Gastroenterol Res

Gastroenterology Research, ISSN 1918-2805 print, 1918-2813 online, Open Access

Article copyright, the authors; Journal compilation copyright, Gastroenterol Res and Elmer Press Inc

Journal website https://www.gastrores.org

Review

Volume 15, Number 6, December 2022, pages 297-307

An Open-Access, Interactive Decision-Support Tool to Facilitate Guideline-Driven Care for Hepatocellular Carcinoma

Figure 2. HCC screening and surveillance algorithm. *For more information on “The Liver Imaging Reporting and Data System (LI-RADS),” visit [56]. AFP: alpha fetoprotein; CLD: chronic liver disease; CT: computed tomography; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HDV: hepatitis D virus; LR: Liver Imaging Reporting and Data System score; M: malignancy; MRI: magnetic resonance imaging; NC: not categorizable; TIV: tumor in vein.

Figure 3. HCC staging algorithm [54]. HCC: hepatocellular carcinoma; ALBI: albumin-bilirubin; PS: ECOG performance status.

**Table 1.** Data Demonstrating the Benefits of Early HCC Surveillance and/or Screening
Study	Aim	Methods	Results
AFP: alpha-fetoprotein; BCLC: Barcelona Clinic Liver Cancer; CI: confidence interval; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HR: hazard ratio; OS: overall survival; SEER: Surveillance, Epidemiology, and End Results; VA: Veterans’ Affairs.
Zhang et al, 2004 [25]	To assess the effect of screening on HCC mortality in people at increased risk	18,816 patients were randomly allocated to a screening (9,373) or control (9,443) group.	HCC mortality rate was significantly lower in the screened group than in controls (83.2/100,000 and 131.5/100,000, respectively, mortality rate ratio of 0.63 (95% CI, 0.41 - 0.98)). Biannual screening reduced HCC mortality by 37%.
Singal et al, 2014 [23]	To determine the effect of HCC surveillance on early-stage tumor detection, receipt of curative therapy, and overall survival in patients with cirrhosis	A systematic literature review from 1990 to 2014 and a search of national meeting abstracts from 2009 to 2012 identified 15,158 patients.	In patients with cirrhosis, HCC surveillance was significantly associated with: 1) improved early-stage detection (odds ratio (OR) 2.08, 95% CI, 1.80 - 2.37); 2) curative treatment rates (OR 2.24, 95% CI, 1.99 - 2.52); 3) prolonged survival (OR 1.90, 95% CI, 1.67 - 2.17).
van Meer et al, 2015 [24]	To explore the effects of HCC surveillance in “real-life” clinical practice	1,074 patients with HCC were diagnosed in the period 2005 - 2012.	Compared to patients not receiving regular HCC surveillance, those receiving HCC surveillance were patients who: 1) had earlier HCC tumor stage at diagnosis (BCLC 0/A: 61% vs. 21%); 2) were more likely to receive potentially curative therapy resection/transplantation (34% vs. 25%); 3) had significantly lower risk of overall mortality (HR 0.50, 95% CI, 0.37 - 0.69).
Mittal et al, 2016 [22]	To evaluate the effectiveness of HCC surveillance in the national VA clinical practice	Medical records of 887 HCC patients between 2005 - 2010 were reviewed.	Patients who received surveillance (vs. those without) were significantly more likely to: 1) have early-stage disease HCC (BCLC stage 0/A 27.2% vs. 11.6%); 2) receive potentially curative (20.9% vs. 11.6%) or palliative (59.2% vs. 45.5%) treatments. Receipt of HCC surveillance was associated with 38% reduction in mortality risk (unadjusted HR 0.62, 95% CI, 0.54 - 0.71). Among patients with HCC, pre-diagnosis HCC surveillance was associated with a significant 38% reduction in overall mortality.
Wu et al, 2016 [26]	To analyze the effectiveness of screening in reducing mortality	52,823 newly diagnosed HCC patients from 2002 to 2007, were classified when they received ultrasonography screening.	On multivariable subgroup analyses, the associations between shorter screening intervals and better survival were observed in nearly all subgroups, especially in younger patients, patients without diabetes and patients with HBV infection.
Singal et al, 2017 [27]	To characterize the association between HCC screening and early tumor detection, curative treatment, and overall survival among patients with cirrhosis	This “real-world” study was a retrospective cohort study of 377 HCC patients diagnosed between June 2012 and May 2013.	Screen-detected patients had a significantly higher proportion of early tumors (BCLC stage A 63.1% vs. 36.4%, P < 0.001) and were more likely to undergo curative treatment (31% vs. 13%, P = 0.02). HCC screening was significantly associated with improved survival in multivariate analysis (HR 0.41; 95% CI, 0.26 - 0.65) after adjusting for patient demographics, Child-Pugh class, and performance status. Median survival of screen-detected patients was 14.6 months, compared with 6.0 months for non-screen-detected patients, with the difference remaining significant after adjusting for lead-time bias (HR 0.59, 95% CI, 0.37 - 0.93).
Choi et al, 2019 [20]	To examine the association between screening receipt and early detection of tumors using multivariable logistic regression	13,714 patients diagnosed with HCC from 2003 through 2013 included in the SEER Program-Medicare database were analyzed.	After correction for lead- and length-time biases, higher proportions of patients with consistent (23%; 95% CI, 21-25%) and inconsistent screening (19%; 95% CI, 19-20%) survived for 3 years compared with patients without screening (13%; 95% CI, 12-14%).

