Hepatocellular carcinoma (HCC) accounts for approximately 80% of all primary liver cancers worldwide, and its mortality has been shown to be increasing in both Europe and the United States.1,2 Despite the availability of several treatment options for HCC, intrahepatic recurrence has been particularly problematic and has been reported to be as high as 80% after 5 years.3,4 Therefore, continuous and intense surveillance to identify early recurrence in the remnant liver of patients with a history of HCC remains a crucial part of HCC management.5–7
In this regard, the most commonly used imaging modality for follow-up after treatment is multiphasic contrast-enhanced computed tomography (CT).6 Indeed, CT has demonstrated many advantages over other modalities by providing better sensitivity and specificity than ultrasound, as well as lower cost, scan time, and the capability to explore extrahepatic metastasis compared with magnetic resonance imaging (MRI).8 However, radiation exposure remains a major drawback of multiphasic CT, although its importance may be much reduced in patients with HCC owing to their shorter life expectancy.9 Exposure of iodinated contrast media is not infrequently related with immediate hypersensitivity reaction, and more frequent moderate to severe reaction was observed in higher contrast media dosage.10,11
To reduce both radiation and contrast media doses (double low-dose) while maintaining acceptable image quality, low kVp imaging or low monoenergetic images of dual-energy CT have been attempted.12–15 Low monoenergetic images would provide better iodine contrast than conventional images given the same iodine concentration.16 Conversely, it may be able to provide a way to reduce the contrast media and radiation dose burden without decreasing image contrast.17,18 However, until now, there has been a paucity of data regarding with diagnostic performance of the double low-dose protocol compared with the standard-dose protocol.19,20
The purpose of this study, therefore, is to investigate the clinical feasibility of the simultaneous reduction of radiation and contrast media doses in patients at risk of HCC using low monoenergetic images (50 keV) obtained using spectral CT.
MATERIALS AND METHODS
This prospective, single-center, randomized study was approved by the Institutional Review Board of Seoul National University Hospital, and informed consents were obtained from all study participants (NCT03045445). Financial support was provided by Philips Healthcare; however, the authors had complete control of the data and information submitted for publication at all times.
Between May 2017 and March 2018, study participants were recuited in our study according to the following eligibility criteria: (a) patients at high risk of developing HCC (chronic hepatitis B or C, or cirrhosis of any cause); (b) those scheduled to undergo contrast-enhanced CT for HCC surveillance due to elevated alpha-fetoprotein levels above the normal range (20 ng/mL) or newly detected nodules at ultrasonography for HCC surveillance; or (c) those under surveillance for HCC recurrence after transarterial chemoembolization (TACE). Exclusion criteria were (a) patients younger than 20 years of age; (b) no risk factors for HCC development; (c) any contraindication to contrast-enhanced CT including iodine hypersensitivity, renal dysfunction (estimated glomerular filtrating ratio < 30 mL/min per 1.73 m2); and a (d) body mass index (BMI) ≥30. Sex, age, weight, BMI, and causes of referral were recorded at the time of enrollment.
All participants were randomly assigned (1:1) into either a standard-dose or double low-dose group via a computer-generated permuted block randomization process managed by our medical research collaboration center, using block sizes of 4 and 6. Randomization was stratified by (a) BMI (≤25 vs >25) and (b) the cause of referral (suspicious HCC at surveillance ultrasound [ultrasonography-detected nodules or elevated alpha-fetoprotein levels without focal lesion at ultrasound] versus HCC surveillance after TACE). Participants, investigators, and outcome assessors were all masked to the allocation.
Early study termination was to be considered when reexamination was required owing to suboptimal image quality in 3 participants in the double low-dose group during the enrollment of the first 10 participants.
