Patients with cirrhosis are at the highest risk for developing hepatocellular carcinoma (HCC), with a variable annual risk of 1%–8%. Currently, biannual abdominal ultrasound (USG) with or without alpha fetoprotein (AFP) is the recommended HCC surveillance strategy for all cirrhotic patients, by major professional liver societies. However, the effectiveness of USG and AFP has been a sprawling subject of debate, due to the conflicting results and the low quality of the evidence. The role of cross-sectional imaging is controversial due to potential harms and cost-effectivity concerns. Several novel serum biomarkers are introduced to HCC screening, but yet to be validated from various geographic regions. A risk-stratified algorithm is required to increase the yield of HCC surveillance, by distinguishing high-risk group who requires more intense screening with the usage of cross-sectional imaging and serum biomarkers, and low-risk group where standard surveillance strategy is redundant. In this review, the strengths and concerns of standard USG based surveillance strategy are discussed together with the efforts to increase the effectiveness of surveillance.
Hepatocellular carcinoma (HCC) is the fifth most common cancer, and the second leading cause of cancer-related deaths globally (1). Most commonly established etiologies for development of HCC are chronic hepatitis B virus infection, hepatitis C virus infection, heavy alcohol drinking and non-alcoholic fatty liver disease. In 90% of cases, these risk factors lead to cirrhosis before HCC development, but there is a small proportion (10%) of HCCs which occurs in a non-cirrhotic liver (2). Patients with cirrhosis are at the highest risk for developing HCC, with a variable annual risk of 1%–8% (3). Several observational cohort studies in patients with cirrhosis and two-large randomized controlled trials in patients with HBV have demonstrated that patients who undergo HCC surveillance have earlier-stage HCC, are more likely to receive potentially curative treatment, and have improved survival than those who presented symptomatically or diagnosed incidentally (4-6). Based on these data, the European Association for the Study of the Liver (EASL), American Association for the Study of the Liver (AASLD), Asian Pacific Association for the Study of the Liver recommend (APASL) and National Comprehensive Cancer Network (NCCN) recommend surveillance to at risk individuals, including all cirrhotic patients regardless of etiology and selected subgroups of chronic HBV patients (7-10) (Table 1).
Currently, biannual abdominal ultrasound (USG) with or without alpha fetoprotein (AFP) is the recommended HCC surveillance strategy for at-risk individuals, by major professional liver societies (Table 2). Likewise, biannual USG with AFP is recommended to at-risk individuals in Turkey Hepatitis B road map, which was proposed by Turkish Liver Studies Association of Turkey (TASL) in 2009 (11). However, the effectiveness of USG has been a sprawling subject of debate, due to the conflicting results and the low quality of the evidence. The main reasons for the enquiry on USG is owing to its patient-related factors such as obesity and nodular view liver in cirrhosis, and operator dependency which results in huge variations in the success of USG across institutions. The addition of AFP to surveillance seems to be withdrawn from recommendations and left to physician’s preference. In this review, we discuss the strengths and concerns of this standard of care surveillance strategy. We also discuss the efforts to increase the yield of surveillance and diminish cost-effectivity concerns.
What do we gain from a standard biannual USG AFP surveillance?
The direct aim of any cancer surveillance program is clear; to detect cancers at at an early curable stage (BCLC 0 or A), which results in a favorable survival expectancy. Therefore, when a lesion is caught at a stage beyond eligibility to curative treatments (BCLC B or C or D), it is not considered to be a surveillance related benefit as it would not have any influence on survival. The sensitivity and specificity of USG for any stage HCC detection exceeds 90%. On the other hand, a recent meta-analysis displayed that USG alone detects early-stage HCC with only a 47% sensitivity rate and the addition of AFP increased the sensitivity rate to 63% (12). This can be explained by the higher omitting rates of small lesions due to limitations of USG in cirrhotic liver. A prior meta-analysis of 13 prospective cohort studies concluded that AFP has no additional value compared with USG alone (13). The demonstrated contribution of AFP in the literature may be due to higher advanced stage HCC detection rates under USG based surveillance.
