Barcelona Clinic Liver Cancer strategy adherence in hepatocellular carcinoma and its influence on long-term outcomes

Introduction

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide (1). Liver transplantation (LT), surgical resection and local ablation are regarded as curative treatment options (2). However, only 10–15% of HCC patients meet the Milan criteria and are eligible for LT (2). Typically, about 20% of patients undergo surgical resection, while 30% of patients can be treated with local thermal ablation (3,4). Despite advances in diagnostic methods and treatment modalities, the 5-year survival rate is below 20% (5).

Several staging systems have been proposed and implemented to guide HCC staging and management (6). Among them, the Barcelona Clinic Liver Cancer (BCLC) prognosis and treatment strategy is widely regarded as the benchmark algorithm for predicting survival for treatment allocated by stage (7). However, it has been criticised for overtreatment, particularly in cases of advanced disease (8,9).

The primary purpose of the BCLC strategy is to standardise treatment decisions and life expectancy following intervention (7). Stages 0–A include single tumors or up to three nodules, each measuring ≤3 cm (7). For solitary disease with normal bilirubin levels and no portal hypertension, surgical resection is the preferred treatment (7). LT is the first-line option for multinodular disease, provided the tumor burden meets the Milan criteria or modern expanded criteria, including the “up-to-seven” tule and Metroticket 2.0 model, which incorporates tumor size and number to predict post-transplant survival (7,10,11). Ablation is the recommended approach for lesions <2 cm in patients ineligible for LT or resection (7). Surgical resection, LT and ablation are considered curative treatment options, with median survival exceeding five years according to the BCLC strategy (7). BCLC stage B includes patients with multinodular disease and preserved liver function (7). These patients are typically treated with transarterial chemoembolization (TACE), with the possibility of downstaging to LT in some cases (7). Stage C involves HCC with extrahepatic spread or invasion of the portal vein, where systemic therapy is the recommended approach (7). In recent years, immune-based combination therapies have improved outcomes in the systemic treatment of advanced HCC (12,13). These advances, together with the growing interest in integrating immunotherapy into perioperative care, highlight the importance of stage-appropriate allocation in multidisciplinary team decision-making. Patients with end-stage liver disease or significant functional impairment fall under stage D, for whom best supportive care is advised (7).

This study evaluated the adherence to BCLC in two Finnish HPB units and investigated the impact of deviations from the strategy on long-term outcomes in a real-world setting. We hypothesised that deviation from the BCLC strategy might influence long-term outcomes negatively. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-639/rc).

Methods

Patient cohort

In this retrospective cohort study, we analysed histologically confirmed HCC diagnosed at Oulu University Hospital in 1986–2022 and Central Finland Central Hospital in 1997–2022. Only patients who received invasive treatment were analysed. Our study cohort was categorised into three treatment groups: (I) surgically treated patients; resection and LT; (II) local ablation therapy; local ablation treatment; radiofrequency ablation (RFA), laser ablation (LA) and microwave ablation (MWA); and (III) transarterial treatment group; TACE and selective internal radiation therapy (SIRT). Of the 299 HCC patients who received invasive treatment, 65 patients were excluded due to missing patient records, generally for patients treated before 1997. Computed tomography (CT) scans were missing from the electronic patient records in 21 cases. Five patients who received percutaneous ethanol injection (PEI) treatment were excluded from the feasibility analysis, as only patients receiving thermoablation were included in the ablation group. The final cohort included 208 patients. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The Finnish Medicines Agency Fimea (Dnro FIMEA/2021/004928) and the Ethical Committee of the North Ostrobothnia’s Hospital District (EETTMK 81/2008) approved the study. All participating hospitals/institutions were informed and agreed the study. Individual consent for this analysis was waived due to the retrospective nature.

Data collection

The patients were identified from the pathological archives using the ICD-10 code C22.0&. Study variables were collected from patient records and pathological reports. All specimens were re-staged according to the 8th edition of the tumor-node-metastasis (TNM) classification. The Charlson Comorbidity Index (CCI) was used to evaluate comorbidities, while complications were classified with the Clavien-Dindo classification system. The cause of death and date of death were obtained from Statistics Finland. Follow-up data were collected until the end of 2022.