All patients were requested to fast for at least 6 hours before the CT examination. Computed tomography scans were performed on a 4-cm z-coverage spectral CT scanner (IQon; Philips Healthcare, the Netherlands) using 120 kVp (gantry rotation time of 0.33 seconds, 64 × 0.625 mm collimation, and a slice thickness of 3 mm with 2 mm reconstruction intervals). The double low-dose protocol targeted a 30% reduction in both radiation and contrast media doses in comparison with the standard-dose protocol. Thus, the dose right index (DRI) was set as 15 in the double low-dose group and as 18 in the standard-dose group. Assumed reference mAs in DRI 18 and 15 were 102 mAs and 69.5 mAs, respectively. Organ-based automatic current modulation was also performed throughout the scan with a combination of DoseRight Z-DOM and 3D-DOM in all participants. Liver DRI was not applied for both protocols.21 A volume of 525 mg I/kg of contrast media was used in the standard-dose group, whereas 368 mg I/kg was used in the double low-dose group.22,23 Contrast media (iobitridol 350 mg/mL) was administered via a power injector (Stellant; Medrad, Pittsburgh, PA) for 35 seconds, followed by a saline flush of 30 mL. Precontrast, portal venous, and delayed phases were obtained before, and 70 seconds and 180 seconds after contrast media administration, respectively. The arterial phase was obtained using the bolus tracking technique, 17 seconds after a trigger threshold of 150 HU at the abdominal aorta. Scan parameters and coverage were identical in all 4 phases. Both hybrid iterative reconstruction images (iDose4) with a level of 4 and monoenergetic (50 keV) images with a spectral level of 4 were reconstructed with vendor-provided software (IntelliSpace Portal Version 9) in all participants. The level of monoenergetic image (50 keV) was determined empirically, given the image contrast and texture.20,24–26
All images were anonymized and randomly distributed to reviewers. Thereafter, 4 fellowship-trained radiologists (J.H.Y., E.S.L., W.C., S.M.L.) with 3 to 7 years of experience after fellowship independently reviewed the images, with the window width and level made adjustable at all times. Image noise, image contrast, and overall image quality were scored on a 5-point scale on arterial and portal venous phases, with the highest score indicating better image quality (Table S1, Supplementary Digital Content, http://links.lww.com/RLI/A510). The location and size of the focal liver lesions except for lipiodol uptake lesions and simple hepatic cysts were recorded. Lesion conspicuity on arterial and portal venous phases was scored on a 5-point scale as follows: score 1, not visible (automatically assigned to missed lesions); score 2, barely delineated; score 3, visible with blurry margin; score 4, visible lesion with relatively sharp margin and acceptable contrast; and score 5, clear contrast and sharp margin.27 Reviewers were also asked to score the lesion for the possibility of HCC based on all phases including precontrast and delayed phases, according to the Liver Imaging-Reporting and Data System v2017.28,29 Threshold growth and ultrasound visibility were not used for scoring. When lesions were reported as LR-4 or LR-5, those lesions were regarded as being reported as HCCs.
One radiologist (J.H.Y.) drew 3 regions of interest in the liver, aorta, portal vein, and subcutaneous fat layer of the anterior abdominal wall. The average Hounsfield unit of the 3 regions of interest was used as a representative value. Image noise was defined as standard deviation of Hounsfield unit in the subcutaneous fat. Contrast-to-noise ratios (CNRs) of the aorta and portal vein were calculated on arterial and portal venous phase as below.18
Standard of Reference
The reference standard for lesion detection was the closest follow-up imaging including standard-dose liver CT or liver MRI taken within 3 months in patients with LR-3, LR-4, LR-5, or LR-M lesions. Interval cancers on follow-up were regarded as true lesions that had been missed at standard/double low-dose CT. In those without focal lesions or with only benign lesions, remote cross-sectional imaging was used instead of 3-month follow-up imaging. Detailed description of the reference standard is provided in Supplementary Digital Content 1, http://links.lww.com/RLI/A510. In brief, HCC was diagnosed using histology or typical imaging features on follow-up CT, MRI, or tumor staining and lipiodol uptake on TACE. Histologic results were used to diagnose metastasis. Benign lesions were confirmed on previous and follow-up images over 3 to 6 months as well as typical imaging features. Detailed criteria for benign and malignant lesions in this study are described in the Supplementary Digital Content 1, http://links.lww.com/RLI/A510.
The primary endpoint of the study was the comparison of lesion conspicuity between iDose images using the standard-dose protocol and 50 keV images using the double low-dose protocol. As secondary outcomes, we compared the quantitative and qualitative image noise, image contrast, overall image quality, detection rates of all lesions, and per-lesion–based sensitivities of HCCs (LR-4 and LR-5) between the 2 protocols (iDose image of standard-dose and 50 keV image of double low-dose). Intraindividual comparison was made between the reconstruction methods (iDose vs 50 keV) for lesion conspicuity and aforementioned secondary outcomes. In addition, the radiation dose and administered amount of contrast media were compared between the 2 groups.
The sample size of this study was determined based on a method proposed in a prior study that investigated the better lesion conspicuity of HCCs on monoenergetic images (50 keV) using single-source rapid kVp switching and reduced contrast media compared with the standard protocol17 (Supplementary Digital Content 2, http://links.lww.com/RLI/A510).
