma free-hand 2D ROIs were placed on transversal slice images in three different macroscopically HCC-free liver segments. In the same liver segments 3D VOIs were placed using the 3D function of the postprocessing platform. ROIs and VOIs were drawn as large as possible, avoiding large vessels and other lesions, and the mean values were calculated. 1517
SAAKE ET AL
A maximum of three HCC lesions were selected in each patient. In the corresponding scans before and after TACE the viable tumor parts were measured according to mRECIST (4), and free-hand ROIs and VOIs were drawn to include approximately 90% of the contrast enhancing parts of the tumors on the selected slice images (ROIs) and of the whole tumors (VOIs), respectively. The tumor borders (approximately 10%) were spared to avoid partial volume effects and inflammation caused by TACE. Image processing of the corresponding dCT scans before and after TACE in each patient was performed in conjunction (side-by-side analysis) to ensure an identical ROI/VOI placement. For each ROI and VOI the area/volume, mean density at each point in time, and the perfusion parameters were recorded. TLC was calculated as the difference between the mean density of the tumor and the mean density of the liver parenchyma for each point in time (15). Scan Time Normalization
Theoretically aortic contrasting should have started at the third scan in all patients. However, despite the performance of a test bolus measurement, in 25 of 76 dCT examinations the time attenuation curve (TAC) of the aorta rose from baseline at the second or fourth scan. We therefore normalized the aortic TAC rise by shifting all measured density values of these data sets by one point in time to the left or right. Consecutively missing density data in the precontrast phase were filled with data from the adjacent precontrast point in time. Missing data in the postcontrast phase were left open. We then labeled the points in time of the 10 consecutive scans: 7, 3, 1, 5, 9, 13, 17, 21, 25, 29 seconds. Data Analysis
The Student t-test was used to analyze differences in TLC between the ROI approach and the VOI approach, as well as between the scans before and after TACE. Differences were considered statistically significant when P < .05. Quantitative values are presented as the mean standard deviation.
RESULTS No complications occurred in any of the dCT scans. In two patients the post-TACE examinations were not evaluable because of a timing error (the dCT scan started after the aortic TAC rise). Sixty-two HCCs were evaluated before TACE, of these 14 had a size less than 2 cm. After TACE, 32 viable HCC remnants were found. Thirty HCCs showed complete necrosis. Mean HCC size according to mRECIST before TACE was 3.7 2.1 cm. Mean size of viable tumor parts after TACE was 2.2 1.0 cm. Table 1 lists perfusion parameters of HCCs and HCC-free liver before and after TACE. 1518
Academic Radiology, Vol 22, No 12, December 2015
TABLE 1. Size and Perfusion Parameters of HCCs and Tumor-free Liver Before and After TACE Parameters
Pre-TACE
Post-TACE
HCC Size (cm) ROI Analysis HCC ROI area (cm2) ALP (mL/100 mL/min) PVP (mL/100 mL/min) HPI (%) Tumor-free liver ALP (mL/100 mL/min) PVP (mL/100 mL/min) HPI (%) VOI analysis HCC VOI volume (cm3) ALP (mL/100 mL/min) PVP (mL/100 mL/min) HPI (%) Tumor-free liver ALP (mL/100 mL/min) PVP (mL/100 mL/min) HPI (%)
3.7 2.1
2.2 1.0
7.9 8.5 59.1 20.7 11.0 11.4 89.3 10.1
2.5 1.9 55.7 17.1 9.6 20.1 90.8 14.9
10.4 6.3 64.3 26.3 22.9 16.9
12.3 8.9 72.6 19.9 20.5 15.7
21.7 39.5 57.9 19.5 11.1 12.4 89.3 10.1
2.6 2.3 54.2 16.0 10.0 17.3 90.1 12.9
10.3 6.1 66.2 24.6 22.6 16.7
12.2 8.7 72.2 19.9 20.4 16.0
ALP, arterial liver perfusion; HCC, hepatocellular carcinoma; HPI, hepatic perfusion index; PVP, portal venous liver perfusion; ROI, region of interest; SD, standard deviation; VOI, volume of interest. Values are presented as the mean SD.
Because of the start time normalization aortic contrasting started at point in time ‘‘1 second’’ in all patients. Peak aortic enhancement was reached on average at 9 seconds after arrival of CM in the abdominal aorta and peak enhancement was 433.0 99.1 HU. Tumor enhancement started at 5 seconds and reached its peak at 17 seconds with 97.8 20.5 HU. Liver parenchyma started to enhance at 5 seconds and increased in density until the end of the scan. TLC reached its maximum between 13 and 17 seconds with 36.4 22.9 HU (range, 0–82 HU) (Fig 1). At this time 85 of 94 HCCs (90.4%) had a TLC greater than 10 HU and 77 of 94 HCCs (81.9%) had a TLC greater than 20 HU. We did not find a statistically significant difference between the TLC TACs for the 2D ROI approach and the 3D VOI approach (P > .05 for all points in time). Both TAC curves run nearly identical (Fig 2). There was also no statistically significant difference between the TLC TACs before and after TACE (P > .05 for all points in time). Highest TLC was reached between 13 and 17 seconds for both subgroups (Fig 3). DISCUSSION We studied the arterial enhancement kinetics of HCCs in the pre-TACE and post-TACE situation and compared a 2D ROI approach to a 3D VOI approach.
