Introduction
Hepatocellular carcinoma (HCC) is a major health problem worldwide, with about 841,000 new cases and 782,000 deaths recorded annually.[1] [2-8] [9] Figure 1 ). Current guidelines recommend HCC screening to reduce HCC mortality in high-risk populations, that is, those with chronic hepatitis, such as chronic hepatitis B (CHB), chronic hepatitis C (CHC), and/or cirrhosis.[10]
Figure 1: The process of HCC screening. AFP: Alpha-fetoprotein; CHB: Chronic hepatitis B; CHC: Chronic hepatitis C; CT: Computed tomography; HCC: Hepatocellular carcinoma; MRI: Magnetic resonance imaging; US: Ultrasonography.
The ideal screening interval for HCC screening is controversial, ranging from a 3 to 12-month periodicity. A 6-month screening interval is recommended by most guidelines (eg, the American Association for the Study of Liver Disease [AASLD],[11] [12] [13] [14]
Which screening modality should be used for HCC screening has also been a subject of debate. Screening for HCC using ultrasonography (US) and alpha-fetoprotein (AFP) has been recommended by professional societies for more than a decade. AFP was omitted from European and American guidelines in 2010 due to its lack of sensitivity, but it remains in the recommendations given by Asian guidelines. How to optimize the performance of US for HCC screening is also not a settled question. US screening can lead to an inadequate quality of HCC screening due to rib shadowing and inadequate beam penetration.[15] [14]
The current guidelines recommend HCC screening strategies for high-risk populations. However, none of these guidelines are based on a systematic review of relevant studies with a critical appraisal of their internal validity. Most guidelines have only cited several other trials/observational studies[16-19] meta-analysis to fill this gap.
Methods
We conducted this systematic review following the recommendations laid out in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.[20]
Database and search strategy
The following databases were searched: PubMed, Embase, the Cochrane library, Clinicaltrials.gov, Web of Science, Google scholar, and Chinese databases (China National Knowledge Infrastructure, Wanfang, VIP, and SinoMed). We searched the literature from inception to June 30, 2021, using the keywords “screening and hepatocellular carcinoma.” The details of the search strategy are presented in Supplementary Table 1, https://links.lww.com/CM9/B259
Study selection
Two groups of reviewers (JCY and SQY, LG and XYZ) independently screened the titles and abstracts of studies and resolved any disagreement by consensus. Next, the full-text paper of each potentially eligible article identified in the screening was retrieved. The two groups independently assessed articles for inclusion. Any discrepancies were resolved by discussion among the reviewers, or if necessary, by consulting a fifth reviewer (FS).
Studies were included for analysis if they (1) had a study population including a high-risk population for HCC (those with CHB, CHC, and/or cirrhosis); (2) exhibited interventions/comparators that compared HCC screening intervals or modalities; (3) described effectiveness and/or harm outcomes; and (4) were comparative studies (randomized controlled trials [RCTs] or cohort studies).
We excluded duplicate studies and studies whose data were lacking or unavailable. Studies comparing screening and non-screening were also excluded. If one study was reported in more than one publication, we only included the most informative article or the longest follow-up study to avoid duplication of information.
Definition of outcomes
HCC-related mortality was the main outcome, given that the goal of cancer screening was to reduce mortality. It refers to the total number of deaths from HCC over a defined time interval (eg, 1 year), divided by the number of people at risk for the disease in the given population over the same interval.[21]
Survival rate was the number of people diagnosed with HCC who were still alive (eg, 1, 3, and 5 years after diagnosis), divided by the total number of people who had the disease originally.[21]
Median survival time was the corresponding survival time when the cumulative survival rate is 0.5 indicates that only 50% of the individuals can survive this time. It provides a general index of survival and prognosis for cancer patients.
The proportion of early HCC was the total number of early HCC cases divided by the total number of HCC cases, representing the intermediate effectiveness outcome of HCC screening. It was defined by Milan criteria or Barcelona clinic liver cancer (BCLC) stage system.
Data extraction
Two reviewers (JCY and XYZ) independently reviewed and extracted the required information from eligible studies using standardized forms. The reviewers resolved any discrepancy through discussion or, if necessary, by conferring with a third reviewer (FS or ZRY). The data extraction form included the following study design items: basic information, population characteristics, screening modalities, screening intervals, effectiveness outcomes, study design, and so on.