Treatment re-evaluation

Treatment modalities were retrospectively re-evaluated by three liver surgeons (M.N., M.K., and H.H.) using patient records and CT scans. Patients were re-staged according to the BCLC strategy of the year of treatment. Cases treated between 1986 and 1999 were re-evaluated according to the 1999 BCLC strategy, while taking into account the treatment options available at the time. All evaluations were performed blinded to patient outcomes. Treatments were assessed to determine adherence to the BCLC strategy, and if not, to identify the recommended treatment modality according to the strategy. Patients were re-evaluated according to (I) tumor burden; tumor size, tumor count, macrovascular invasion, extrahepatic spread and alpha-fetoprotein (AFP); (II) liver function; future liver remnant, Child-Pugh stage, indirect signs of increased portal pressure and level of albumin, thrombocytes, international normalized ratio (INR) and bilirubin; (III) patient profile; Eastern Cooperative Oncology Group (ECOG) performance status, estimated adherence to treatment and overall operability; and (IV) surgical resectability. We also analysed re-interventions.

Exposure

The primary exposure was adherence to the BCLC staging and treatment strategy at the time of given treatment, compared to receiving treatment not aligned with the BCLC strategy.

Outcomes

The primary outcomes of this study were adherence to the BCLC strategy and 1-, 3-, and 5-year overall mortality. Secondary outcomes included 30-day mortality, 90-day mortality, and the rate of complications.

Statistical analysis

Differences in baseline characteristics were presented as proportions, means with standard deviation (SD) and medians with interquartile range (IQR) as appropriate. Overall survival (OS) rates were compared using Kaplan-Meier and log-rank test. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using univariable and multivariable Cox regression analyses. If the univariable analysis was associated with increased mortality, multivariable logistic regression analysis was performed adjusting for gender (male, female), age (continuous), CCI (0–1, 2 or higher), cirrhosis (yes, no), Child-Pugh points (A, B or C), TNM classification (1, 2 or higher), tumor grade (1–2, 3), BCLC stage (0–A, B–D) and treatment adherence to BCLC strategy (yes, no). We used IBM SPSS Statistics 29.0 (RRID: SCR_016479) for statistical analysis.

Results

Patients

A total of 208 patients were included in the analysis: 93 received surgical treatment, 29 underwent local ablations, and 86 received transarterial treatment. Among patients treated with ablation, 2 underwent MWA, 2 underwent LA, and 25 underwent RFA. Of those receiving transarterial therapy, 83 underwent TACE and 3 received SIRT. The median age was 72 years (IQR 67–78 years). The majority were men (77.4%), did not have histologically confirmed cirrhosis (56.7%), had Child-Pugh class A (82.3%) and had a median CCI of 1.7. The median follow-up time was 1.9 years (IQR 0.9–3.5 years). Patients’ BCLC stages were distributed as follows: stage 0 (2%), stage A (52%), stage B (22%), stage C (22%) and stage D (2%).

Treatments re-evaluations

According to the re-evaluation, 145 patients (69.7%) received first-line treatment in accordance with the BCLC strategy. Adherence to the strategy was associated with lower body mass index (BMI), female sex, surgical treatment and a lower American Society of Anesthesiologists (ASA) classification (Table 1). In the surgical group, 17 (18.3%) patients should have received an alternative treatment (Figure 1). Among these, the BCLC strategy recommended ablation in three cases, TACE in 11 cases, and systemic therapy or best supportive care in three cases (Figure 1). The most commonly disregarded factor in surgically overtreated patients was tumor burden: 12 had multinodular disease, and the BCLC strategy would have recommended TACE, systemic therapy or best supportive care over surgery. Insufficient liver function was disregarded in five cases, including four with elevated portal pressure and one with advanced cirrhosis. Additionally, two patients had an inadequate clinical profile for surgery. Multiple factors were neglected in overtreating patients with surgery for three patients.

Figure 1 Illustration of the re-evaluation process and the correct treatment according to the BCLC strategy. BCLC, Barcelona Clinic Liver Cancer.

The re-evaluation process showed that 17 (58.6%) patients in the ablation group and 52 (60.5%) patients in the transarterial group received treatment according to the strategy (Figure 1). Most ablation patients treated outside the strategy were re-staged to BCLC B (Figure 1). Similarly, patients who received transarterial therapies outside the BCLC strategy had BCLC stage C or D disease (Figure 1). Adherence to the BCLC strategy improved over time, reaching 77.5% in the most recent period [2019–2022], compared to only 53.8% during 2011–2014 (Figure 2).

Figure 2 Treatment trends stratified by adherence to the BCLC strategy. BCLC, Barcelona Clinic Liver Cancer.