Academic Radiology, Vol 22, No 12, December 2015
Figure 1. Mean TACs of aorta, portal vein, liver parenchyma, HCC, and TLC of all dCT scans. TLC reached its maximum between 13 and 17 seconds after aortic contrast arrival. dCT, liver dynamic CT; HCC, hepatocellular carcinoma; TAC, time attenuation curve; TLC, tumor to liver contrast.
Figure 2. TACs of TLC for ROI and VOI measurements. Both curves run parallel without a statistically significant difference (P > .05). Bars indicate standard deviations. TAC, time attenuation curve; TLC, tumor to liver contrast; ROI, region of interest; VOI, volume of interest.
The time interval for an intravenously injected bolus of CM to appear in the aorta (transit time) varies largely between different individuals, especially in patients with cardiocirculatory diseases (16). We therefore performed a test bolus injection and calculated the point in time of optimal TLC relative to the aortic contrast arrival. The TAC of arterial contrast after injection of a certain amount of CM typically displays a bell-shaped form. Height and time of peak arterial enhancement depend on the iodine delivery rate (IDR, in milligrams per second) and the injection duration (16). The IDR is a function of injection flow rate (milliliters per second) and iodine concentration of the CM (milligrams per milliliter). Therefore, timing for optimal arterial enhancement highly depends on the used CM injection protocol. At a given IDR, arterial enhancement continuously increases over time with longer injection durations because of the cumulative effects of bolus broadening and recirculation (16). At a given injection duration, HCC
CT ARTERIAL PHASE TIMING IN HCC
Figure 3. TACs of TLC for ROI measurements before and after TACE. Both curves run parallel without a statistically significant difference (P > .05). Bars indicate standard deviations. TAC, time attenuation curve; TACE, transarterial chemoembolization; TLC, tumor to liver contrast; ROI, region of interest.
conspicuity in hepatic arterial phase increases with higher flow rates or IDR (9). At a given iodine dose, peak arterial enhancement is reached earlier in time with higher flow rates (17). Hence, our results are specific to the used injection protocol and cannot be generalized. dCT is a relatively new scan mode. To our knowledge, there is only one previously published work on scan timing in HCC using dCT data (11). However, Kagawa et al. used a considerably higher amount of CM at a lower injection flow rate (mean 34.8 g at 3.9 mL/s [assuming an iodine concentration of 300 mg/mL] vs. 21 g at 6 mL/s in our study). The reported maximum TLC of HCC was reached later than in our cohort (21 seconds after aortic contrast arrival vs. 13–17 seconds in our study), but the reported mean TLC (38 HU) was comparable to our result (36 HU). In a three-phase liver CT study peak HCC TLC also was reported later than in our study (24.8 seconds after aortic bolus arrival) (18). Again, the iodine dose in this study was higher and the flow rate was lower than in our study. In some older reports on liver arterial phase scan timing no bolus tracking was used (19,20) or a mixed spectrum of liver disorders was investigated (21). The possibility to calculate color-coded liver perfusion parameter maps is a major benefit of dCT. These parameter maps facilitated the recognition of viable tumor remnants in this study and the differentiation from normal liver parenchyma and embolized tumor parts, especially on post-TACE examinations (Fig 4). However, for perfusion imaging the optimal contrast bolus geometry is very compact. This can be achieved by using low iodine doses (12–18 g) at high IDR (13,22). This demand is in contrast to the high iodine dose protocols recommended in HCC (mean 31 g) (9). We chose an intermediate iodine dose (21 g). To maximize TLC, we used a high IDR (injection flow rate, 6 mL/s; concentration of the CM, 350 mg/mL) heated up to body temperature to reduce viscosity. This approach proved feasible 1519
SAAKE ET AL
Academic Radiology, Vol 22, No 12, December 2015
Figure 4. Seventy-year-old woman with large HCC in the right lobe of the liver. dCT scan 1 day after TACE. (a and d) Transversal and coronal temporal maximum intensity projection images, (b and e) transversal and coronal ALP parameter maps, (c) transversal PVP parameter map, (f) TAC of a free-hand ROI in a viable HCC remnant. The 20.7 cm coverage in z-axis of the used dCT scan mode allows the examination of nearly the entire liver. After TACE extensive necrosis of this large HCC is achieved. Color-coded perfusion maps facilitate the recognition of viable HCC remnants (arrows) and the differentiation from intraparenchymal CM from prior TACE (arrowheads). The TAC of a viable HCC remnant shows the typical arterial perfusion pattern. ALP, arterial liver perfusion; CM, contrast medium; dCT, liver dynamic CT; HCC, hepatocellular carcinoma; PVP, portal venous liver perfusion; TAC, time attenuation curve; TACE, transarterial chemoembolization. (Color version of figure is available online.)