The χ2 test was used for comparison of categorical variables, and the Student t test, Mann-Whitney U test, or paired t test was used for continuous variables as appropriate. Interobserver agreement was assessed using the intraclass coefficient. Lesion conspicuity was analyzed using generalized estimating equation (GEE) analysis, owing to the presence of multiple lesions in a patient. Normal distribution and the identity link function were applied, and lesion conspicuity was presented with 95% confidence interval (CI).
To assess diagnostic performance, reader averaged figures of merit (FOMs) were obtained using weighted JAFROC (jackknife alternative free-response receiver operating characteristic) analysis with random readers and random lesions. Lesion detection rates of each group were also obtained using GEE analysis with normal distribution and the identity link function. Per-lesion HCC diagnosis was defined as when authors scored the lesion as LR-4 or LR-5 and were analyzed using GEE with binominal distribution and a logit link function. Lesion conspicuity, lesion detection, and HCC diagnosis were evaluated in all participants and in subgroups stratified by BMI (<25 vs ≥25) and lesion size (<20 mm vs ≥20 mm).
All statistical analyses were performed using commercially available software packages (SAS version 9.4; SAS Institute Inc, Cary, NC; IBM SPSS, version 23; SPSS Inc, IBM Company, Armonk, NY; Medcalc; Medcalc Software, Mariakerke, Belgium) and JAFROC software version 4.2.1. A P value of less than 0.05 was considered to indicate a statistically significant difference.
Between May 2017 and March 2018, 68 study participants were enrolled and allocated to the standard-dose (n = 33) and double low-dose groups (n = 35), respectively (Fig. 1). One man in the standard-dose group withdrew his consent before undergoing CT and was excluded from the study. Finally, 67 study participants (male-to-female ratio, 59:8; mean age, 64 ± 9 years) comprised our study population (Table 1). There were no significant differences in body weight (69.4 ± 10 kg vs 61.9 ± 9 kg, P = 0.94) or BMI (24.5 ± 2.3 vs 24.2 ± 2.4, P = 0.58) between the 2 groups. Compared with the standard-dose group, total DLP (1070.1 ± 255.6 mGy·cm vs 738.3 ± 102.7 mGy·cm, P < 0.001) and CTDIvol (8.8 ± 1.7 mGy vs 6.1 ± 0.6 mGy, P < 0.001) was lower by 30% in the double low-dose group (Table 1). The amount of contrast media administered was also significantly lower in the double low-dose group than in the standard-dose group (116.9 ± 15.7 mL vs 83.1 ± 9.9 mL, P < 0.001). No participants underwent reexamination owing to suboptimal image quality.
A total of 171 focal liver lesions were determined on follow-up imaging in 60 participants (99 lesions in the standard-dose group [n = 29] and 72 lesions in the double low-dose group [n = 31]). Lesions included HCCs (n = 107), dysplastic nodules (n = 51), hemangiomas (n = 6), regenerative nodules (n = 2), treated lesions other than lipiodol (n = 2), metastasis (n = 1), adenocarcinoma (n = 1), and a focal fat deposition (n = 1). There were no significant differences in lesion size between the standard-dose group (14.7 ± 6.8 mm) and the double low-dose group (15.8 ± 12.3 mm, P = 0.43). Detailed information regarding lesion confirmation is provided in Supplementary Digital Content 3, http://links.lww.com/RLI/A510.
Comparison of Lesion Conspicuity Between Standard-Dose iDose and Double Low-Dose 50 keV Images
Lesion conspicuity was significantly higher on 50 keV images of the double low-dose group than on the iDose images of the standard-dose group on both arterial (2.62 [95% CI, 2.31–2.93] vs 2.02 [95% CI, 1.73–2.30], P = 0.004) and portal venous phases (2.39 [95% CI, 2.11–2.67] vs 1.88 [95% CI, 1.67–2.10], P = 0.005; Table 2, Figs. 2,3) At subgroup analysis, double low-dose 50 keV showed significantly higher lesion conspicuity than standard-dose iDose image in small lesions (<20 mm) on both arterial and portal venous phases (P = 0.002~0.003, Table 2), but no difference was observed between the 2 groups in lesions 20 mm or larger on either phase (P = 0.28~0.35, Table 2).
Comparison of Lesion Detection and Per-Lesion Sensitivity of an HCC Diagnosis Between Standard-Dose iDose and Double Low-Dose 50 keV Images
There were no significant differences in lesion detection between the 2 groups (Table 3, FOM: 0.63 with standard-dose iDose and 0.65 with double low-dose 50 keV, P = 0.52). On subgroup analysis stratified by BMI (<25 vs ≥25) and lesion size (<20 mm vs ≥20 mm), no significant differences were observed between the 2 groups (Table 3, P = 0.3~0.99). As for the per-lesion sensitivity of an HCC diagnosis (LR-4 or LR-5) in the 4 reviewers, double low-dose 50 keV revealed a sensitivity of 50.0% (92/184 [95% CI, 36.3–63.7]), whereas standard-dose iDose showed a sensitivity of 39.3% (96/244, [95% CI, 31.1–48.2]). The difference was −10.7% (95% CI, −27.1 to 5.8), but it did not reach statistical significance (P = 0.2).
