Surgical resection could provide better outcomes for patients with hepatocellular carcinoma and tumor rupture
Executive Summary
Spontaneous tumor rupture is the third most common cause of death among patients with hepatocellular carcinoma (HCC), trailing only tumor progression and liver failure. This analysis of 91 treatment-naïve patients with ruptured HCC demonstrates that surgical resection (SR) significantly improves long-term survival compared to non-surgical interventions.
Key findings include:
Survival Disparity: The cumulative 5-year overall survival (OS) rate for the SR group was 55.1%, while the non-SR group reached 0% (p < 0.001).
Treatment Efficacy: Non-surgical treatment (TACE alone or best supportive care) resulted in a median OS of only 2.6 months.
Combination Therapy: Sequential therapy involving transarterial chemoembolization (TACE) followed by SR yielded clinical outcomes similar to SR alone, suggesting that the surgical component is the primary driver of survival.
Clinical Determination: SR remained the strongest predictor of survival regardless of the Barcelona Clinic Liver Cancer (BCLC) stage or the albumin-bilirubin (ALBI) grade.
Clinical Context and Background
Primary liver cancer is the third leading cause of cancer mortality globally. HCC accounts for 90% of these cases. Ruptured HCC is a life-threatening emergency often diagnosed via hemodynamic instability, hemoperitoneum, or imaging studies (CT scans/angiography). While the incidence of rupture is lower in Western countries (<3%), it ranges from 2.3% to 26% in Asia.
Despite its severity, data regarding the optimal treatment for ruptured HCC—typically TACE, SR, or a combination—have historically been scarce. This study aims to identify the treatment modality that yields the best prognosis for treatment-naïve patients.
Study Methodology and Patient Demographics
The study retrospectively analyzed 91 patients diagnosed with treatment-naïve HCC and tumor rupture between 2008 and 2020 at Taipei Veterans General Hospital.
Treatment Distribution
Surgical Resection (SR) Group (n=58):
38 patients received SR alone.
20 patients received sequential TACE followed by SR (median interval: 14 days).
Non-SR Group (n=33):
28 patients received TACE only.
5 patients received best supportive care (BSC).
Baseline Characteristics
Patients in the SR group generally exhibited better liver function markers than the non-SR group, including:
Higher serum albumin levels.
Lower prothrombin-time international normalized ratio (PT INR).
Higher rates of Child–Pugh class A and ALBI grade 1.
Lower BCLC stages (though SR was beneficial across all stages).
Continuous variables such as age (median 63.0), gender (78% male), and tumor size (median 8.6 cm) were comparable across the cohort.
Comparative Analysis of Survival Outcomes
Overall Survival (OS)
The study found a stark contrast in survival based on the inclusion of surgery in the treatment plan.
Key Survival Insights
Inefficacy of TACE Monotherapy: There was no significant difference in OS between patients receiving TACE alone and those receiving BSC (p = 0.852).
Combination vs. Monotherapy SR: No significant difference in OS was observed between SR alone and the TACE plus SR sequential therapy (p = 0.816).
Impact of Staging: While ALBI grade 1 and BCLC stages A or B generally correlated with better OS, the SR group outperformed the non-SR group across all sub-strata, including patients with more advanced ALBI grades (2 or 3) and BCLC stages (C or D).
Prognostic Factors and Multivariate Analysis
Multivariate analysis identified several independent factors that significantly influence the overall survival of patients with ruptured HCC.
Predictors of Poor Overall Survival
Non-SR Treatment: The strongest predictor of mortality, with a hazard ratio (HR) of 6.649.
Serum α-fetoprotein (AFP) ≥ 100 ng/mL: Associated with poorer outcomes (HR 2.979).
ALBI Grade 2 or 3: Indicative of lower liver functional reserve (HR 2.013).
Alkaline Phosphatase (Alk-P) ≥ 100 U/L: Correlated with poor OS.
Serum Albumin ≤ 3.5 mg/dL: Correlated with poor OS.
Viral Etiology Observations
HBsAg Positivity: Interestingly, patients with Hepatitis B (HBV) showed better OS than those without (HR 0.368, p = 0.001). This may be due to HBV-related HCC patients often having better liver functional reserve compared to those with HCV-related cirrhosis, despite having more aggressive tumor phenotypes.
Surgical Outcomes and Recurrence
Among the 58 patients who underwent surgery, 24 died during a median follow-up of 34.1 months.
Recurrence-Free Survival (RFS)
Recurrence Rate: 28 patients (48.3%) experienced tumor recurrence.
Median RFS: 8.69 months.
Cumulative RFS Rates: 41.6% at 1 year, 32.8% at 2 years, and 24.1% at 3 years.
Recurrence Patterns:
Intra-hepatic metastasis alone: 53.6%
Extra-hepatic recurrence alone: 25.0%
Combined intra- and extra-hepatic: 21.4%
Factors Predicting Poor RFS
Independent factors associated with poor recurrence outcomes after surgery include:
Serum Alk-P level ≥ 100 U/L.
Presence of macrovascular invasion.
Ishak modified histologic activity index ≥ 3.
Discussion and Study Limitations
Clinical Implications
The data suggests that for treatment-naïve HCC patients with tumor rupture, SR provides an "acceptable long-term outcome." While TACE is often the first-line choice for immediate hemostasis in hemodynamically unstable patients, it does not provide long-term survival benefits unless followed by surgical resection. The study notes: "Patients with ruptured HCC should be considered to undergo SR if they have no contraindication, regardless of what therapies they received at the beginning of rupture event."
Limitations
Retrospective Design: Potential selection bias, particularly as patients in better physical condition were more likely to be selected for SR.
Geographic Specificity: The cohort primarily consisted of Asian patients with viral hepatitis-related HCC; results may vary for other ethnicities or non-viral etiologies.
Systemic Therapy: The impact of recent advances in systemic therapies (TKIs and ICIs) could not be fully assessed due to the diverse regimens used in the cohort after tumor progression.
Follow-up Disparity: The median follow-up was 34.1 months for the SR group but only 2.6 months for the non-SR group, reflecting the high early mortality rate in non-surgical cases.
Conclusion
Surgical resection is the optimal treatment modality for patients with treatment-naïve HCC and tumor rupture at diagnosis, leading to a 5-year OS rate of 55.1%. Non-surgical interventions, including TACE without follow-up surgery, offer poor prognoses with near-zero survival at four years. Sequential combination therapy (TACE followed by SR) is a viable alternative to SR alone, offering similar long-term outcomes.