Risk of bias assessment in individual studies
Cochrane's tool for assessing risk of bias was used to assess quality in RCTs.[22] [23]
Statistical analysis
Data synthesis
STATA software version 15.0 (StataCorp LP, College Station, TX, USA) was used for all statistical analyses and to generate forest plots. For proportion of early HCC and HCC mortality, the results were expressed as risk ratio (RR) with 95% confidence intervals (CIs). Because most eligible studies only provide the number of survival patients instead of the hazard ratio, survival rates were also pooled using RR with 95% CIs; the median survival time was expressed as median survival ratio (MSR) with 95% CIs.
We pooled results for RCTs and observational studies separately, using a random-effects model separately. For cases with limited data (with only one study), narrative analyses were conducted to summarize the results. Heterogeneity was assessed using the chi-square test on Cochrane's Q and quantified with I 2 values.
Assessment of publication bias
To assess symmetry in the funnel plots, Egger's test was used to evaluate the presence of publication bias when ten or more studies were available; P < 0.05 was considered indicative of statistically significant publication bias.[24]
Subgroup analyses
We did not perform subgroup analyses because only one to three studies were available for each outcome.
Sensitivity analyses
We performed a sensitivity analysis by excluding studies with a high risk of bias.
Results
Literature search
The inclusion process is presented in the PRISMA diagram [Figure 2 ]. The search yielded 7846 potentially relevant records. After abstracts and full texts were screened, 13 studies were included in the meta-analysis .
Figure 2: PRISMA flowchart of included studies on hepatocarcinoma screening. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Characteristics of included studies
The characteristics of the eligible studies are summarized in Table 1 . All studies were published between 2002 and 2021, and most were conducted in Europe and Asia. No study compared the potential harm of different screening intervals/modalities. Of the 13 studies reviewed, including two RCTs and six cohort studies, compared the effectiveness of different screening intervals; the other three RCTs and two cohort studies compared the effectiveness of different screening modalities. In terms of reporting outcomes, 11 studies reported proportion of early HCC, which four studies defined early HCC using Milan criteria and other four studies using BCLC stage system, whereas three studies did not report the definition of early HCC. Two studies provided HCC mortality, one study reported 1-year survival rate, three studies reported the 5-year survival rate, and four studies provided median survival time. There were no studies reported the harm outcomes.
Table 1: Characteristics of included studies comparing different screening intervals and modalities of hepatocarcinoma screening.
In addition, most cohort studies and RCTs exhibited a low risk of bias. The details of the bias risk assessment are presented in Supplementary Table 2, https://links.lww.com/CM9/B259
Comparison of different screening intervals
One RCT in France compared the effectiveness of 3-month vs. 6-month screening intervals. [19] vs. 638 for 6-month screening), 53 and 70 cases were diagnosed with HCC, respectively. After 3 years of follow-up, there were no differences in the risk for early HCC (RR = 1.18, 95% CI: 0.97–1.42) or HCC mortality (RR = 0.87, 95% CI: 0.65–1.18) between the two screening intervals.
Another RCT, conducted in China, compared 4- and 12-month screening intervals in patients with chronic viral hepatitis, who were screened via US.[25]
Five retrospective cohort studies compared the 6-month vs. 12-month screening intervals (20,210 vs. 6123 HCC patients) screened via US in cirrhosis and chronic hepatitis patients.[17,18,26-28] Figures 3–5 , the pooled results in meta-analysis demonstrated that the 6-month group had a higher proportion of early HCC (RR = 1.17, 95% CI: 1.08–1.26, I 2 = 0.0%), higher 5-year survival rate (RR = 1.39, 95% CI: 1.07–1.82, I 2 = 63.8%), and longer median survival (MSR = 1.30, 95% CI: 1.28–1.31, I 2 = 0.0%) than the 12-month screening interval.
Figure 3: Comparison of proportion of early HCC between the 6 and 12-month screening intervals. HCC: Hepatocellular carcinoma; RR: Risk ratio.
Figure 4: Comparison of 5-year survival rate between the 6 and 12-month screening intervals. HCC: Hepatocellular carcinoma; RR: Risk ratio.