both for calculation of perfusion parameter maps and for sufficient tumor enhancement. Ichikawa et al. studied the correlation between the subjective tumor conspicuity and the quantitative tumor TLC in HCCs. They found that a ‘‘good’’ contrast was associated with a mean TLC of 33.7 HU (23), which is lower than the mean TLC in our study (36.4 HU). The used dCT data sets were suitable for the analysis of optimal scan timing in HCC because of the 40-second long scan duration, starting before the bolus arrival and scanning until the arterial bolus outflow. Therefore, the point in time of aortic bolus arrival was imaged and the TAC rise of all examinations could be normalized. In our cohort in 33% of dCT examinations the aortic enhancement start deviated from the expected point in time calculated from a test bolus measurement. We believe this fact could result from changes in cardiac output between the test bolus injection and the dCT scan. The quality of dCT data can be improved by patient training. Breathing during the scans produces motion artifacts, which can only be compensated in part by the automated motion correction during image processing and can result in interpolation artifacts. Therefore, all patients were trained to hold their breath during the dCT scan as long as possible. In case they could not hold their breath any longer, they were instructed to breath intermittently during table move-up (repositioning without scan), rather than during table move-down (scan). Only one data set had to be excluded because of heavy breathing artifacts. 1520
Interestingly, we did not find a significant difference between the less time-consuming ROI approach (drawing an ROI around the HCC on only one slice image) and the more elaborate VOI approach (circumscribing the HCC on multiple consecutive slice images). In our cohort a low tube voltage (100 kV) had been used to reduce the radiation dose. According to a recent report, the tube voltage might be reduced even further to 80 kV in liver CT without compromising the contrast enhancement, image quality, and detection of HCCs (24). Our study is limited in a few ways. First, in a part of our cohort the HCCs had been treated previously by TACE or radiofrequency ablation. We did not perform a subgroup analysis as the number of patients was less than 10 for both previous treatment modalities. However, as we concentrated on viable tumor parts only, we do not believe this previous treatment to influence our study results. Second, histologic confirmation and grading of HCC was only available in a part of our patients, and thus we did not correlate TLC to HCC grading. Yet, our aim was to develop a robust scanning protocol applicable to all patients with HCC irrespective of the subtype. Third, the temporal resolution of the used dCT scan was 4 seconds only. A higher temporal sampling would have provided more data points and with it a more exact determination of the peak enhancement, but would also have increased the radiation dose. If a single liver arterial phase scan is intended in the clinical scenario, we recommend the performance of bolus tracking. Using a low volume, high flow injection protocol (60 mL at
Academic Radiology, Vol 22, No 12, December 2015
6 mL/s), peak arterial enhancement can be expected between 13 and 17 seconds after aortic TAC rise. Therefore, we suggest a threshold of 100 HU for the aortic ROI and a scan delay of 15 seconds. CONCLUSIONS For the proposed contrast injection protocol the optimal TLC was reached between 13 and 17 seconds after aortic contrast arrival, both before and after TACE. REFERENCES 1. European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56: 908–943. 2. Sieghart W, Hucke F, Peck-Radosavljevic M. Transarterial chemoembolization: modalities, indication, and patient selection. J Hepatol 2015; 62: 1187–1195. 3. Saraswat VA, Pandey G, Shetty S. Treatment algorithms for managing hepatocellular carcinoma. J Clin Exp Hepatol 2014; 4(suppl 3):80–89. 4. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010; 30:52–60. 5. Bruix J, Sherman M, Llovet JM, et al. EASL Panel of Experts on HCC. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001; 35:421–430. 6. Alba E, Valls C, Dominguez J, et al. Transcatheter arterial chemoembolization in patients with hepatocellular carcinoma on the waiting list for orthotopic liver transplantation. AJR Am J Roentgenol 2008; 190:1341–1348. 7. Lee JH, Lee JM, Kim SJ, et al. Enhancement patterns of hepatocellular carcinomas on multiphasic multidetector row CT: comparison with pathological differentiation. Br J Radiol 2012; 85:e573–e583. 8. Hennedige T, Yang ZJ, Ong CK, et al. Utility of non-contrast-enhanced CT for improved detection of arterial phase hyperenhancement in hepatocellular carcinoma. Abdom Imaging 2014; 39:1247–1254. 9. Yanaga Y, Awai K, Nakaura T, et al. Optimal contrast dose for depiction of hypervascular hepatocellular carcinoma at dynamic CT using 64-MDCT. AJR Am J Roentgenol 2008; 190:1003–1009. 10. Wu D, Tan M, Zhou M, et al. Liver computed tomographic perfusion in the assessment of microvascular invasion in patients with small hepatocellular carcinoma. Invest Radiol 2015; 50:188–194.