Comparison of Image Quality Between Standard-Dose iDose and Double Low-Dose 50 keV Images
On arterial and portal venous phases, double low-dose 50 keV images showed significantly less noise, stronger image contrast, and better image quality than standard-dose iDose images (Table 4, P < 0.001 for all; Fig. 4). On quantitative analysis, contrast-to-noise ratios of the aorta and portal vein were significantly higher on double low-dose 50 keV images than on standard-dose iDose images (Table 4, P < 0.001). Qualitative image noise, however, was not significantly different with each other (Table S2, Supplementary Digital Content, http://links.lww.com/RLI/A510, P = 0.4~0.5). Intraclass coefficients were 0.60 to 0.87, based on an average-rating (k = 4), consistency, 2-way model. Estimates with 95% CI of each variable are provided in Supplementary Digital Content 4, http://links.lww.com/RLI/A510.
Comparison of iDose and 50 keV Images in All Participants
In all participants including both standard-dose and double low-dose groups, qualitatively assessed image noise, image contrast, and overall image quality were better on 50 keV images than on iDose images (P < 0.001 for all, Table S2, Supplementary Digital Content, http://links.lww.com/RLI/A510; Fig. 5). These results were consistent across BMI (≤25 and >25) and protocol (standard-dose and double low-dose; P < 0.001 for all, Table S2, Supplementary Digital Content, http://links.lww.com/RLI/A510). Qualitatively assessed lesion conspicuity was also higher on 50 keV images than on iDose in all participants (2.5 [95% CI, 2.23–2.82] vs 1.93 [95% CI, 1.74–1.93] on arterial phase and 2.35 [95% CI, 2.16–2.55] vs 1.83 [95% CI, 1.67–1.99] on portal venous phase, P < 0.001 for all), regardless of BMI and lesions size (P < 0.001 for all, Table S3, Supplementary Digital Content, http://links.lww.com/RLI/A510). Regarding the detection of all focal liver lesions, 50 keV images showed better lesion detection than iDose in all participants (FOM: 0.81 vs 0.74, respectively, P < 0.001; Table S4, Supplementary Digital Content, http://links.lww.com/RLI/A510, Fig. 6), and for the diagnosis of HCCs (LR-4 or LR-5), 50 keV showed higher per-lesion sensitivity (47.2% [202/428; 95% CI, 38.2–56.3]) than iDose (35.5% [152/428; 95% CI, 28.9–42.7], P < 0.001).
Our study results revealed that low monoenergetic images (50 keV) allowed significantly better focal liver lesion conspicuity even after lowering both radiation and contrast media doses by 30%, compared with standard-dose iDose images in nonobese patients. Furthermore, 50 keV images obtained using the double low-dose CT protocol revealed higher image contrast, and better image quality than standard-dose iDose images at both arterial and portal venous phases. Previous studies had already reported that low monoenergetic images of dual-energy CT can provide better image quality than conventional images, which may help lower contrast media or radiation doses.19,30,31 However, it has remained uncertain as to how much radiation and contrast media doses could be reduced and more importantly whether a double dose reduction can be achieved simultaneously without compromising diagnostic performance. In our study, we have demonstrated that a simultaneous reduction of 30% in both radiation dose and iodine amount can be made without compromising image quality in participants with a BMI <30 compared with hybrid iterative reconstruction images at standard dose. Considering the importance of minimizing radiation and contrast media doses, we believe that our findings can be of great clinical value.
Simultaneous radiation and contrast media dose reduction would particularly be useful for patients who undergo multiple CT scans. Patients with a suspicion of HCC or a history of HCC belong to this category owing to the demand for an intense follow-up strategy due to the high risk of HCC recurrence. However, radiation exposure is often underestimated in oncologic patients due to their relatively short life expectancy and the clinicians' focus on the immense benefit of early detection of recurrence. Indeed, patients with very early or early-stage HCCs who have a life expectancy of longer than 5 years usually undergo multiple CT scans at 3- to 4-month intervals so as to detect recurrence.32 Moreover, even oncologic patients without any evidence of disease are often under surveillance so as not to miss a chance to control potential recurrence. So, we firmly believe that it would be necessary to reduce radiation dose even in these oncologic patients under surveillance. Contrast media dose reduction would also be important for those patients because renal dysfunction is common in oncologic patients and cirrhotic patients.33,34 In addition, recent work has suggested that iodine would increase the radiation dose by 35% in the liver and 54% in the kidney by increasing radiation absorption.33,35,36 Therefore, we believe that reduced radiation and contrast doses using DECT while maintaining image quality and diagnostic performance would hold great clinical value for patients with a high risk of HCCs who need to undergo multiple multiphasic liver CT scans.