The indirect, but actual goal of surveillance is to decrease cancer-related mortality in patients with cirrhosis. A recently published case-control study has demonstrated that neither USG, nor AFP decreases the HCC-related mortality (14). The suboptimal performance of USG in reaching direct and indirect goals of HCC surveillance highlights the need for alternative surveillance strategies. Nevertheless, the global acceptance of USG in surveillance relies on the absence of risks, non-invasiveness and lower costs, which is comprehensible. Model-based simulation studies have demonstrated that biannual USG for all cirrhotic patients is cost-effective compared to no surveillance, although average survival extension was less then 6 months (15). Despite the contradictions, there is still evidence suggesting the usage of AFP in combination with USG for patients with cirrhosis until superior surveillance strategies are available. The only subgroup of patients with cirrhosis who are not recommended to undergo standard surveillance program Child-Pugh Class C cirrhosis, unless they are awaiting liver transplantation, given the low probability of treatment eligibility when HCC occurs.
What are the potential harms?
HCC surveillance with USG AFP can not constitute a direct physical harm; however there are potential downstream harms associated with diagnostic evaluation process. False negative results are common in USG-based surveillance. These suspicious liver lesions typically undergo subsequent computed tomography (CT) and/or magnetic resonance imaging (MRI), and followed-up in shorter intervals, which bears radiation exposure, possible contrast injury, and financial burden (16-18). When the lesion can not be characterized with these cross-sectional imaging, patients may undergo biopsy, which is associated with risks of bleeding, tumor seeding and injury to nearby organs (19). Besides, this process and follow-up period may bring an unmeasurable psychosocial burden to the patient. A recent report has exposed that 75% of patients under surveillance are concerned that they will die from the disease, not specifically questioning the effect of routine intervals of surveillance, but it’s impact on quality of life is apparent (20). These potential harms have been weighted in a cohort of cirrhosis, and 27.5% of patients were exposed to surveillance-related physical harms. Of which 22.8% were USG related, and 11.4% were AFP related (21). In our Turkish cirrhotic cohort, we demonstrated that annual MRI-based surveillance strategy carries a lower (6.5%) physical harm rate, not investigating the financial and psychosocial burden.
Is there any place for cross-sectional imaging?
The role of cross-sectional imaging is controversial. Several studies and meta-analyses have investigated the performance of MRI and CT (22, 23). Generally, there is a trend towards higher success in MRI compared to CT. In a randomized trial, annual CT exhibited a 62.5% sensitivity rate in the surveillance of patients with cirrhosis to detect an early-stage HCC, which did not significantly differ from biannual USG (24). In addition to the lack of demonstrated benefits, CT-based surveillance is restricted due to its physical risks including radiation exposure and contrast-induced nephrotoxicity (16, 17). Another study conducted to compare biannual liver-specific contrast enhanced MRI and USG showed that biannual MRI had a sensitivity of 83.7% in detecting early-stage HCC, whereas it was only 25.6% in the biannual USG arm (25). Although biannual MRI exhibits satisfactory results in the literature, the main barriers for MRI to enter the surveillance programs have been concerns with regard to cost-effectivity, contraindications, long scan times, and limited availability (18). Abbreviated-protocol screening MRI, which was proposed as a shorter version of conventional MRI screening, showed comparable results to complete-protocol diagnostic MRI and made MRI a more assertive and cost-effective tool as a candidate for HCC surveillance (26,27). Besides, cost-effectivity of biannual MRI in the HCC surveillance of patients with cirrhosis was proven using the cohort-based Markov model recently (28). Furthermore, to standardize the reporting and increase the diagnostic specificity of HCCs in CT or MRI, The Liver Imaging Reporting and Data System (LI-RADS) was developed. The latest 2018 version of LI-RADS, which was first supported and endorsed by the American College of Radiology in 2011 and now is integrated into the latest HCC guidelines of AASLD in 2018, helps the radiologists to standardize reporting of liver lesions and clinicians to optimize the management of liver lesions detected in surveillance (8, 29). In a recent study of our group, we evaluated the efficacy of an annual contrast-enhanced MRI as a HCC-surveillance tool. In our cirrhotic cohort of 294 patients with consistent annual surveillance with MRI; we demonstrated the satisfactory performance of MRI in the surveillance of HCC, in terms of detecting most of the lesions in earlier curable stages (85.8%) and indicating high sensitivity and specificity (sensitivity; 83.3% and 80% and specificity; 95.4% and 91.4 for detecting early and very early-stage HCC, respectively) with no additional benefit of biannual AFP (30).