Figure 5: Comparison of median survival time between the 6- and 12-month screening intervals. m1: Median survival of 6-month group; m2: Median survival of 12-month group; MSR: Median survival ratio; total1: The number of HCC in the 6-month group; total2: The number of HCC in the 12-month group.
The other retrospective cohort study[29] vs. >12-month screening intervals in cirrhosis patients screened via US, 97 and 38 cases were diagnosed HCC, respectively. And found that the ≤12-month group had a higher proportion of early HCC (RR = 1.53, 95% CI: 1.26–1.87) than the >12-month screening group.
Comparison of different screening modalities
Three RCTs and two cohort studies compared the effectiveness of different screening modalities (eg, US, CT, and MRI) in cirrhosis or CHB patients. Because only one study examined each outcome, descriptive analysis was conducted, with the results shown in Table 2 .
Table 2 -
Summary of comparing different screening modalities.
Effectiveness outcome (RR, 95% CI)
Included studies
Study design
Screen modalities
N of screen population
N of HCC
HCC mortality
Proportion of early HCC
Pocha et al
[30]
RCT
US/6M vs. CT/12M
Cirrhosis (83 vs. 80)
9 vs. 8
0.69 (0.23–2.09)
0.89 (0.40–1.96)
Rhee et al
[31]
RCT
US/6M vs. MRI/6M
Cirrhosis (188 vs. 189)
10 vs. 12
NA
0.60 (0.37–0.97)
Kudo et al
[32]
RCT
CEUS/4M vs. B-mode US/4M
Cirrhosis (309 vs. 313)
28 vs. 26
NA
1.08 (1.00–1.23)
Kim et al
[33]
Cohort study
US/6M vs. US/6M + CT/12M
CHB (825 vs. 822)
96 vs. 105
NA
2.15 (1.56–2.98)
Kim et al
[34]
Cohort study
US/6M vs. US/6M + CT/12M
Cirrhosis (659 vs. 576)
90 vs. 94
NA
1.31 (1.13–1.51)
CEUS: Contrast-enhanced US; CHB: Chronic hepatitis B; CI: Confidence interval; CT: Computed tomography; HCC: Hepatocellular carcinoma; M: Screening interval is x months (eg, 3M means screening interval was 3 months); MRI: Magnetic resonsance imaging; NA: Not reported; No.: Number; RCT: Random clinical trial; RR: Risk ratio.
One RCT compared the biannual US to annual CT for HCC screening in cirrhosis patients. [30] [31] [32]
In addition, two cohort studies compared the screening effectiveness of the biannual US and biannual US combined with annual CT in patients with cirrhosis and CHB patients, respectively.[33,34]
Results of sensitivity analyses
As shown in Supplementary Table 3, https://links.lww.com/CM9/B259
Discussion
Comparison of different screening intervals
The results of comparing different screening intervals indicated that shorter screening intervals (3- or 4-month) were no better than longer ones (6- or 12-month). However, within the longer intervals, 6-month screening was better than 12-month screening when US was used. No studies have reported on the potential harm of different screening intervals. Our study was a systematic review to compare the effectiveness of different HCC screening intervals in a high-risk population.
Most guidelines suggest that tumor screening intervals should be determined based on the mean tumor volume doubling time (TVDT).[12] [35-37]
Current evidence and most guidelines recommend screening only for high-risk populations, those with chronic hepatitis such as CHB, CHC, and cirrhosis. However, the guideline of JSH further classified high-risk groups into generally high-risk group and extremely high-risk group who have both viral hepatitis and cirrhosis. JSH believed extremely high-risk group are more likely to develop HCC than generally high-risk group. JSH proposed that the detectability of small nodules (<2 cm in diameter) in the liver was superior in the 3-month interval group than in the 6-month interval group. Therefore, it recommended different screening intervals using US and/or AFP for two groups: every 6 months for the generally high-risk group, and every 3 to 4 months for the extremely high-risk group.[14]
The current evidence suggest that the 6-month screening interval is the best for HCC screening with US in patients in a high-risk population. However, it is maybe necessary to classify high-risk populations into subgroups and recommend different screening intervals according to the natural history of different subgroups.
