Hyperglycemia is a significant prognostic factor of hepatocellular carcinoma after curative therapy

Abstract

Aim: To evaluate whether metabolic factors are related to distant recurrence of hepatocellular carcinoma (HCC) and survival after curative treatment.

Methods: This retrospective study included 344 patients whose HCC was treated curatively by radiofrequency ablation (RFA) therapy. The mean age was 67.6 years and the mean observation period was 4.04 years. The etiological background of liver disease was hepatitis B virus infection in 30, hepatitis C virus infection in 278, excessive alcohol drinking in 9, and other in 27 patients. The Child-Pugh classification grade was A (n = 307) or B (n = 37). The number of HCC nodules was one in 260, two in 61, and three in 23 patients. For surveillance of HCC recurrence after curative therapy with RFA, patients were radiologically evaluated every 3 mo. Factors associated with distant recurrence of HCC or survival were studied.

Results: Inadequate maintenance of blood glucose in diabetic patients was associated with higher incidence of distant recurrence. The 1-, 2-, and 3-year recurrence rates were significantly higher in diabetic patients with inadequate maintenance of blood glucose compared with the others: 50.6% vs 26.8%, 83.5% vs 54.4%, and 93.8% vs 73.0%, respectively (P = 0.0001). Inadequate maintenance of blood glucose was an independent predictor of distant recurrence [adjusted relative risk 1.97 (95%CI, 1.33-2.91), (P = 0.0007)] after adjustment for other risk factors, such as number of HCC nodules [2.03 (95%CI, 1.51-2.73), P < 0.0001] and initial level of serum alpha fetoprotein (AFP) [1.43 (95%CI, 1.04-1.97), P = 0.028]. Obesity was not an independent predictor of recurrence. The incidence of distant recurrence did not differ between diabetic patients with adequate maintenance of blood glucose and non-diabetic patients. Among 232 patients who had HCC recurrence, 138 had a second recurrence. The 1-, 2-, and 3-year rates of second recurrence were significantly higher in diabetic patients with inadequate maintenance of blood glucose than in the others: 9.0% vs 5.9%, 53.1% vs 24.3%, and 69.6% vs 42.3%, respectively (P = 0.0021). Inadequate maintenance of blood glucose in diabetic patients [1.99 (95%CI, 1.23-3.22), P = 0.0049] and presence of multiple HCC nodules [1.53 (95%CI, 1.06-2.22), P = 0.024] were again significantly associated with second HCC recurrence. Inadequate maintenance of blood glucose in diabetic patients was also a significant predictor of poor survival [2.77 (95%CI, 1.38-5.57), P = 0.0046] independent of excessive alcohol drinking [6.34 (95%CI, 1.35-29.7), P = 0.019], initial level of serum AFP [3.40 (95%CI, 1.88-6.18), P < 0.0001] and Child-Pugh classification grade B [2.24 (95%CI, 1.12-4.46), P = 0.022]. Comparing diabetic patients with inadequate maintenance of blood glucose vs the others, the 1-, 2-, and 3-year survival rates were significantly lower in diabetic patients with inadequate maintenance of blood glucose: 92% vs 99%, 85% vs 96%, and 70% vs 92%, respectively (P = 0.0003).

Conclusion: Inadequate maintenance of blood glucose in diabetic patients is a significant risk factor for recurrence of HCC and for poor survival after curative RFA therapy.

Keywords: Hepatocellular carcinoma; Hyperglycemia; Radio frequency ablation; Recurrence; Survival.

Figure 1

Kaplan-Meier curves showing a higher rate of hepatocellular carcinoma recurrence in diabetic patients with hyperglycemia. A: The cumulative incidence of the recurrence of hepatocellular carcinoma (HCC) was significantly higher in diabetic patients with inadequate maintenance of blood glucose (blood glucose ≥ 200 mg/dL solid line) than in the others (dotted line) (P = 0.0001); B: The HCC recurrence rate was significantly higher in diabetic patients with inadequate maintenance of blood glucose (solid line) than in diabetic patients with adequate maintenance of blood glucose (blood glucose < 200 mg/dL, broken line) or non-diabetic patients (dotted line) (P = 0.0001). There was no significant difference in HCC recurrence rate between diabetic patients with adequate maintenance of blood glucose and non-diabetic patients.

Figure 2

Diabetic patients with inadequate maintenance of blood glucose have higher rate of hepatocellular carcinoma recurrence after stratification by other risk factors. A: P = 0.006 for single hepatocellular carcinoma (HCC) nodule; B: P = 0.025 for multiple HCC nodules; C: P = 0.005 for AFP ≥ 100 ng/mL; D: P = 0.017 for α-fetoprotein (AFP) < 100 ng/mL. The cumulative incidence of the recurrence of HCC was significantly higher in diabetic patients with inadequate maintenance of blood glucose (solid line) than in the others (dotted line). after stratification by number of HCC nodules and by initial level of AFP.

Figure 3

Kaplan-Meier curves showing a higher rate of second recurrence of hepatocellular carcinoma in diabetic patients with inadequate maintenance of blood glucose. A: The cumulative incidence of the second recurrence of hepatocellular carcinoma (HCC) was significantly higher in diabetic patients with inadequate maintenance of blood glucose (blood glucose ≥ 200 mg/dL solid line) than in the others (dotted line) (P = 0.002); B: The rate of second recurrence of HCC was significantly higher in diabetic patients with inadequate maintenance of blood glucose (solid line) than in diabetic patients with adequate maintenance of blood glucose (blood glucose < 200 mg/dL, broken line) or non-diabetic patients (dotted line) (P = 0.004). There was no significant difference in the rate of second recurrence of HCC between diabetic patients with adequate maintenance of blood glucose and non-diabetic patients.

Figure 4

Patients with inadequate maintenance of blood glucose have a lower survival rate. A: The survival rate after curative local ablation therapy for hepatocellular carcinoma (HCC) was significantly lower in diabetic patients with inadequate maintenance of blood glucose (blood glucose ≥ 200 mg/dL solid line) than in the others (dotted line) (P = 0.0003); B: The survival rate was significantly lower in diabetic patients with inadequate maintenance of blood glucose (solid line) than in diabetic patients with adequate maintenance of blood glucose (blood glucose < 200 mg/dL, broken line) or non-diabetic patients (dotted line) (P = 0.0003). There was no significant difference in survival rate between diabetic patients with adequate maintenance of blood glucose and non-diabetic patients.