Introduction
Liver cancer is the sixth most common malignancy worldwide, yet its management is beset by persistent gaps between guideline recommendations and real-world clinical implementation 23. Despite decades of guideline development by EASL, AASLD, and Asian professional societies, a striking 63% of HCC cases globally are still diagnosed after symptom onset rather than through surveillance programs—a statistic that has remained unchanged across a 19-year study period encompassing 50,554 cases 5. This diagnostic delay is the single most consequential practice gap in HCC care, as it effectively precludes curative intent therapy in the majority of patients. Surveillance failure, treatment underuse, variable response assessment, and inadequate post-treatment monitoring compound one another across the cascade of care, creating a multifactorial crisis with direct survival consequences 11.
Surveillance and Diagnostic Delay
Guideline-recommended semi-annual ultrasound with or without AFP has not translated into population-level early detection. Meta-analytic evidence indicates that ultrasound sensitivity for early-stage HCC is only 47–63%, with significant degradation in patients with obesity, macronodular cirrhosis, and MASLD-associated disease 1525. The consequence is stark: only 37% of HCC cases are diagnosed via surveillance globally, with rates as low as 29% in Africa, 31% in North America, 41% in Europe, and 42% in Asia 5. Critically, even when surveillance is attempted, suboptimal intervals profoundly reduce efficacy—surveillance at intervals ≥12 months captures only 19% of cases, compared with 39% at intervals <12 months 5.
Beyond test performance, system-level and social barriers drive underuse. In the United States, approximately 20% of cirrhotic patients receive semi-annual surveillance, with particularly low uptake in patients with alcohol-related liver disease, MASLD-related cirrhosis, and those not seen regularly by gastroenterologists 26. Patient-level barriers include financial limitations, transportation, and low health literacy, while provider-level barriers include misconceptions about surveillance benefit and competing clinical priorities 826. A multilevel analysis identified that ethnic minorities experience compounded disparities at multiple cascade stages, framing surveillance underuse as a health equity crisis rather than merely a clinical problem 811.
Structurally, Eastern countries implement coordinated population-level surveillance programs, whereas Western countries rely predominantly on individual patient adherence—a fundamental design difference that explains divergent early detection rates and survival outcomes 4. Taiwan and other Asia-Pacific regions also face challenges translating guidelines into practice despite established regional frameworks 24.
A growing blind spot across all regions is non-cirrhotic HCC, particularly in the context of rising MASLD prevalence. Current LI-RADS diagnostic criteria are designed for cirrhotic or hepatitis B populations, and no standardized screening or management guidelines exist for the non-cirrhotic population, where approximately 20% of all HCC cases now occur 17.
Staging Inaccuracies and Guideline Adherence
The Barcelona Clinic Liver Cancer (BCLC) staging system provides an integrated framework for treatment allocation, yet real-world adherence remains imperfect. A prospective analysis found that only 69.7% of patients receiving invasive treatment were managed according to BCLC strategy, with BCLC adherence improving from 53.8% (2011–2014) to 77.5% (2019–2022) 28. The survival implications are profound: 5-year overall survival for surgically treated patients following BCLC strategy was 78.9% versus 23.5% for those treated outside it, with deviation associated with a multivariable hazard ratio of 3.1 28. Common deviations included surgical overtreatment of multinodular disease better served by TACE, and insufficient assessment of portal pressure or liver function reserve 28.
Regional guideline heterogeneity further complicates staging standardization. American (AASLD), European (EASL), and Asian (JSH, CSCO) guidelines diverge in their recommendations for diagnosis, staging thresholds, and treatment sequencing, creating confusion at centers where internationally trained clinicians interact with multinational patient populations 9.
Treatment Access, Adherence, and Regional Patterns
| Domain | United States | Europe | China/Japan |
|---|---|---|---|
| First-line systemic therapy pattern | Sorafenib predominant (78%); median treatment duration only 60 days 16 | Atezolizumab-bevacizumab first-line per EASL 2024 guidance 1 | PD-1 inhibitor plus TKI combinations (e.g., sintilimab-lenvatinib); ORR 36.7–52.8% 14 |
| Second-line progression | Only 17% of US patients progress to second-line therapy 16 | Variable; guideline-concordant sequential therapy emphasized 1 | Aggressive conversion therapy with surgical resection for selected responders 22 |
| Locoregional therapy | TACE most common prior to systemic therapy 16 | TACE/TARE for BCLC-B; quality indicators mandate offering 27 | TACE combined with systemic therapy; conversion surgery in selected cases 1422 |
| Transplant access | Growing indication; post-LT surveillance unstandardized 7 | Standardized Milan/up-to-7 criteria; heterogeneity post-LT 7 | Limited organ availability; aggressive downstaging reported 22 |
| Multidisciplinary care | MDT improves survival but implementation is variable 26 | QI framework mandates MDT decision-making 27 | Regional variation; major centers increasingly adopt MDT 24 |
The US real-world data reveal a particularly troubling treatment pattern: sorafenib median treatment duration of only 60 days, generating $17,642 in total costs per patient per month while providing limited survival benefit 16. This short duration likely reflects a combination of tolerability challenges, disease progression, and the absence of structured second-line pathways, as only 17% of patients accessed subsequent therapy 16. In contrast, Chinese centers report high ORRs with PD-1 inhibitor-TKI combinations and conversion therapy enabling surgical resection in selected patients with portal vein tumor thrombus—a patient population traditionally considered untreatable—with three of eight operated patients achieving pathological complete response 1422.