CT ARTERIAL PHASE TIMING IN HCC
11. Kagawa Y, Okada M, Yagyu Y, et al. Optimal scan timing of hepatic arterial-phase imaging of hypervascular hepatocellular carcinoma determined by multiphasic fast CT imaging technique. Acta Radiol 2013; 54: 843–850. 12. Bruix J, Sherman M, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53: 1020–1022. 13. Kim SH, Kamaya A, Willmann JK. CT perfusion of the liver: principles and applications in oncology. Radiology 2014; 272:322–344. 14. Deak PD, Smal Y, Kalender WA. Multisection CT protocols: sex- and agespecific conversion factors used to determine effective dose from doselength product. Radiology 2010; 257:158–166. 15. Baron RL. Understanding and optimizing use of contrast material for CT of the liver. AJR Am J Roentgenol 1994; 163:323–331. 16. Fleischmann D. How to design injection protocols for multiple detectorrow CT angiography (MDCTA). Eur Radiol 2005; 15(suppl 5):E60–E65. 17. Murakami T, Onishi H, Mikami K, et al. Determining the optimal timing for early arterial phase hepatic CT imaging by measuring abdominal aortic enhancement in variable contrast injection protocols. J Comput Assist Tomogr 2006; 30:206–211. 18. Yamaguchi I, Kidoya E, Suzuki M, et al. Optimizing scan timing of hepatic arterial phase by physiologic pharmacokinetic analysis in bolus-tracking technique by multi-detector row computed tomography. Radiol Phys Technol 2011; 4:43–52. 19. Murakami T, Kim T, Kawata S, et al. Evaluation of optimal timing of arterial phase imaging for the detection of hypervascular hepatocellular carcinoma by using triple arterial phase imaging with multidetector-row helical computed tomography. Invest Radiol 2003; 38:497–503. 20. Kanematsu M, Goshima S, Kondo H, et al. Optimizing scan delays of fixed duration contrast injection in contrast-enhanced biphasic multidetectorrow CT for the liver and the detection of hypervascular hepatocellular carcinoma. J Comput Assist Tomogr 2005; 29:195–201. 21. Goshima S, Kanematsu M, Kondo H, et al. MDCT of the liver and hypervascular hepatocellular carcinomas: optimizing scan delays for bolus-tracking techniques of hepatic arterial and portal venous phases. AJR Am J Roentgenol 2006; 187:W25–W32. 22. Lell MM, Jost G, Korporaal JG, et al. Optimizing contrast media injection protocols in state-of-the art computed tomographic angiography. Invest Radiol 2015; 50:161–167. 23. Ichikawa T, Okada M, Kondo H, et al. Recommended iodine dose for multiphasic contrast-enhanced mutidetector-row computed tomography imaging of liver for assessing hypervascular hepatocellular carcinoma: multicenter prospective study in 77 general hospitals in Japan. Acad Radiol 2013; 20:1130–1136. 24. Noda Y, Kanematsu M, Goshima S, et al. Reducing iodine load in hepatic CT for patients with chronic liver disease with a combination of low-tubevoltage and adaptive statistical iterative reconstruction. Eur J Radiol 2015; 84:1–18.
1521
INTRODUCTION
T
ransarterial chemoembolization (TACE) is the recommended first-line therapy for hepatocellular carcinoma (HCC) in intermediate stage of the disease (Barcelona Clinic Liver Cancer scoring system stage B) (1). It is the most common first-line treatment for HCC worldwide, and currently almost half of all TACE treatments are performed in Barcelona Clinic Liver Cancer stage C (2). Classic anatomic tumor response criteria are insufficient for treatment monitoring after TACE as they do not take into account tumor necrosis induced by treatment (3). Therefore, modified Response Evaluation Criteria in Solid Tumors (mRECIST) are generally applied for HCC today, using the reduction in viable tumor mass to assess treatment response. Viable tumor is defined as uptake
Acad Radiol 2015; 22:1516–1521 From the Department of Radiology, University of Erlangen-Nuremberg, Erlangen, Germany. Received June 2, 2015; accepted August 23, 2015. Marc Saake and Michael M Lell contributed equally to this work. Address correspondence to: M.S. e-mail: [email protected] ªAUR, 2015 http://dx.doi.org/10.1016/j.acra.2015.08.021
1516
of contrast agent in the arterial phase of computed tomography (CT) or magnetic resonance imaging (4,5). Most HCCs show increased enhancement in the arterial phase (6,7). Absence of contrast uptake after TACE indicates therapy-induced tumor devascularization. However, complete devascularization is not always achieved and the amount of contrast enhancement in viable tumors can vary (8). Therefore, optimization of arterial contrast should be aimed at. Beside the contrast injection protocol, the scan timing is the essential parameter for the resulting tumor to liver contrast (TLC). Liver dynamic CT (dCT) is a special mode available on modern CT scanners, repeatedly scanning the complete or a part of the liver when a contrast bolus flows through the vessels and liver parenchyma (9,10). We used the resulting four-dimensional (4D) data set (consisting of multiple sequential 3D spiral scans) to analyze the HCC enhancement over time. Recently, Kagawa et al. (11) investigated the optimal scan time for hepatic arterial-phase imaging of HCC. However, they used a higher amount of contrast medium (CM), a longer injection time, and evaluated only the highest density area of the tumor on transversal CT images (2D regions of interest
Academic Radiology, Vol 22, No 12, December 2015
[ROIs]). We assumed 3D volumes of interest (VOIs) could better reflect the 3D properties of HCCs and segmented the entire tumors in volume data sets. The aim of this study was to determine the optimal arterial phase delay for maximal HCC to liver contrast before and after TACE using a low iodine dose protocol. MATERIALS AND METHODS Study Population
Institutional review board approval was obtained before the commencement of this retrospective analysis. Informed consent of the patients was obtained. Sixty-three patients who had undergone dCT in our department between August 2010 and January 2013 were retrospectively screened for the study. All examinations had been performed because of clinical indication. Inclusion criteria were cirrhotic liver, performance of TACE, and dCT before and after TACE. Exclusion criteria were an age less than 18 years and incomplete or nonevaluable examinations (eg, because of massive artifacts). Diagnosis of HCC was based on histology or imaging criteria according to the 2011 guidelines on HCC by the American Association for the Study of Liver Diseases (12). In all patients multiphasic pre-TACE liver CTor magnetic resonance imaging had been performed and all available imaging data were considered for defining the HCC lesions. Twenty-five of the screened patients did not fulfill all inclusion and exclusion criteria. A total of 38 patients (31 male; mean age 69 years, range 49–90 years) were included in the final analysis. Histology had been performed in 18 patients (HCC differentiation—grade 1, n = 2; grade 2, n = 13; grade 3, n = 3). HCCs had not been previously treated in 25 patients. In eight patients previous TACE and in five patients previous radiofrequency ablation had been performed and follow-up imaging had demonstrated HCC recurrence. Transarterial Chemoembolization
Chemoembolization was performed using epirubicin-loaded drug-eluting beads (DC Bead, beads size 100–300 mm, maximum dose of epirubicin 50 mg; Biocompatibles UK Ltd, Surrey, UK) from superselective microcatheter positions under fluoroscopy until hemostasis was reached. If the amount of epirubicin-loaded beads was not sufficient to reach hemostasis, the procedure was continued using bland embolization (up to a maximum of two additional vials of 100–300 mm beads). Dynamic CT of the Liver
In all patients dCT scans were performed at the same day before the TACE procedure for TACE planning (preTACE) and were repeated on the following day after the TACE procedure to evaluate therapy success (post-TACE).
