HCC

Introduction Secondary prevention of oesophageal variceal bleeding traditionally relies on combination therapy with non-selective beta-blockers and endoscopic band ligation in patients with cirrhosis. However, patients with hepatocellular carcinoma (HCC) represent a distinct high-risk population with advanced portal hypertension, impaired liver reserve and competing oncologic mortality, raising uncertainty about whether standard variceal prophylaxis strategies provide similar benefit in this setting.

Problem Statement Although propranolol combined with endoscopic band ligation is widely accepted for secondary prophylaxis of variceal bleeding in cirrhosis, evidence specifically supporting this approach in patients with HCC has been limited. The balance between efficacy, tolerability and survival benefit in patients with advanced liver cancer and portal hypertension remains unclear.

Summary This randomized trial demonstrates that adding propranolol to endoscopic band ligation does not improve outcomes in patients with HCC undergoing secondary prevention of oesophageal variceal bleeding. Rates of early re bleeding, cumulative recurrent bleeding and overall survival were similar between patients treated with combination therapy and those receiving band ligation alone. Importantly, the study population largely consisted of patients with advanced disease and impaired hepatic reserve, reflecting a clinically relevant real-world HCC cohort. Large varices emerged as the primary predictor of recurrent bleeding, emphasizing the dominant role of portal hypertensive severity rather than beta-blocker therapy in determining outcomes. These findings challenge the routine extrapolation of cirrhosis-based secondary prophylaxis strategies to patients with HCC and suggest that the additional use of propranolol may not provide meaningful clinical benefit in this population. The study supports a more individualized approach to variceal management in HCC, particularly in patients with advanced tumor burden and decompensated liver disease.

Introduction and Summary This commentary discusses the role of serum biomarkers in hepatocellular carcinoma surveillance, particularly after a randomised trial by Hirode et al. evaluated whether adding AFP, AFP-L3, and DCP to routine ultrasound improves early HCC detection. The original trial found that adding these biomarkers to biannual ultrasound did not significantly improve early-stage HCC detection compared with ultrasound alone. This challenges the routine use of biomarker panels in all high-risk patients. However, the authors of this letter argue that biomarkers should not be dismissed too quickly. They highlight important methodological issues that may influence interpretation. Problem Statement HCC surveillance is difficult because ultrasound has variable sensitivity, especially in obesity, cirrhosis, and nodular liver disease. Biomarkers may help, but their value depends on patient risk, biomarker thresholds, tumour biology, and timing of measurement. The key question is not simply whether biomarkers should be added to ultrasound for everyone, but which patients may benefit most and how biomarkers should be interpreted longitudinally. Key Points Raised by the Authors

1. Baseline HCC Risk Was Not Clearly Stratified The authors note that although both trial groups appeared balanced clinically, baseline HCC risk scores were not clearly reported. This matters because lower-risk patients, especially those without cirrhosis, may reduce the apparent benefit of biomarkers.
2. Risk-Based Surveillance May Be Better Instead of a uniform surveillance strategy, the authors suggest using validated HCC risk scores to adjust surveillance intensity, biomarker cutoffs, and cost-effectiveness.
3. AFP-L3 May Have Limited Added Value Although AFP-L3 showed relatively better individual diagnostic accuracy, the GALAD score, which includes AFP-L3, numerically performed slightly worse than the ASAP model, which excludes it. This raises the possibility that AFP-L3 may add limited independent value in some populations.
4. AFP-L3 Should Be Tested in Specific Subgroups The authors suggest evaluating AFP-L3, particularly in patients with negative ultrasound and AFP <20 ng/mL, where its incremental value would be clinically more meaningful.
5. Ultrasound False Positives Remain a Major Problem A high proportion of positive ultrasound findings did not lead to HCC diagnosis. Biomarkers may be useful not only for detecting cancer but also for helping distinguish benign ultrasound abnormalities from true malignancy.
6. More Direct Comparison Is Needed The authors request performance data for ultrasound alone within the biomarker arm, so the true incremental value of biomarkers can be better quantified.
7. Longitudinal Biomarker Trends May Be More Informative Rather than analysing biomarkers only from baseline, aligning biomarker changes to the actual date of HCC diagnosis may reveal rising trends before cancer detection. Clinical Relevance This letter provides an important caution: a negative overall trial result does not mean biomarkers have no role in HCC surveillance. Their value may be greatest in selected high-risk patients, ultrasound-negative patients, patients with poor ultrasound visualisation, or those showing rising biomarker trends over time. For clinicians, the key message is that biomarkers should not replace ultrasound, and routine addition for all patients may not be justified. However, risk-adapted and longitudinal biomarker strategies may still improve future surveillance models. Conclusion The commentary supports the trial’s important finding that routine addition of AFP, AFP-L3, and DCP to ultrasound may not significantly improve early HCC detection in a broad surveillance population. However, it argues that further subgroup analysis, risk stratification, ultrasound false-positive assessment, and longitudinal biomarker kinetics are needed. The future of HCC surveillance may not be “ultrasound versus biomarkers,” but rather personalised surveillance using risk scores, imaging quality, biomarker combinations, and dynamic trends over time.