Comparison of different screening modalities
There were three RCTs and two cohort studies that compared the effectiveness of different screening modalities in patients with cirrhosis and CHB. The results indicated that the effectiveness of biannual MRI or biannual US combined with annual CT was better than the biannual US, and there were no differences between the biannual US and annual CT. In addition, one RCT showed that screening by contrast-enhanced US increased the proportion of early HCC over B-mode US in cirrhosis patients with a 4-month screening interval. We did not find a systematic review that had compared different screening modalities in a HCC high-risk population.
Most current guidelines generally recommend US and AFP for HCC screening in a high-risk population. Considering that the accuracy of AFP is low, European and American guidelines (eg, EASL guidelines, AASLD guidelines) only recommend US as the screening modality. This may be related to the fact that there are more cirrhosis patients in Europe and the United States and the accuracy of AFP screening for HCC in cirrhosis patients is low.[11,12] [13] [38] [39] [14] [15,30]
As mentioned above, current guidelines and many studies only recommend using US to screen HCC in a high-risk population, instead of classifying US subtypes. However, the results of one RCT suggested that it may be necessary to select the appropriate US subtypes for HCC screening in different high-risk populations (ie, chronic hepatitis including CHB, CHC, and/or cirrhosis).
In the future, we should choose different screening modalities for different populations to improve the effectiveness of HCC screening. Without a doubt, high-quality prospective studies are needed to better define the roles of different screening modalities.
Strengths and limitations
Our study had several strengths. It is a systematic review to compare the effectiveness of different HCC screening intervals/modalities in a high-risk population. Moreover, we systematically identified and included both RCTs and observational studies of the effectiveness of HCC screening.
Despite these strengths, our systematic review had several limitations. First, the lack of RCTs data comparing 6- to 12-month HCC screening intervals may cause question on the cost-effectiveness of 6-month screening intervals. Second, publication bias could not be analyzed because there were <10 studies for each outcome, which rendered the use of funnel plots improper. Finally, due to the authors’ limited knowledge of health economics, our study did not compare evidence-based evaluations of the effects of different screening intervals or different screening modalities on health economics.
Conclusion
In summary, a comparison of different screening intervals suggested that 6 months may be the best interval for US screening. The result indicated that the effectiveness of CT and MRI is better than US when screening intervals are the same, there were no differences between the biannual US and annual CT. However, MRI and CT are more expensive than US, CT also can increase the risk of radiation exposure. The fact there are few relevant studies provide evidence for the effectiveness of screening intervals and screening modalities at present. Most evidence came from retrospective cohort studies. Moreover, the incidence of HCC varies with different disease backgrounds. Future studies and guidelines need to recommend more accurate screening strategies based on the natural history of the different high-risk populations (ie, CHB, CHC, and other chronic hepatitis, cirrhosis). High-quality prospective studies are needed to determine the actual effectiveness and harm of different screening intervals and modalities.
Funding
This work was supported by grants from the National Natural Science Foundation of China (Nos. 71673003, 72074011), Special Project of Clinical Toxicology, Chinese Society of Toxicology (Nos. CST2020CT605, CST2021CT102), the second batch of Key Projects of Scientific Act for Drug Regulation of China, (No. [2021]37-10), Special Project for Director, China Center for Evidence Based Traditional Chinese Medicine (No. 2020YJSZX-2).
Conflict of interest
None.
References
1. Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: new trends. J Hepatol 2020;72:250–261. doi: 10.1016/j.jhep.2019.08.025.
2. Chimed T, Sandagdorj T, Znaor A, Laversanne M, Tseveen B, Genden P, et al. Cancer incidence and cancer control in Mongolia: results from the National Cancer Registry 2008-12. Int J Cancer 2017;140:302–309. doi: 10.1002/ijc.30463.
3. Hori M, Matsuda T, Shibata A, Katanoda K, Sobue T, Nishimoto H. Cancer incidence and incidence rates in Japan in 2009: a study of 32 population-based cancer registries for the Monitoring of Cancer Incidence in Japan (MCIJ) project. Jpn J Clin Oncol 2015;45:884–891. doi: 10.1093/jjco/hyv088.
4. Jung KW, Won YJ, Oh CM, Kong HJ, Lee DH, Lee KH. Prediction of cancer incidence and mortality in Korea, 2017. Cancer Res Treat 2017;49:306–312. doi: 10.4143/crt.2017.130.