CT ARTERIAL PHASE TIMING IN HCC
All scans were performed on a 128-section CT scanner (Somatom Definition AS+; Siemens, Erlangen, Germany) using a standardized 4D spiral protocol with 20.7 cm coverage in z-axis. Ten consecutive spiral scans in craniocaudal scan direction were performed within 40 seconds, with one scan and the subsequent table reposition to the cranial start position lasting for 2 seconds each. Aortic bolus arrival time was measured using the test bolus method with an injection of 5 mL iodinated CM (iomeprol 350 mg iodine/mL, Imeron 350; Bracco Imaging, Konstanz, Germany) during breath hold in inspiration. Then, the dCT scan was performed during breath hold in inspiration with a scan start time of 8 seconds before the measured aortic test bolus peak. Sixty milliliters of CM, followed by 30 mL of saline flush, were injected at body temperature (37 C) via an 18-gauge cannula into a cubital vein at a rate of 6 mL/s using a double-piston power injector (Accutron CT2; Medtron, Saarbruecken, Germany). Analogous to other published works we used a fixed amount of CM (13). Scan parameters were tube voltage, 100 kV; tube currenttime product, 150 mAs; collimation, 128 0.6 mm; rotation time, 0.3 seconds; CT dose index volume, 71.02 mGy. The effective radiation dose of one complete dCT scan was calculated as 22.8 mSv, based on the dose-length product using the conversion coefficient for 100 kV tube voltage and 32 cm body phantom (0.0151 mSv/(mGy cm) (14)). Image reconstruction parameters were section thickness, 3 mm; increment, 2 mm; reconstruction kernel, B20f. Image Processing
Image processing was performed by a board-certified radiologist with 7 years of experience in abdominal imaging using dedicated body perfusion analysis software on a clinical multimodality postprocessing platform (syngo.via VA30, CT Body Perfusion; Siemens). Data preprocessing consisted of automated motion correction, bone removal, and vessel segmentation. ROIs were placed in the abdominal aorta at the level of the celiac artery, the portal vein, and the spleen parenchyma to differentiate between the arterial and portal venous perfusion of the liver. Color-coded liver perfusion parameter maps (arterial liver perfusion, portal venous liver perfusion, and hepatic perfusion index) were calculated and were used in evaluation of liver parenchyma and for detection of viable tumor remnants after TACE. ROI/VOI Placement
For evaluation of nontumorous liver parenchyma free-hand 2D ROIs were placed on transversal slice images in three different macroscopically HCC-free liver segments. In the same liver segments 3D VOIs were placed using the 3D function of the postprocessing platform. ROIs and VOIs were drawn as large as possible, avoiding large vessels and other lesions, and the mean values were calculated. 1517
SAAKE ET AL
A maximum of three HCC lesions were selected in each patient. In the corresponding scans before and after TACE the viable tumor parts were measured according to mRECIST (4), and free-hand ROIs and VOIs were drawn to include approximately 90% of the contrast enhancing parts of the tumors on the selected slice images (ROIs) and of the whole tumors (VOIs), respectively. The tumor borders (approximately 10%) were spared to avoid partial volume effects and inflammation caused by TACE. Image processing of the corresponding dCT scans before and after TACE in each patient was performed in conjunction (side-by-side analysis) to ensure an identical ROI/VOI placement. For each ROI and VOI the area/volume, mean density at each point in time, and the perfusion parameters were recorded. TLC was calculated as the difference between the mean density of the tumor and the mean density of the liver parenchyma for each point in time (15). Scan Time Normalization
Theoretically aortic contrasting should have started at the third scan in all patients. However, despite the performance of a test bolus measurement, in 25 of 76 dCT examinations the time attenuation curve (TAC) of the aorta rose from baseline at the second or fourth scan. We therefore normalized the aortic TAC rise by shifting all measured density values of these data sets by one point in time to the left or right. Consecutively missing density data in the precontrast phase were filled with data from the adjacent precontrast point in time. Missing data in the postcontrast phase were left open. We then labeled the points in time of the 10 consecutive scans: 7, 3, 1, 5, 9, 13, 17, 21, 25, 29 seconds. Data Analysis
The Student t-test was used to analyze differences in TLC between the ROI approach and the VOI approach, as well as between the scans before and after TACE. Differences were considered statistically significant when P < .05. Quantitative values are presented as the mean standard deviation.