Table 1. Data Demonstrating the Benefits of Early HCC Surveillance and/or Screening

Study

Aim

Methods

Results

AFP: alpha-fetoprotein; BCLC: Barcelona Clinic Liver Cancer; CI: confidence interval; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HR: hazard ratio; OS: overall survival; SEER: Surveillance, Epidemiology, and End Results; VA: Veterans’ Affairs.

Zhang et al, 2004 [25]

To assess the effect of screening on HCC mortality in people at increased risk

18,816 patients were randomly allocated to a screening (9,373) or control (9,443) group.

HCC mortality rate was significantly lower in the screened group than in controls (83.2/100,000 and 131.5/100,000, respectively, mortality rate ratio of 0.63 (95% CI, 0.41 - 0.98)). Biannual screening reduced HCC mortality by 37%.

Singal et al, 2014 [23]

To determine the effect of HCC surveillance on early-stage tumor detection, receipt of curative therapy, and overall survival in patients with cirrhosis

A systematic literature review from 1990 to 2014 and a search of national meeting abstracts from 2009 to 2012 identified 15,158 patients.

In patients with cirrhosis, HCC surveillance was significantly associated with: 1) improved early-stage detection (odds ratio (OR) 2.08, 95% CI, 1.80 - 2.37); 2) curative treatment rates (OR 2.24, 95% CI, 1.99 - 2.52); 3) prolonged survival (OR 1.90, 95% CI, 1.67 - 2.17).

van Meer et al, 2015 [24]

To explore the effects of HCC surveillance in “real-life” clinical practice

1,074 patients with HCC were diagnosed in the period 2005 - 2012.

Compared to patients not receiving regular HCC surveillance, those receiving HCC surveillance were patients who: 1) had earlier HCC tumor stage at diagnosis (BCLC 0/A: 61% vs. 21%); 2) were more likely to receive potentially curative therapy resection/transplantation (34% vs. 25%); 3) had significantly lower risk of overall mortality (HR 0.50, 95% CI, 0.37 - 0.69).

Mittal et al, 2016 [22]

To evaluate the effectiveness of HCC surveillance in the national VA clinical practice

Medical records of 887 HCC patients between 2005 - 2010 were reviewed.

Patients who received surveillance (vs. those without) were significantly more likely to: 1) have early-stage disease HCC (BCLC stage 0/A 27.2% vs. 11.6%); 2) receive potentially curative (20.9% vs. 11.6%) or palliative (59.2% vs. 45.5%) treatments. Receipt of HCC surveillance was associated with 38% reduction in mortality risk (unadjusted HR 0.62, 95% CI, 0.54 - 0.71). Among patients with HCC, pre-diagnosis HCC surveillance was associated with a significant 38% reduction in overall mortality.

Wu et al, 2016 [26]

To analyze the effectiveness of screening in reducing mortality

52,823 newly diagnosed HCC patients from 2002 to 2007, were classified when they received ultrasonography screening.

On multivariable subgroup analyses, the associations between shorter screening intervals and better survival were observed in nearly all subgroups, especially in younger patients, patients without diabetes and patients with HBV infection.

Singal et al, 2017 [27]

To characterize the association between HCC screening and early tumor detection, curative treatment, and overall survival among patients with cirrhosis

This “real-world” study was a retrospective cohort study of 377 HCC patients diagnosed between June 2012 and May 2013.