During the follow-up period, 83 re-interventions were recorded. These were mostly repeat TACE treatments (n=72). One resection and 10 RFAs were also recorded in cases with recurrent disease. Of the 83 re-interventions, 50 (60.2%) were performed according to the BCLC strategy. Specifically, one resection, 8 RFAs and 41 transarterial treatments adhered to the strategy. When the primary intervention was performed according to the BCLC strategy, 51.9% of re-interventions also followed the strategy. When patients received the primary treatment according to the strategy, the rate was 64.3%.

Short-term outcomes

Patients treated in accordance with the BCLC strategy had lower 30-day mortality, 90-day mortality and recurrence rates compared with those treated outside the strategy. Table 2 shows details regarding short-term outcomes and recurrence rates.

Long-term outcomes

Surgical patients

For the 76 surgical patients treated according to the strategy, the 1-, 3-, and 5-year survival rates were 92.1%, 84.2%, and 78.9%, respectively (Figure 3). In contrast, for the 17 patients who received surgical treatment outside the strategy, the 1-, 3-, and 5-year survival rates were 82.4%, 41.2%, and 23.5%, respectively (Figure 3). Median survival was 7.0 years (IQR 3.9–10.8 years) when treatment followed the BCLC strategy, compared to 2.1 years (IQR 1.1–3.0 years) for patients operated outside the BCLC strategy. Recurrence rates among surgical patients were 57% when treatment followed the BCLC strategy, compared to 71% when the treatment deviated from strategy. In the univariable analysis for patients treated surgically, deviation from the BCLC strategy was associated with increased overall mortality (HR 4.8; 95% CI: 2.3–10.0, P<0.001) (Table 3). In the multivariable analysis adjusted for confounding factors, deviation from the strategy was also associated with increased overall mortality (HR 3.1; 95% CI: 1.0–9.2, P=0.04) (Table 3).

Figure 3 OS of surgically treated HCC patients according to adherence to the BCLC strategy. BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; OS, overall survival.

Ablation patients

For the 17 patients who received ablation according to the BCLC strategy, the survival rates were 88.2%, 47.1% and 29.4%, respectively (Figure 4). When ablation treatment was given outside the BCLC, the 1-, 3- and 5-year survival rates were 75.0%, 50.0% and 41.7%, respectively (Figure 4). Median survival did not differ between groups and was 2.4 years (IQR 1.6–4.0 years) after ablation according to the BCLC strategy and 2.4 years (IQR 1.5–4.0 years) after ablation outside the BCLC strategy. However, patients receiving ablation treatment had a recurrence rate of 76.5% when adhering to the strategy, compared to 100% when treatment deviated from the strategy. For ablated patients, the univariable analysis showed no association with increased overall mortality for treatments given outside BCLC (HR 0.9; 95% CI: 0.3–2.2).

Figure 4 OS of the locoregionally treated HCC patients according to adherence to the BCLC strategy. BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; OS, overall survival.

Transarterial patients

When the BCLC strategy was followed, the 1-, 3- and 5-year survival rates were 80.8%, 50.0% and 40.4%, respectively (Figure 4). When the transarterial procedure was performed outside the BCLC strategy, the survival rates were 58.8%, 44.1% and 35.3%, respectively (Figure 4). Median survival did not differ between groups and was 2.4 years (IQR 1.2–4.4 years) when transarterial treatment was given according to the BCLC strategy, and 2.0 years (IQR 0.9–4.4 years) after treatment outside the strategy. In the univariable analysis for patients who received transarterial treatment, deviation from the BCLC strategy was not associated with increased overall mortality (HR 1.4; 95% CI: 0.8–2.4). When comparing BCLC B patients who underwent surgical treatment outside the strategy (n=11) with those who received transarterial therapy according to the BCLC strategy (n=52), no significant difference in survival was observed (Figure 5).

Figure 5 OS of BCLC B patients treated surgically outside the BCLC strategy compared with those treated with transarterial treatment according to the strategy. BCLC, Barcelona Clinic Liver Cancer; OS, overall survival.

Eligibility for surgical treatment

A total of 115 patients who received locoregional therapy, 11 (9.6%) were found to be eligible for surgical treatment. The most common reason for non-eligibility for surgery was liver function, affecting 61 (53.0%) patients. In 10 cases, liver function was the sole limiting factor. Patient characteristics prevented surgical treatment in 58 (50.4%) cases, and tumor burden was the primary limiting factor in 50 (43.5%) cases.

Discussion

Our study demonstrates a relatively high adherence of 70% to the BCLC treatment strategy, which appears to be associated with improved survival outcomes in HCC patients across two Finnish centres. Treatment decisions that deviate from the strategy should be made with caution.