RESULTS No complications occurred in any of the dCT scans. In two patients the post-TACE examinations were not evaluable because of a timing error (the dCT scan started after the aortic TAC rise). Sixty-two HCCs were evaluated before TACE, of these 14 had a size less than 2 cm. After TACE, 32 viable HCC remnants were found. Thirty HCCs showed complete necrosis. Mean HCC size according to mRECIST before TACE was 3.7 2.1 cm. Mean size of viable tumor parts after TACE was 2.2 1.0 cm. Table 1 lists perfusion parameters of HCCs and HCC-free liver before and after TACE. 1518
Academic Radiology, Vol 22, No 12, December 2015
TABLE 1. Size and Perfusion Parameters of HCCs and Tumor-free Liver Before and After TACE Parameters
Pre-TACE
Post-TACE
HCC Size (cm) ROI Analysis HCC ROI area (cm2) ALP (mL/100 mL/min) PVP (mL/100 mL/min) HPI (%) Tumor-free liver ALP (mL/100 mL/min) PVP (mL/100 mL/min) HPI (%) VOI analysis HCC VOI volume (cm3) ALP (mL/100 mL/min) PVP (mL/100 mL/min) HPI (%) Tumor-free liver ALP (mL/100 mL/min) PVP (mL/100 mL/min) HPI (%)
3.7 2.1
2.2 1.0
7.9 8.5 59.1 20.7 11.0 11.4 89.3 10.1
2.5 1.9 55.7 17.1 9.6 20.1 90.8 14.9
10.4 6.3 64.3 26.3 22.9 16.9
12.3 8.9 72.6 19.9 20.5 15.7
21.7 39.5 57.9 19.5 11.1 12.4 89.3 10.1
2.6 2.3 54.2 16.0 10.0 17.3 90.1 12.9
10.3 6.1 66.2 24.6 22.6 16.7
12.2 8.7 72.2 19.9 20.4 16.0
ALP, arterial liver perfusion; HCC, hepatocellular carcinoma; HPI, hepatic perfusion index; PVP, portal venous liver perfusion; ROI, region of interest; SD, standard deviation; VOI, volume of interest. Values are presented as the mean SD.
Because of the start time normalization aortic contrasting started at point in time ‘‘1 second’’ in all patients. Peak aortic enhancement was reached on average at 9 seconds after arrival of CM in the abdominal aorta and peak enhancement was 433.0 99.1 HU. Tumor enhancement started at 5 seconds and reached its peak at 17 seconds with 97.8 20.5 HU. Liver parenchyma started to enhance at 5 seconds and increased in density until the end of the scan. TLC reached its maximum between 13 and 17 seconds with 36.4 22.9 HU (range, 0–82 HU) (Fig 1). At this time 85 of 94 HCCs (90.4%) had a TLC greater than 10 HU and 77 of 94 HCCs (81.9%) had a TLC greater than 20 HU. We did not find a statistically significant difference between the TLC TACs for the 2D ROI approach and the 3D VOI approach (P > .05 for all points in time). Both TAC curves run nearly identical (Fig 2). There was also no statistically significant difference between the TLC TACs before and after TACE (P > .05 for all points in time). Highest TLC was reached between 13 and 17 seconds for both subgroups (Fig 3). DISCUSSION We studied the arterial enhancement kinetics of HCCs in the pre-TACE and post-TACE situation and compared a 2D ROI approach to a 3D VOI approach.
Academic Radiology, Vol 22, No 12, December 2015
Figure 1. Mean TACs of aorta, portal vein, liver parenchyma, HCC, and TLC of all dCT scans. TLC reached its maximum between 13 and 17 seconds after aortic contrast arrival. dCT, liver dynamic CT; HCC, hepatocellular carcinoma; TAC, time attenuation curve; TLC, tumor to liver contrast.
Figure 2. TACs of TLC for ROI and VOI measurements. Both curves run parallel without a statistically significant difference (P > .05). Bars indicate standard deviations. TAC, time attenuation curve; TLC, tumor to liver contrast; ROI, region of interest; VOI, volume of interest.
The time interval for an intravenously injected bolus of CM to appear in the aorta (transit time) varies largely between different individuals, especially in patients with cardiocirculatory diseases (16). We therefore performed a test bolus injection and calculated the point in time of optimal TLC relative to the aortic contrast arrival. The TAC of arterial contrast after injection of a certain amount of CM typically displays a bell-shaped form. Height and time of peak arterial enhancement depend on the iodine delivery rate (IDR, in milligrams per second) and the injection duration (16). The IDR is a function of injection flow rate (milliliters per second) and iodine concentration of the CM (milligrams per milliliter). Therefore, timing for optimal arterial enhancement highly depends on the used CM injection protocol. At a given IDR, arterial enhancement continuously increases over time with longer injection durations because of the cumulative effects of bolus broadening and recirculation (16). At a given injection duration, HCC
CT ARTERIAL PHASE TIMING IN HCC
Figure 3. TACs of TLC for ROI measurements before and after TACE. Both curves run parallel without a statistically significant difference (P > .05). Bars indicate standard deviations. TAC, time attenuation curve; TACE, transarterial chemoembolization; TLC, tumor to liver contrast; ROI, region of interest.