Studies have demonstrated that low monoenergetic images would provide higher iodine contrast owing to the increased photoelectric absorption of iodine.37,38 However, until recently, an energy level below 70 keV had not been used owing to concerns over increasing image noise.39,40 Indeed, despite recent technical advances in reducing image noise, low monoenergetic images of 40 to 50 keV have not been preferred over low kV imaging owing to concerns of image noise.38,41–43 However, in our study, 50 keV images were demonstrated to provide less subjective image noise and better image quality than iDose images, which is different from the results reported in a prior study.43 We believe that image noise suppression at low keV is the key factor that may explain this difference in our results. A single-source dual-layer DECT provides spatial and temporal coherence, and is free from cross-scatter between the 2 tubes that increases image noise. Moreover, the spatial and temporal coherence between the low and high energy data allow spectral decomposition at the projection-domain, which has a theoretical advantage over image-domain decomposition. Advanced noise modeling that includes spectral anticorrelative noise suppression effectively reduces noise of monoenergetic images at all keV levels and is especially important for low keV imaging.44,45 Indeed, our observation is consistent with that of a previous study, which demonstrated the consistent image noise of monoenergetic images generated from dual-layer spectral CT at various energy levels ranging from 40 keV to 200 keV.25,46 One concern is a potential alteration of image texture at low keV due to the different noise power spectrum.24,37 It requires radiologists' caution to determine low keV level for the clinical use.
Finally, in our study, although 50 keV images of the double low-dose group provided better image quality and lesion conspicuity than iDose images of the standard-dose group, no significant difference in lesion detection was noted between the 2 groups. However, we also found that the 50 keV images in our study showed significantly higher FOMs and HCC sensitivity than iDose images when using the same radiation/contrast media doses. Thus, further studies are warranted to demonstrate the noninferiority or superiority of the diagnostic performance of 50 keV images compared with conventional images.
Our study has several limitations. First, as the number of participants in our study was relatively small, the statistical power for the comparison of lesion detection may have been weakened. However, it was an inevitable limitation as we could not know the exact number of liver lesions at the time of enrollment owing to the format of a randomized prospective study. Second, the diagnosis of focal liver lesions was made radiologically in most HCCs and benign lesions. However, this was the consequence of adhering to current clinical guidelines, which support imaging-based diagnosis for HCC. Also, it is not recommended to perform biopsy for definite or likely benign lesions. Third, we obtained monoenergetic images from dual layer spectral CT using their noise reduction algorithm. Therefore, we do not know whether our study results would be directly applicable to monoenergetic images obtained using a dual-source technique or a rapid kVp switching method. Fourth, overall lesion conspicuity and lesion detection were low in both groups. Our study might underestimate the overall performance of CT, probably because of small size of lesions (<20 mm) and inclusion of cirrhotic nodules such as regenerative/dysplastic nodules, which are not well seen at CT in general. Fifth, we did not directly compare 50 keV images between standard-dose and double low-dose groups, because our purpose is to use the advantage of monoenergetic image for reducing radiation exposure and contrast media amount, rather than improving image quality as possible. It might be needed to measure the impact of double low-dose with using 50 keV at standard-dose as a reference standard. In addition, our keV level (50 keV) was determined empirically, so further study with monoenergetic images with lower than 50 keV might be needed to see any improvement of diagnostic performance on monoenergetic images at double low-dose. Last, we did not include those with a BMI ≥30. This limitation stemmed from the fact that we had little information to predict the effect of both contrast media and radiation dose reduction in these patients. As spectral CT does not increase radiation exposure compared with 120 kVp single energy CT, further studies including patients with large body habitus are warranted.
In conclusion, low monoenergetic spectral CT images (50 keV) were able to provide better focal liver lesion conspicuity than standard-dose iDose images at lower radiation and contrast media doses in nonobese patients.
We thank Chris Woo, BA, for his editorial assistance and Youngmi Chun, BA, for her technical assistance. We also appreciate the statistical advice from the Medical Research Collaborating Center at Seoul National University Hospital and Seoul National University College of Medicine.
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