Serum Insulin-Like Growth Factor-1 Levels Predict Outcomes of Patients with Advanced Hepatocellular Carcinoma Receiving Antiangiogenic Therapy

Abstract

Purpose: Patients with liver cirrhosis or hepatocellular carcinoma (HCC) have decreased serum insulinlike growth factor (IGF)-1 levels. We evaluated whether IGF-1 levels were associated with the outcomes of patients with advanced HCC treated with systemic antiangiogenic therapy.Experimental Design: The study was based on patients with advanced HCC who were enrolled in two clinical trials evaluating first-line combination antiangiogenic therapy. Serum samples were collected before treatment and four to six weeks after the start of treatment. The levels of IGF-1, IGF-2, and IGF-binding protein-3 (IGFBP3) were analyzed for their associations with treatment outcomes.Results: A total of 83 patients were included in the study. Patients who had high (!the median level) baseline IGF-1 levels had significantly higher disease control rate (DCR) than patients who had low (<the median level) levels (71% vs. 39%, P ¼ 0.003). The levels of posttreatment IGF-1, and pre-or posttreatment IGF-2 and IGFBP3 were not associated with DCR. Patients with high baseline IGF-1 levels, compared with patients with low levels, had significantly longer progression-free survival (PFS; median, 4.3 vs. 1.9 months, P ¼ 0.014) and overall survival (OS; median, 10.7 vs. 3.9 months, P ¼ 0.009). The high baseline IGF-1 level remains an independent factor associated with favorable PFS and OS in multivariate analysis.Conclusions: High pretreatment IGF-1 levels were associated with better DCR, PFS, and OS of patients who received antiangiogenic therapy for advanced HCC. This finding warrants validation in large studies.

Serum Insulin-like Growth Factor-I Level Is an Independent Predictor of Recurrence and Survival in Early Hepatocellular Carcinoma: A Prospective Cohort Study

“…However, the IGF-I/IGFBP-3 ratios were not significantly different according to age or liver function. Consistent with previous reports (12,21), patients with chronic hepatitis C infection had lower levels of IGF-I, IGFBP-3, and IGF-I/ IGFBP-3 ratios than patients with chronic liver disease of other etiologies. When we studied the associations between IGF axis components and tumor factors, such as tumor size and number, serum AFP levels, and histologic findings, no significant correlations were found.…”

“…11). Low-serum IGF-I levels were also associated with a poor response to antiangiogenic therapy, leading to an unfavorable prognosis in patients with advanced hepatocellular carcinoma (12). These findings suggest that the levels of IGF-I serve not only as an indicator of hepatic reserve, but also as a potential biomarker of the extent of the disease, response to noncurative treatment, and prognosis.…”

“…Kaseb and colleagues showed that lowplasma IGF-I levels were associated with advanced clinicopathologic factors and shorter OS in patients with heterogeneous stages of hepatocellular carcinoma (11,21). Similarly, low-baseline serum IGF-I levels correlated with poor treatment response, progression-free survival, and OS in patients who received antiangiogenic therapy for advanced hepatocellular carcinoma (12). Together with our results, these findings suggest that the mitogenic activity of IGF-I may not play a determinant role in the development and progression of hepatocellular carcinoma.…”

“…The present study has several limitations. First, the study was conducted at a single institution, and the cutoff level of IGF-I (105 ng/mL) that was used to divide the patient population was significantly higher than in previous cohort studies (12,21). The difference may be attributable to several factors, including (i) different ethnicity (i.e., Asians), (ii) relatively early stages of hepatocellular carcinoma (only including patients treated with curative modalities), (iii) a relatively low proportion of patients with chronic hepatitis C in our cohort, and (iv) different methods for cutoff determination (i.e., data-oriented and outcome-oriented).…”

High Serum Transforming Growth Factor-β1 Levels Predict Outcome in Hepatocellular Carcinoma Patients Treated with Sorafenib

“…The median PFS was 3.7 months (95% confidence interval; CI, 2.2-4.9), and the median OS was 7.4 months (95% CI, 5.6-11.3). The treatment outcomes of the 91-patient cohort were similar to those of other advanced HCC patient cohorts that had been reported from our institute (24,25).…”