The adherence increased over time, reaching 77.5% in recent years. This is in line with the BCLC strategy update from 2022, which has been reported to be more clinically applicable than previous versions (7). However, our results also reflect routine clinical practice, where strict classification of patients according to the BCLC strategy if often challenging because of the heterogenous nature of patient characteristics and disease presentation. Our findings align with several nationwide reports, emphasising the importance of treatment planning within a specialist hepatopancreatobiliary multidisciplinary team (7).

In the surgical group, 17 (18.3%) patients were overtreated by resection and re-staged as BCLC B and C. In our study, the 5-year OS rate was 42.0% for all resected patients, consistent with previously published survival rates (14-20). However, recurrence occurred in 67 (58.7%) patients, exceeding the recurrence rates reported in other studies, ranging from 26.2% to 48.6% (21-25). The higher recurrence rate is partly due to the surgically treated BCLC B and C patients, with recurrence rates of 70.5%. Cirrhosis likely influenced surgical decision-making in our cohort, as impaired hepatic reserve often limits resectability (26). The laparoscopic approach can increase operability in selected cirrhotic patients; however, it was implemented to a lesser extent in our cohort (26). Moreover, these patients showed a dismal 5-year OS rate of 23.5% compared to 78.9% when resection was performed in accordance with the BCLC strategy. Median survival was 6.4 years for the surgical group, which is in line with previous publications (7).

In our study, patients treated with ablation had a 1-year survival rate of 82.8%, consistent with previous literature (15-17). However, long-term outcomes were poor, with a 5-year OS rate of only 8.3% and a median survival of 2.4 years. In contrast, other studies have reported significantly higher 5-year survival rates, reaching up to 60%, and according to the BCLC strategy, median survival should exceed 5 years (7,15-17). The likely reason for the poor results is overtreatment, since BCLC allocation for nearly 60% of misstaged ablation patients would have been TACE or best supportive care. The study design might also explain the modest ablation results, since only histologically confirmed HCC cases were included. Thus, many ablation-treated patients were excluded, as clinical practice guidelines do not recommend biopsies when tumors are classified as Liver Imaging Reporting and Data System (LI-RADS) 5 (27). Additionally, the ablation group had the highest average CCI score, Child-Pugh score, and proportion of cirrhosis out of all treatment groups. The overall recurrence rate in the ablation group was 64.7%, consistent with previous studies (15,16).

The long-term results for patients receiving transarterial treatment were consistent with previous studies, with a median survival of 2.0 years, which is within expectations for BCLC B patients (7,19,20). Vital tumor presence at imaging following TACE was detected in 42.5% of cases, comparable with earlier reports (28,29).

Grouping transarterial and ablation therapies into broad categories may have influenced the observed outcomes. Although there is no strong evidence that one ablation technique is clearly superior to another (30), MWA is generally considered to provide more consistent ablative zones and reduced heat-sink effects (31) and it became available only in the later part of the study period. In addition, some therapies are indicated for specific clinical contexts. For instance, SIRT is typically reserved for larger tumors with vascular invasion, which may have further affected comparability between groups (32). However, our study was not designed to compare ablation techniques or transarterial therapies with each other, and the small subgroup sizes would not have allowed for such analyses. Previous studies have reported a variable adherence of 52–86% to the BCLC strategy worldwide (33-35). In our re-evaluation, 81.7% of resections and 60.0% of locoregional therapies adhered to the strategy. The most frequent deviations involved overtreatment of patients by surgery and locoregional therapies. Tumor burden was the most common factor overlooked in surgically overtreated patients. This is reflected in a higher TNM stage among patients treated surgically outside the BCLC strategy, which may partly account for the modest outcomes observed in this group. Our observation of overtreatment in surgically as well as locoregionally managed patients suggests that these individuals might have derived a greater prognostic benefit by adhering to the BCLC strategy, especially in the era of modern systemic therapy (12,13). Although immune-based combination therapies have demonstrated improved survival in advanced disease, they are increasingly being explored in perioperative settings without yet showing clear prognostic benefit in this context (36). Therefore, the threshold for deviating from guideline-concordant allocation should arguably be higher, particularly in BCLC B–C patients, for whom enrolment in clinical trials is recommended. Interestingly, BCLC B patients who were treated surgically outside the strategy had long-term outcomes similar to those treated with angiological therapy according to the strategy, indicating substantial disease heterogeneity. Although a tumor may be technically resectable, several additional factors influence patient survival, including underlying chronic liver disease and the patient’s overall clinical condition. These factors plausibly explain our finding of comparable long-term survival among BCLC B patients, regardless of whether they underwent surgery or angiological therapy. Additionally, BCLC C-D patients were frequently overtreated with locoregional therapy, as 7% of ablation patients and 26% of patients should have been allocated to systemic therapy or best supportive care. Similarly, 39.8% of re-interventions were performed outside the BCLC strategy. Only 9.6% of BCLC 0–A patients were undertreated by ablation, with liver function and patient characteristics being the main factors limiting surgical eligibility.