Contrast-enhanced ultrasound (CEUS) has been proposed as another advantageous radiologic tool for surveillance in the last decade. The examination is performed by injecting intravenous microbubble contrast agents without renal excretion with the advantage of real-time dynamic imaging. The CEUS technique is generally considered safe and well tolerated, may be even used in renal failure patients. It’s use in clinical practice is suggested by the latest version of EASL guidelines on the management of HCC, as a part of work-up of focal liver lesions and as a diagnostic tool for HCC, where available (7). CEUS demonstrated a superior performance than conventional USG in detecting early HCCs in a head to head prospective multicenter randomized controlled trial, and has a sensitivity rate of 85% and specificity of 91% for HCCs detected in cirrhotic liver (31, 32). CEUS appears as a more sensible tool than non-contrast USG for HCC screening, where available. However, it still has several limitations such as lack of specificity on differentiation between HCC and intrahepatic cholangiocarcinoma, which occurs in %2 to %5 of all new nodules in cirrhosis (33, 34). For this reason, a dedicated Contrast Enhanced Ultrasound Liver Imaging Reporting and Data System (CEUS LI-RADS) was developed in 2016, which uses the the size, type, presence of washout, degree of arterial phase enhancement, and the timing and degree of washout to categorize focal liver lesions in patients at high risk for HCC (35). The CEUS LI-RADS algorithm has been reported to be highly specific for the diagnosis of HCC, and may help CEUS take the lead in the race among radiologic tools for HCC surveillance (36).
Considering all limitations with standard non-contrast USG, a better improved radiologic surveillance tool is required. To overcome the financial burden and increase the yield, inclusion of advanced imaging tools to surveillance can be narrowed for only selected patients with higher risk of HCC development.
Any promising serologic biomarker to be used in HCC surveillance?
Novel biomarkers are introduced in the screening of many cancer types for early detection and prognosis determination, such as biochemical metabolites, proteins and RNA. AFP has been widely accepted and used in combination with USG for HCC surveillance. However, AFP is not able to detect early HCCs in %80 of cases, which made its usage in surveillance controversial. Another criticism for current biomarkers, especially for AFP, appear to be drawn from its inconsistent performance characteristics across various etiologies of chronic liver disease and different regions. Thus, there has been interest in developing novel biomarkers with more success in early detection and utilizable in different regions. Future of biomarker screening is promising, with numerous other molecules under research such as osteopontin, alfa fetoprotein-L3 (AFP-L3), des-gamma-carboxy prothrombin (DCP), glypican-3 (GCP3) and alpha-1-fucosidase.
Since the conventional liver tissue biopsy is an invasive procedure and representive of only biopsied small portion of the tumor, it is unable to represent tumor heterogeneity. Over the past years, a new diagnostic method namely liquid biopsy has emerged as a promising tool for both detecting early HCCs, determining the prognosis and molecular profiling. Liquid biopsy has the advantage of being quick, easy obtainable, minimally invasive and representative of comprehensive tissue profile (66). The liquid biopsy techniques are mainly based on detecting circulating tumor cells, micro RNAs, tumor cell-free DNAs, tumor derived/associated extracellular vesicles, and metabolites and proteins (67). There are a large number of liquid biopsy biomarkers studied in the early detection of HCCs which suggested that those could be promising biomarkers and attractive option for AFP negative early HCCs, however those candidate biomarkers must be internationally validated using methodologies easily transferable into the clinical settings.
Is one-size-fits all strategy convenient for surveillance of HCC in cirrhotic patients?
The risk of HCC is not uniform, and may increase due to underlying parameters. However, despite our increasing awareness of prognostic and etiological risk factors, most patients present with advanced stages at the time of diagnosis, and less than 20% are eligible for curative treatment options (39). The most critical game-changer intervention for the HCC course remains improving the detection rates at an early stage. To achieve this goal, the most accurate approach may be to optimize screening strategies and better reveal the higher risk patients who requires more intense surveillance with better imaging modalities and/or serum biomarkers. This opinion is supported by a recent report, where the cost-effectivity of risk stratified HCC surveillance, which outperformed the currently recommended non-stratified biannual USG in all patients, has been proven using a Markov decision-analytic modeling (40). We illustrate our opinion of a risk-stratified algorithm in the surveillance of HCC among cirrhotic patients in figure 1, of which the players are yet to be determined.
