Recurrence and tumor-related death after resection of hepatocellular carcinoma in patients with metabolic syndrome

Abstract

Background & aims: Metabolic syndrome (MS) is a growing epidemic and a risk factor for the development of hepatocellular carcinoma (HCC). This study investigated the long-term outcomes of liver resection (LR) for HCC in patients with MS. Rates, timing, patterns, and treatment of recurrences were investigated, and cancer-specific survivals were assessed.

Methods: Between 2001 and 2021, data from 24 clinical centers were collected. Overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival were analyzed as well as recurrence patterns and treatment. The analysis was conducted using a competing-risk framework. The trajectory of the risk of recurrence over time was applied to a competing risk analysis. For post-recurrence survival, death resulting from tumor progression was the primary endpoint, whereas deaths with recurrence relating to other causes were considered as competing events.

Results: In total, 813 patients were included in the study. Median OS was 81.4 months (range 28.1-157.0 months), and recurrence occurred in 48.3% of patients, with a median RFS of 39.8 months (range 15.7-174.7 months). Cause-specific hazard of recurrence showed a first peak 6 months (0.027), and a second peak 24 months (0.021) after surgery. The later the recurrence, the higher the chance of receiving curative intent approaches (p = 0.001). Size >5 cm, multiple tumors, microvascular invasion, and cirrhosis were independent predictors of recurrence showing a cause-specific hazard over time. RFS was associated with death for recurrence (hazard ratio: 0.985, 95% CI: 0.977-0.995; p = 0.002).

Conclusions: Patients with MS undergoing LR for HCC have good long-term survival. Recurrence occurs in 48% of patients with a double-peak incidence and time-specific hazards depending on tumor-related factors and underlying disease. The timing of recurrence significantly impacts survival. Surveillance after resection should be adjusted over time depending on risk factors.

Impact and implications: Metabolic syndrome (MS) is a growing epidemic and a significant risk factor for the development of hepatocellular carcinoma (HCC). The present study demonstrated that patients who undergo surgical resection for HCC on MS have a good long-term survival and that recurrence occurs in almost half of the cases with a double peak incidence and time-specific hazards depending on tumor-related factors and underlying liver disease. Also, the timing of recurrence significantly impacts survival. Clinicians should therefore adjust follow-up after surgery accordingly, considering timing of recurrence and specific risk factors. Also, the results of the present study might help design future trials on the use of adjuvant therapy following resection.

Keywords: Hepatocellular carcinoma; Metabolic syndrome; Metabolic-associated fatty liver disease; Nonalcoholic fatty liver disease; Obesity; Recurrence; Steatosis.

Graphical abstract

Fig. 1

Time-specific hazards of hepatocellular carcinoma (HCC) recurrence and death without tumor recurrence.

Fig. 2

Treatment of recurrences over time. Potentially curative: resection, ablation, transplantation; Locoregional: radioembolization or chemoembolization. BSC, best supportive care.

Fig. 3

Time-specific HRs of tumor size >5 cm, microvascular invasion, multiple tumors, and cirrhosis for HCC recurrence. Gray areas represent 95% CIs; consequently, the lower limit above 1 indicates p <0.05. HCC, hepatocellular carcinoma.

Fig. 4

Time-specific hazards of death resulting from tumor progression and death from causes other than progression from the date of tumor relapse.

Fig. 5

Time-specific hazards of death resulting from tumor recurrence according to RFS. RFS, recurrence-free survival.