Regardless of BCLC and other existing strategies [National Comprehensive Cancer Network (NCCN), British Society of Gastroenterology (BSG), European Society for Medical Oncology (ESMO)], significant variations exist between surgeons, centres, and countries in preoperative risk assessment, staging, and treatment selection (34). However, overtreatment is not beneficial on most occasions, and correct treatment allocation is the main goal of the BCLC strategy (34). Several reports have criticised BCLC for undertreatment, which mainly concerns BCLC stage B, and rarely C (8,9). Another proposed weakness of the latest BCLC strategy is that surgical resection can’t be implemented in multinodular disease and ECOG 1 patients, despite evidence showing that surgical outcomes in these groups are comparable or superior to alternative treatment options (8,9). However, our study does not provide robust evidence to support or refute this criticism. While patients resected beyond the BCLC strategy in our cohort showed poor outcomes, with a 5-year survival rate of 23.5% and a median survival of 2.1 years, the small sample size of only 17 patients limits the reliability of these findings. Therefore, no strong conclusions can be drawn regarding the appropriateness of surgical treatment in this context.

The overall complication rate for resected patients was 57.3%, which is higher than previously published rates of 27.6–31.0% (14,21,22). However, the rate of complications in the surgical group decreased over time, and the complication rates in the surgical group from the last decade are comparable to prior studies (14,21,22). This improvement may partly reflect advances in surgical technique and the adoption of the laparoscopic approach. It is likely that in retrospective assessment of perioperative data, complication data may be incomplete.

The strengths of this study include comprehensive follow-up data and tumor homogeneity, as all cases were histologically confirmed. However, this also presents a limitation, since many patients receiving locoregional therapy are diagnosed based on radiological findings (LI-RADS 4–5), leading to their exclusion from this cohort. By collecting background information and details about follow-up after treatment, we provide a reliable comparison of complications, outcomes and survival between different treatment modalities. Additionally, the ability to re-evaluate preoperative CT scans was a strength of this study.

Limitations of this study include its retrospective nature. The long follow-up time presents challenges due to incomplete data from the earliest years. The oncological treatment landscape and surgical techniques have developed, reducing the reliability of direct comparisons across the study period. Patients were included from 1986 onwards, whereas the BCLC strategy was introduced in 1999, which may have influenced treatment allocation and the retrospective assessment of adherence. Since only histologically confirmed HCC cases were included in our study, a potentially clinically relevant selection bias may affect the results for the locoregionally treated patients. Given the retrospective nature of the study, the rationale for requiring biopsy-confirmed diagnosis prior to locoregional treatment is unclear, as is the proportion of cases treated without histological confirmation. Given these limitations, the results concerning the locoregionally treated patient cohort are only limitedly generalisable. Missing CT scans for 21 patients further limited accurate reassessment and led to their exclusion. The open surgical technique was more common in our study, while current international guidelines favour the laparoscopic technique. Furthermore, the operations were performed by multiple surgeons in both centres, which could enhance generalisability but limit reproducibility. Finally, the size of the study population imposes constraints, limiting the statistical power of our findings.

Conclusions

In conclusion, our study suggests that adherence to the BCLC strategy generally offers survival benefits in a real-world setting. Patients treated outside the strategy should be carefully selected, highlighting the importance of careful multidisciplinary evaluation in determining appropriate treatment modalities.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-639/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-639/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-639/prf

Funding: The study was supported by the Finnish State Research Fund, Irja Karvonen Cancer Foundation, Dorothea Olivia, Karl Walter and Jarl Walter Foundation, and Finska läkaresällskapet rf (to N.S.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-639/coif). N.S. reports financial support from the Finnish State Research Fund, Irja Karvonen Cancer Foundation, Dorothea Olivia, Karl Walter and Jarl Walter Foundation, and Finska läkaresällskapet rf. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The Finnish Medicines Agency Fimea (Dnro FIMEA/2021/004928) and the Ethical Committee of the North Ostrobothnia’s Hospital District (EETTMK 81/2008) approved the study. All participating hospitals/institutions were informed and agreed the study. Individual consent for this analysis was waived due to the retrospective nature.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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