conspicuity in hepatic arterial phase increases with higher flow rates or IDR (9). At a given iodine dose, peak arterial enhancement is reached earlier in time with higher flow rates (17). Hence, our results are specific to the used injection protocol and cannot be generalized. dCT is a relatively new scan mode. To our knowledge, there is only one previously published work on scan timing in HCC using dCT data (11). However, Kagawa et al. used a considerably higher amount of CM at a lower injection flow rate (mean 34.8 g at 3.9 mL/s [assuming an iodine concentration of 300 mg/mL] vs. 21 g at 6 mL/s in our study). The reported maximum TLC of HCC was reached later than in our cohort (21 seconds after aortic contrast arrival vs. 13–17 seconds in our study), but the reported mean TLC (38 HU) was comparable to our result (36 HU). In a three-phase liver CT study peak HCC TLC also was reported later than in our study (24.8 seconds after aortic bolus arrival) (18). Again, the iodine dose in this study was higher and the flow rate was lower than in our study. In some older reports on liver arterial phase scan timing no bolus tracking was used (19,20) or a mixed spectrum of liver disorders was investigated (21). The possibility to calculate color-coded liver perfusion parameter maps is a major benefit of dCT. These parameter maps facilitated the recognition of viable tumor remnants in this study and the differentiation from normal liver parenchyma and embolized tumor parts, especially on post-TACE examinations (Fig 4). However, for perfusion imaging the optimal contrast bolus geometry is very compact. This can be achieved by using low iodine doses (12–18 g) at high IDR (13,22). This demand is in contrast to the high iodine dose protocols recommended in HCC (mean 31 g) (9). We chose an intermediate iodine dose (21 g). To maximize TLC, we used a high IDR (injection flow rate, 6 mL/s; concentration of the CM, 350 mg/mL) heated up to body temperature to reduce viscosity. This approach proved feasible 1519
SAAKE ET AL
Academic Radiology, Vol 22, No 12, December 2015
Figure 4. Seventy-year-old woman with large HCC in the right lobe of the liver. dCT scan 1 day after TACE. (a and d) Transversal and coronal temporal maximum intensity projection images, (b and e) transversal and coronal ALP parameter maps, (c) transversal PVP parameter map, (f) TAC of a free-hand ROI in a viable HCC remnant. The 20.7 cm coverage in z-axis of the used dCT scan mode allows the examination of nearly the entire liver. After TACE extensive necrosis of this large HCC is achieved. Color-coded perfusion maps facilitate the recognition of viable HCC remnants (arrows) and the differentiation from intraparenchymal CM from prior TACE (arrowheads). The TAC of a viable HCC remnant shows the typical arterial perfusion pattern. ALP, arterial liver perfusion; CM, contrast medium; dCT, liver dynamic CT; HCC, hepatocellular carcinoma; PVP, portal venous liver perfusion; TAC, time attenuation curve; TACE, transarterial chemoembolization. (Color version of figure is available online.)
both for calculation of perfusion parameter maps and for sufficient tumor enhancement. Ichikawa et al. studied the correlation between the subjective tumor conspicuity and the quantitative tumor TLC in HCCs. They found that a ‘‘good’’ contrast was associated with a mean TLC of 33.7 HU (23), which is lower than the mean TLC in our study (36.4 HU). The used dCT data sets were suitable for the analysis of optimal scan timing in HCC because of the 40-second long scan duration, starting before the bolus arrival and scanning until the arterial bolus outflow. Therefore, the point in time of aortic bolus arrival was imaged and the TAC rise of all examinations could be normalized. In our cohort in 33% of dCT examinations the aortic enhancement start deviated from the expected point in time calculated from a test bolus measurement. We believe this fact could result from changes in cardiac output between the test bolus injection and the dCT scan. The quality of dCT data can be improved by patient training. Breathing during the scans produces motion artifacts, which can only be compensated in part by the automated motion correction during image processing and can result in interpolation artifacts. Therefore, all patients were trained to hold their breath during the dCT scan as long as possible. In case they could not hold their breath any longer, they were instructed to breath intermittently during table move-up (repositioning without scan), rather than during table move-down (scan). Only one data set had to be excluded because of heavy breathing artifacts. 1520
Interestingly, we did not find a significant difference between the less time-consuming ROI approach (drawing an ROI around the HCC on only one slice image) and the more elaborate VOI approach (circumscribing the HCC on multiple consecutive slice images). In our cohort a low tube voltage (100 kV) had been used to reduce the radiation dose. According to a recent report, the tube voltage might be reduced even further to 80 kV in liver CT without compromising the contrast enhancement, image quality, and detection of HCCs (24). Our study is limited in a few ways. First, in a part of our cohort the HCCs had been treated previously by TACE or radiofrequency ablation. We did not perform a subgroup analysis as the number of patients was less than 10 for both previous treatment modalities. However, as we concentrated on viable tumor parts only, we do not believe this previous treatment to influence our study results. Second, histologic confirmation and grading of HCC was only available in a part of our patients, and thus we did not correlate TLC to HCC grading. Yet, our aim was to develop a robust scanning protocol applicable to all patients with HCC irrespective of the subtype. Third, the temporal resolution of the used dCT scan was 4 seconds only. A higher temporal sampling would have provided more data points and with it a more exact determination of the peak enhancement, but would also have increased the radiation dose. If a single liver arterial phase scan is intended in the clinical scenario, we recommend the performance of bolus tracking. Using a low volume, high flow injection protocol (60 mL at