Introduction Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality in patients with cirrhosis. Despite advances in treatment, outcomes are largely determined by stage at diagnosis, making surveillance critical. Current strategies rely on ultrasound with AFP, but limitations in sensitivity and poor real-world uptake have created a need for better risk stratification and improved surveillance tools. Why This Guideline Is Required Traditional surveillance approaches are suboptimal due to: Underuse in clinical practice Limited sensitivity of ultrasound Changing epidemiology (rise of MASLD and alcohol-related liver disease) Lack of validated biomarkers and risk-based strategies This guideline focuses on improving risk stratification, surveillance efficiency, and early detection. 20 Key Takeaways for Clinicians

1. Prevention of cirrhosis is the most effective HCC strategy Treat viral hepatitis, alcohol use, and metabolic syndrome early.
2. Surveillance saves lives Early detection improves access to curative therapies and survival.
3. Standard surveillance = Ultrasound + AFP every 6 months Still the recommended global standard.
4. Semiannual surveillance is superior to annual surveillance. It detects earlier-stage tumours and improves outcomes.
5. Ultrasound has limitations Reduced sensitivity in obesity, MASLD, and advanced liver disease.
6. AFP improves sensitivity when added to ultrasound A combination is better than ultrasound alone.
7. Surveillance is underutilised Less than 25% of eligible cirrhosis patients undergo regular screening.
8. Target population = All cirrhosis patients Regardless of aetiology.
9. Select non-cirrhotic HBV patients need surveillance Based on age, ethnicity, and risk scores.
10. No routine surveillance in non-cirrhotic MASLD or HCV Unless better risk stratification tools are available.
11. Surveillance not useful in limited life expectancy Especially non-transplant candidates with advanced disease.
12. Harms of surveillance must be considered False positives, anxiety, cost, and unnecessary procedures.
13. Biomarkers like GALAD are promising but not ready Do not replace ultrasound + AFP yet.
14. Liquid biopsy is the future—but still experimental Requires validation in large prospective trials.
15. Multicancer detection panels should NOT be used Not validated for HCC surveillance populations.
16. MRI has higher sensitivity, but is not routine Cost, access, and practicality limit widespread use.
17. Abbreviated MRI is promising May become a future alternative in selected patients.
18. Risk stratification is the future of surveillance Not all cirrhosis patients have equal risk.
19. Current risk models are imperfect Limited validation and modest predictive performance.
20. HBV risk scores (PAGE-B, REAL-B) are useful Can guide surveillance decisions in non-cirrhotic HBV patients. Practical Clinical Message HCC surveillance is evolving from a uniform approach to a personalised strategy. While ultrasound + AFP remains the backbone, future progress will depend on risk-based surveillance, better biomarkers, and improved patient selection. Conclusion This guideline reinforces that current surveillance methods are effective but imperfect. The next phase in HCC care lies in precision surveillance, combining clinical risk, biomarkers, and imaging innovations to improve early detection while minimising harm.