Screen-detected patients had a significantly higher proportion of early tumors (BCLC stage A 63.1% vs. 36.4%, P < 0.001) and were more likely to undergo curative treatment (31% vs. 13%, P = 0.02). HCC screening was significantly associated with improved survival in multivariate analysis (HR 0.41; 95% CI, 0.26 - 0.65) after adjusting for patient demographics, Child-Pugh class, and performance status. Median survival of screen-detected patients was 14.6 months, compared with 6.0 months for non-screen-detected patients, with the difference remaining significant after adjusting for lead-time bias (HR 0.59, 95% CI, 0.37 - 0.93).

Choi et al, 2019 [20]

To examine the association between screening receipt and early detection of tumors using multivariable logistic regression

13,714 patients diagnosed with HCC from 2003 through 2013 included in the SEER Program-Medicare database were analyzed.

After correction for lead- and length-time biases, higher proportions of patients with consistent (23%; 95% CI, 21-25%) and inconsistent screening (19%; 95% CI, 19-20%) survived for 3 years compared with patients without screening (13%; 95% CI, 12-14%).

**Table 2.** HCC Disproportionally Affects Racial and Ethnic Subgroups
Study	Methods	Results
CI: confidence interval; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; SEER: Surveillance, Epidemiology, and End Results.
Yu et al, 2006 [33]	Patient age, tumor stage, rates of surgical intervention and survival were analyzed in Black (n = 1718) and White (n = 9,752) HCC cases between 1992 and 2001.	Black patients with HCC were: 1) significantly younger at diagnosis (P < 0.0001); 2) more likely to have regional and distant metastasis at presentation (P < 0.0005); 3) less likely to have surgery performed (P < 0.001). Overall survival rates were lower in Blacks (P = 0.0033).
Altekruse et al, 2014 [35]	HCC incidence data from SEER 18 registries and liver cancer mortality data from the National Center for Health Statistics were analyzed	HCC incidence and HCC mortality increased among Blacks, Hispanics, and Whites aged 50 years and over. During 2006 - 2010, among individuals 50 - 64 years of age, Blacks and Hispanics had higher incidence and mortality rates than Asians/Pacific Islanders.
Ha et al, 2016 [36]	Population-based cohort study using SEER cancer registry data from 2003 to 2011 to investigate race-specific disparities in HCC incidence and survival	Asians had the highest HCC incidence, followed by Blacks, Hispanics, and non-Hispanic Whites. Hispanics had the greatest increase in HCC incidence (+35.8%), whereas Asians experienced a 5.5% decrease. The overall 5-year HCC survival rate was highest among Asians (26.1%; 95% CI, 24.5-27.6%) and lowest among Blacks (21.3%; 95% CI, 19.5-23.1%).
Shaltiel et al, 2021 [34]	Single-center retrospective cohort study of patients with HCV and HCC from 2003 to 2018	Compared to non-Black patients, Black patients had: 1) less early-stage HCC (20.2% vs. 32.3%; P < 0.05); 2) larger tumors (median (interquartile range): 3.5 cm (2.2 - 6.2 cm) vs. 3.1 cm (2.1 - 5.1 cm); P < 0.01); 3) more poorly differentiated tumors (30.3% vs. 20.5%; P < 0.05); 4) more microvascular invasion (67.2% vs. 56.5%; P < 0.05).

Table 2. HCC Disproportionally Affects Racial and Ethnic Subgroups

Study

Methods

Results

CI: confidence interval; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; SEER: Surveillance, Epidemiology, and End Results.

Yu et al, 2006 [33]

Patient age, tumor stage, rates of surgical intervention and survival were analyzed in Black (n = 1718) and White (n = 9,752) HCC cases between 1992 and 2001.

Black patients with HCC were: 1) significantly younger at diagnosis (P < 0.0001); 2) more likely to have regional and distant metastasis at presentation (P < 0.0005); 3) less likely to have surgery performed (P < 0.001). Overall survival rates were lower in Blacks (P = 0.0033).

Altekruse et al, 2014 [35]

HCC incidence data from SEER 18 registries and liver cancer mortality data from the National Center for Health Statistics were analyzed

HCC incidence and HCC mortality increased among Blacks, Hispanics, and Whites aged 50 years and over. During 2006 - 2010, among individuals 50 - 64 years of age, Blacks and Hispanics had higher incidence and mortality rates than Asians/Pacific Islanders.