Academic Radiology, Vol 22, No 12, December 2015
6 mL/s), peak arterial enhancement can be expected between 13 and 17 seconds after aortic TAC rise. Therefore, we suggest a threshold of 100 HU for the aortic ROI and a scan delay of 15 seconds. CONCLUSIONS For the proposed contrast injection protocol the optimal TLC was reached between 13 and 17 seconds after aortic contrast arrival, both before and after TACE. REFERENCES 1. European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56: 908–943. 2. Sieghart W, Hucke F, Peck-Radosavljevic M. Transarterial chemoembolization: modalities, indication, and patient selection. J Hepatol 2015; 62: 1187–1195. 3. Saraswat VA, Pandey G, Shetty S. Treatment algorithms for managing hepatocellular carcinoma. J Clin Exp Hepatol 2014; 4(suppl 3):80–89. 4. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010; 30:52–60. 5. Bruix J, Sherman M, Llovet JM, et al. EASL Panel of Experts on HCC. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001; 35:421–430. 6. Alba E, Valls C, Dominguez J, et al. Transcatheter arterial chemoembolization in patients with hepatocellular carcinoma on the waiting list for orthotopic liver transplantation. AJR Am J Roentgenol 2008; 190:1341–1348. 7. Lee JH, Lee JM, Kim SJ, et al. Enhancement patterns of hepatocellular carcinomas on multiphasic multidetector row CT: comparison with pathological differentiation. Br J Radiol 2012; 85:e573–e583. 8. Hennedige T, Yang ZJ, Ong CK, et al. Utility of non-contrast-enhanced CT for improved detection of arterial phase hyperenhancement in hepatocellular carcinoma. Abdom Imaging 2014; 39:1247–1254. 9. Yanaga Y, Awai K, Nakaura T, et al. Optimal contrast dose for depiction of hypervascular hepatocellular carcinoma at dynamic CT using 64-MDCT. AJR Am J Roentgenol 2008; 190:1003–1009. 10. Wu D, Tan M, Zhou M, et al. Liver computed tomographic perfusion in the assessment of microvascular invasion in patients with small hepatocellular carcinoma. Invest Radiol 2015; 50:188–194.
CT ARTERIAL PHASE TIMING IN HCC
11. Kagawa Y, Okada M, Yagyu Y, et al. Optimal scan timing of hepatic arterial-phase imaging of hypervascular hepatocellular carcinoma determined by multiphasic fast CT imaging technique. Acta Radiol 2013; 54: 843–850. 12. Bruix J, Sherman M, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53: 1020–1022. 13. Kim SH, Kamaya A, Willmann JK. CT perfusion of the liver: principles and applications in oncology. Radiology 2014; 272:322–344. 14. Deak PD, Smal Y, Kalender WA. Multisection CT protocols: sex- and agespecific conversion factors used to determine effective dose from doselength product. Radiology 2010; 257:158–166. 15. Baron RL. Understanding and optimizing use of contrast material for CT of the liver. AJR Am J Roentgenol 1994; 163:323–331. 16. Fleischmann D. How to design injection protocols for multiple detectorrow CT angiography (MDCTA). Eur Radiol 2005; 15(suppl 5):E60–E65. 17. Murakami T, Onishi H, Mikami K, et al. Determining the optimal timing for early arterial phase hepatic CT imaging by measuring abdominal aortic enhancement in variable contrast injection protocols. J Comput Assist Tomogr 2006; 30:206–211. 18. Yamaguchi I, Kidoya E, Suzuki M, et al. Optimizing scan timing of hepatic arterial phase by physiologic pharmacokinetic analysis in bolus-tracking technique by multi-detector row computed tomography. Radiol Phys Technol 2011; 4:43–52. 19. Murakami T, Kim T, Kawata S, et al. Evaluation of optimal timing of arterial phase imaging for the detection of hypervascular hepatocellular carcinoma by using triple arterial phase imaging with multidetector-row helical computed tomography. Invest Radiol 2003; 38:497–503. 20. Kanematsu M, Goshima S, Kondo H, et al. Optimizing scan delays of fixed duration contrast injection in contrast-enhanced biphasic multidetectorrow CT for the liver and the detection of hypervascular hepatocellular carcinoma. J Comput Assist Tomogr 2005; 29:195–201. 21. Goshima S, Kanematsu M, Kondo H, et al. MDCT of the liver and hypervascular hepatocellular carcinomas: optimizing scan delays for bolus-tracking techniques of hepatic arterial and portal venous phases. AJR Am J Roentgenol 2006; 187:W25–W32. 22. Lell MM, Jost G, Korporaal JG, et al. Optimizing contrast media injection protocols in state-of-the art computed tomographic angiography. Invest Radiol 2015; 50:161–167. 23. Ichikawa T, Okada M, Kondo H, et al. Recommended iodine dose for multiphasic contrast-enhanced mutidetector-row computed tomography imaging of liver for assessing hypervascular hepatocellular carcinoma: multicenter prospective study in 77 general hospitals in Japan. Acad Radiol 2013; 20:1130–1136. 24. Noda Y, Kanematsu M, Goshima S, et al. Reducing iodine load in hepatic CT for patients with chronic liver disease with a combination of low-tubevoltage and adaptive statistical iterative reconstruction. Eur J Radiol 2015; 84:1–18.
1521