5. Chen WQ, Sun KX, Zhen RS, Zhang SW, Zeng HM, Zou XN, et al. Report of cancer incidence and mortality in different areas of China, 2014. China Cancer 2018;27:1–14. doi: 10.11735/j.issn.1004-0242.2018.01.A001.
6. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69:7–34. doi: 10.3322/caac.21551.
7. Ferlay J, Colombet M, Soerjomataram I, Dyba T, Randi G, Bettio M, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018. Eur J Cancer 2018;103:356–387. doi: 10.1016/j.ejca.2018.07.005.
8. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 2013;49:1374–1403. doi: 10.016/j.ejca.2012.12.027.
9. Harris RP, Wilt TJ, Qaseem A. A value framework for cancer screening: advice for high-value care from the American College of Physicians. Ann Intern Med 2015;162:712–717. doi: 10.7326/M14-2327.
10. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet 2018;391:1301–1314. doi: 10.1016/s0140-6736(18)30010-2.
11. Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 2018;67:358–380. doi: 10.1002/hep.29086.
12. Galle PR, Forner A, Llovet JM, Mazzaferro V, Piscaglia F, Raoul JL, et al. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol 2018;69:182–236. doi: 10.1016/j.jhep.2018.03.019.
13. Omata M, Cheng AL, Kokudo N, Kudo M, Lee JM, Jia J, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int 2017;11:317–370. doi: 10.1007/s12072-017-9799-9.
14. Kokudo N, Hasegawa K, Akahane M, Igaki H, Izumi N, Ichida T, et al. Evidence-based clinical practice guidelines for hepatocellular carcinoma: the Japan Society of Hepatology 2013 update (3rd JSH-HCC Guidelines). Hepatol 2015;45:123–127. doi: 10.1111/hepr.12464.
15. Andersson KL, Salomon JA, Goldie SJ, Chung RT. Cost effectiveness of alternative surveillance strategies for hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol 2008;6:1418–1424. doi: 10.1016/j.cgh.2008.08.005.
16. Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 2004;130:417–422. doi: 10.1007/s00432-004-0552-0.
17. Santi V, Trevisani F, Gramenzi A, Grignaschi A, Mirici-Cappa F, Del Poggio P, et al. Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival. J Hepatol 2010;53:291–297. doi: 10.1016/j.jhep.2010.03.010.
18. Trevisani F, De Notariis S, Rapaccini G, Farinati F, Benvegnu L, Zoli M, et al. Semiannual and annual surveillance of cirrhotic patients for hepatocellular carcinoma: effects on cancer stage and patient survival (Italian experience). Am J Gastroenterol 2002;97:734–744. doi: 10.1111/j.572-0241.2002.05557.
19. Trinchet JC, Chaffaut C, Bourcier V, Degos F, Henrion J, Fontaine H, et al. Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3- and 6-month periodicities. Hepatology 2011;54:1987–1997. doi: 10.002/hep.24545.
20. Knobloch K, Yoon U, Vogt PM. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement and publication bias. J Craniomaxillofac Surg 2011;39:91–92. doi: 10.1016/j.jcms.2010.11.001.
21. Kramer BS, Croswell JM. Cancer screening: the clash of science and intuition. Annu Rev Med 2009;60:125–137. doi: 10.1146/annurev.med.60.101107.134802.
22. Higgins JP, Altman DG, G⊘tzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;34:59–68. doi: 10.1136/bmj.d5928.
23. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:603–605.
https://pubmed.ncbi.nlm.nih.gov/20652370/ .
24. Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 2011;343:40–50. doi: 10.1136/bmj.d4002.
25. Wang JH, Chang KC, Kee KM, Chen PF, Yen YH, Tseng PL, et al. Hepatocellular carcinoma surveillance at 4-vs. 12-month intervals for patients with chronic viral hepatitis: a randomized study in community. Am J Gastroenterol 2013;108:416–424. doi: 10.1038/ajg.2012.445.
26. Del Poggio P, Olmi S, Ciccarese F, Di Marco M, Rapaccini GL, Benvegnù L, et al. Factors that affect efficacy of ultrasound surveillance for early stage hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol 2014;12:1927–1933. doi: 10.1016/j.cgh.2014.02.025.