Post-transplant HCC management represents a particularly underaddressed gap across all regions. A national US survey found that while 79% of transplant centers risk-stratify patients, approximately 50% did not adjust surveillance protocols based on risk level, and no consensus exists on recurrence prevention, optimal immunosuppression, or immunotherapy use due to rejection risk 712. This represents a critical unmet need as HCC becomes an increasingly common transplantation indication globally.
Response Assessment: Criteria Heterogeneity and Its Consequences
Response assessment after both locoregional and systemic therapy lacks global standardization. A meta-analysis of 34 randomized trials demonstrated that mRECIST correlates more strongly with overall survival than RECIST (R = 0.677 vs. 0.532), though the surrogacy remains modest—sufficient for phase II proof-of-concept endpoints but inadequate as a primary phase III outcome measure 13. For post-TACE assessment specifically, quantitative EASL (qEASL) demonstrates cost-effectiveness superiority, being dominant over both mRECIST and RECIST in 69–71% of probabilistic sensitivity analyses 18. Japan has formalized HCC-specific response assessment through the RECICL 2021 revision, which incorporates mRECIST and RECIST 1.1 for systemic therapies while preserving locoregional criteria inappropriate for RECIST evaluation 21. Early AFP response—defined as ≥20% reduction at 6 weeks—has emerged in Japanese real-world data as a practical early predictor of treatment benefit with atezolizumab-bevacizumab 19.
Evidence-Based Strategies to Bridge the Gaps
A consensus-based quality indicator (QI) framework identifies 23 measurable practice standards spanning diagnosis, staging, and management 27. Table 2 summarizes key mitigation strategies aligned with each gap domain.
| Practice Gap | Evidence-Based Mitigation Strategy |
|---|---|
| Surveillance underuse | Structured recall programs; patient navigator interventions; provider education 268 |
| Low ultrasound sensitivity | Risk-stratified surveillance: abbreviated MRI for high/intermediate-risk patients (sensitivity 80.6–91.6%) 1525 |
| Non-cirrhotic HCC blind spot | Improve risk stratification and generate evidence for surveillance protocols in non-cirrhotic MASLD and selected HBV populations 17 |
| BCLC deviation | Mandatory multidisciplinary tumor board review before treatment initiation; QI monitoring of BCLC adherence 2728 |
| Short systemic therapy duration | Timely access to well-tolerated first-line immunotherapy-based regimens; structured second-line pathways 16 |
| Post-transplant heterogeneity | Standardized risk-stratified post-LT surveillance protocols; multicentre registries 712 |
| Response criteria inconsistency | Adopt mRECIST for systemic therapy; qEASL for post-TACE assessment; AFP kinetics as early surrogate 131819 |
| Disparities in vulnerable populations | Systems-level interventions: patient navigation, telehealth, financial counseling integrated into HCC clinics 1126 |
The 2024 EASL guidelines emphasize that multiparametric, individualized patient assessment through multidisciplinary evaluation is not optional but foundational, acknowledging that current practice frequently falls short of this coordinated standard 1. Real-world data confirm that MDT involvement is independently associated with earlier-stage diagnosis, shorter time to treatment, higher curative therapy rates, and improved overall survival 26. Treatment should commence within 4 weeks of MDT decision as a measurable quality standard 27.
Conclusion
Despite widespread guideline dissemination, diagnostic delay remains a persistent challenge in HCC care. The path forward requires systems-level transformation—risk-stratified surveillance tailored to individual patient profiles, consistent multidisciplinary decision-making, greater standardization of response assessment criteria, and quality indicator monitoring across the full cascade of care. Regional disparities between the US, Europe, and Asia largely reflect differences in healthcare infrastructure, access, and program design, underscoring that implementation science must accompany clinical advances to meaningfully improve survival outcomes in HCC.