Ha et al, 2016 [36]

Population-based cohort study using SEER cancer registry data from 2003 to 2011 to investigate race-specific disparities in HCC incidence and survival

Asians had the highest HCC incidence, followed by Blacks, Hispanics, and non-Hispanic Whites. Hispanics had the greatest increase in HCC incidence (+35.8%), whereas Asians experienced a 5.5% decrease. The overall 5-year HCC survival rate was highest among Asians (26.1%; 95% CI, 24.5-27.6%) and lowest among Blacks (21.3%; 95% CI, 19.5-23.1%).

Shaltiel et al, 2021 [34]

Single-center retrospective cohort study of patients with HCV and HCC from 2003 to 2018

Compared to non-Black patients, Black patients had: 1) less early-stage HCC (20.2% vs. 32.3%; P < 0.05); 2) larger tumors (median (interquartile range): 3.5 cm (2.2 - 6.2 cm) vs. 3.1 cm (2.1 - 5.1 cm); P < 0.01); 3) more poorly differentiated tumors (30.3% vs. 20.5%; P < 0.05); 4) more microvascular invasion (67.2% vs. 56.5%; P < 0.05).

**Table 3.** ECOG Performance Scale [57]
Performance scale (PS)	Description
ECOG: Eastern Cooperative Oncology Group.
0	Fully active, able to carry on all pre-disease performance without restriction
1	Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work
2	Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours
3	Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours
4	Completely disabled; cannot carry on any selfcare; totally confined to bed or chair
5	Dead

Table 3. ECOG Performance Scale [57]

Performance scale (PS)

Description

ECOG: Eastern Cooperative Oncology Group.

Fully active, able to carry on all pre-disease performance without restriction

Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work

Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours

Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours

Completely disabled; cannot carry on any selfcare; totally confined to bed or chair

Dead

**Table 4.** Liver Transplantation Criteria in Early to Intermediate Stage HCC Additional Staging Criteria to Consider in BCLC-Staged Patients
Milan Criteria [58]	UNOS Downstaging Criteria [55]	AFP criteria [61]
HCC: hepatocellular carcinoma; BCLC: Barcelona Clinic Liver Cancer; CI: confidence interval; AFP: alpha-fetoprotein; DS: down-staging; LRT: locoregional therapy; LT: liver transplantation; TTD: total tumor diameter; UNOS: United Network of Organ Sharing.
Single HCC lesion < 5 cm or up to three HCC lesions all < 3 cm with no extrahepatic spread of HCC.	A single HCC lesion 5.1 - 8.0 cm.	If initial AFP level was > 1,000 ng/mL, it must drop to less than 500 ng/mL following DS by LRT to qualify for waitlisting for LT with UNOS Exception Criteria.
	Two to three HCC lesions ≤ 5 cm.
	Four to five HCC lesions ≤ 3 cm.
	TTD must be ≤ 8 cm with no extrahepatic spread of HCC.
	HCC must be down-staged to Milan criteria by LRT for automatic waitlisting for LT with an HCC exception by UNOS.

Table 4. Liver Transplantation Criteria in Early to Intermediate Stage HCC Additional Staging Criteria to Consider in BCLC-Staged Patients

Milan Criteria [58]

UNOS Downstaging Criteria [55]

AFP criteria [61]

HCC: hepatocellular carcinoma; BCLC: Barcelona Clinic Liver Cancer; CI: confidence interval; AFP: alpha-fetoprotein; DS: down-staging; LRT: locoregional therapy; LT: liver transplantation; TTD: total tumor diameter; UNOS: United Network of Organ Sharing.

Single HCC lesion < 5 cm or up to three HCC lesions all < 3 cm with no extrahepatic spread of HCC.

A single HCC lesion 5.1 - 8.0 cm.

If initial AFP level was > 1,000 ng/mL, it must drop to less than 500 ng/mL following DS by LRT to qualify for waitlisting for LT with UNOS Exception Criteria.

Two to three HCC lesions ≤ 5 cm.

Four to five HCC lesions ≤ 3 cm.

TTD must be ≤ 8 cm with no extrahepatic spread of HCC.

HCC must be down-staged to Milan criteria by LRT for automatic waitlisting for LT with an HCC exception by UNOS.