27. Wu CY, Hsu YC, Ho HJ, Chen YJ, Lee TY, Lin JT. Association between ultrasonography screening and mortality in patients with hepatocellular carcinoma: a nationwide cohort study. Gut 2016;65:693–701. doi: 10.1136/gutjnl-2014-308786.
28. Song JJ, Lu wy, Zhao ZW, Fan XX, Tu JF, Ji JS. Association between ultrasound screening frequency and mortality in patients with hepatocellular carcinoma. Chinese Med J 2016;96:3652–3655. doi: 10.3760/cma.j.issn.0376-2491.2016.45.009.
29. Khalili K, Menezes R, Kim TK, Yazdi LK, Jang HJ, Sharma S, et al. The effectiveness of ultrasound surveillance for hepatocellular carcinoma in a Canadian centre and determinants of its success. Can J Gastroenterol Hepatol 2015;29:267–273. doi: 10.1155/2015/563893.
30. Pocha C, Dieperink E, McMaken KA, Knott A, Thuras P, Ho SB. Surveillance for hepatocellular cancer with ultrasonography vs. computed tomography - a randomised study. Aliment Pharmacol Ther 2013;38:303–312. doi: 10.1111/apt.12370.
31. Rhee H, An C, Kim DY, Choi JY, Han KH, Kim MJ. Unenhanced MRI versus ultrasonography for hepatocellular carcinoma surveillance: preliminary results of a prospective randomized trial (miracle-HCC). Liver Cancer 2018;7:95–98.
32. Kudo M, Ueshima K, Osaki Y, Hirooka M, Imai Y, Aso K, et al. B-mode ultrasonography versus contrast-enhanced ultrasonography for surveillance of hepatocellular carcinoma: a prospective multicenter randomized controlled trial. Liver Cancer 2019;8:271–280. doi: 10.1159/000501082.
33. Kim JH, Kang SH, Lee M, Choi HS, Jun BG, Kim TS, et al. Individualized surveillance of chronic hepatitis B patients according to hepatocellular carcinoma risk based on PAGE-B scores. Eur J Gastroenterol Hepatol 2021;33:1564–1572. doi: 10.1097/meg.0000000000001870.
34. Kim JH, Kang SH, Lee M, Choi HS, Jun BG, Kim TS, et al. Improved detection of hepatocellular carcinoma by dynamic computed tomography in cirrhotic patients with chronic hepatitis B: a multicenter study. J Gastroenterol Hepatol 2020;35:1795–1803. doi: 10.1111/jgh.15046.
35. Furlan A, Marin D, Agnello F, Di Martino M, Di Marco V, Lagalla R, et al. Hepatocellular carcinoma presenting at contrast-enhanced multi-detector-row computed tomography or gadolinium-enhanced magnetic resonance imaging as a small (≤ 2 cm), indeterminate nodule: growth rate and optimal interval time for imaging follow-up. J Comput Assist Tomogr 2012;36:20–25. doi: 10.1097/rct.0b013e31823ed462.
36. Kubota K, Ina H, Okada Y, Irie T. Growth rate of primary single hepatocellular carcinoma: determining optimal screening interval with contrast enhanced computed tomography. Dig Dis Sci 2003;48:581–586. doi: 10.1023/A:1022505203786.
37. Taouli B, Goh JS, Lu Y, Qayyum A, Yeh BM, Merriman RB, et al. Growth rate of hepatocellular carcinoma: evaluation with serial computed tomography or magnetic resonance imaging. J Comput Assist Tomogr 2005;29:425–429. doi: 10.1097/01.rct.0000164036.85327.05.
38. Simmons O, Fetzer DT, Yokoo T, Marrero JA, Yopp A, Kono Y, et al. Predictors of adequate ultrasound quality for hepatocellular carcinoma surveillance in patients with cirrhosis. Aliment Pharmacol Ther 2017;45:169–177. doi: 10.1111/apt.13841.
39. Colli A, Fraquelli M, Casazza G, Massironi S, Colucci A, Conte D, et al. Accuracy of ultrasonography, spiral CT, magnetic resonance, and alpha-fetoprotein in diagnosing hepatocellular carcinoma: a systematic review. Am J Gastroenterol 2006;101:513–515. doi: 10.1111/j.1572-0241.2006.00467.x.