A number of scoring systems were developed to predict the risk of HCC, mainly focusing on chronic hepatitis B virus (41-48) and hepatitis C virus (49-53), and only a few targeted all cirrhotic patients regardless of etiology (54-56) (Table 3). Among them the Risk Estimation for Hepatocellular Carcinoma in chronic hepatitis B (REACH-B) and the Platelets, Age, Gender in chronic hepatitis B (PAGE-B), Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) are the most popular and externally validated ones. In 2014, ADRESS-HCC risk model was developed which aimed to predict 1-year HCC risk. ADRESS-HCC only categorized etiologies into three groups (autoimmune, alcohol/metabolic, viral), which was unsatisfactory to weigh the different etiologies and treatment response status. In 2017, Toronto Hepatocellular Carcinoma Risk Index (THRI) was developed to predict 10 year HCC risk, using simple clinical and laboratory parameters (age, gender, etiology, platelet) (56). Moreover, THRI weighed etiologies in more detail, including the sustained virological response status of HCV-related cirrhosis. Performance of THRI has been illustrated in three different cohorts from different regions (Canada, Netherlands and China) (56, 57). These three cohorts showed similar efficacy of THRI to predict HCC development. We recently validated the efficacy of THRI in our Turkish cirrhotic cohort and found a similar area under the ROC curve (AUROC) value to the Canadian, Dutch and Chinese cohorts, very interestingly with the same optimal cut-off value of 240 to distinguish high risk HCC group (58). These emerging evidence encourages the usage of THRI and/or other validated scoring systems using the combination of clinical and laboratory variables in the risk-stratified surveillance algorithm.
Combination of available clinical and laboratory variables has been evaluated to develop HCC risk-predictive scores in recent years, although their performance is somewhat limited and yet to be adopted in clinical practice. To further adjust HCC prediction, the combination of three biomarkers (AFP, AFP-L3 and DCP) with sex and age has been proposed as a diagnostic model (GALAD) (59), which later on combined with USG (presence of solid lesion on surveillance) and showed better results (GALADUS) (60). GALAD score showed remarkable performance in surveillance with AUROC values of 0.95 [95% confidence interval (CI), 0.93–97], sensitivity of 92% and specificity of 85%. Besides the performance of GALAD for early HCC detection remained high as well (AUROC: 0.92 [95% CI, 0.88–0.96], sensitivity 92%, specificity 79%). Another risk score, namely Doylestown algorithm, incorporates biomarkers (AFP and fucosylated biomarkers) and relevant clinical variables (age, gender and ALT) with ALP (61). To supplement these inadequate clinical scores, new molecular biomarkers have been investigated. Several germ line single-nucleotide polymorphisms in epidermal growth factor and myeloperoxidase has been identified and validated as an HCC risk predictor, and a liver-derived 186-gene signature has been proposed as a prognostic parameter (62-67). Although they were considered as candidates for patients with cirrhosis in most need of surveillance, all are far away from being in widespread use due to heterogeneity in etiologic and differential characteristics of HCC globally. Validation studies from different geographic regions are required before further affirmative comments for these combined clinical and serologic prediction models.
Our knowledge on cost-effectivity of performing HCC-surveillance is based on model-based studies, because following the patients without performing surveillance is not an option for trials, as surveillance has become standard of care globally. Despite the questionable quality of evidence, the literature suggests to perform surveillance. The standard of care with biannual USG AFP is premature, and it is not rational to implement the same strategy to every cirrhotic patient. The key of increasing the yield and cost-effectivity lies on the risk-stratified surveillance strategy. There is a growing evidence and advance in the integration of cross-sectional imaging modalities and serum biomarkers to HCC surveillance. The evolving HCC-risk stratification models may be helpful for us to tailor surveillance strategy and integrate costly tools to be used in selected patients. Further studies are needed to better stratify the risk for HCC and to determine improved surveillance strategies, including imaging and biomarkers.
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