Decreased Blood Flow after Sorafenib Administration Is an Imaging Biomarker to Predict Overall Survival in Patients with Advanced Hepatocellular Carcinoma

Abstract

Background: Sorafenib is a multikinase inhibitor targeting Raf and protein tyrosine kinases, which are involved in cell growth and tumor angiogenesis. Sorafenib administration induces temporary inhibition of tumor growth and a decrease in arterial blood flow in a considerable number of hepatocellular carcinoma (HCC) patients. We retrospectively evaluated the association between decreased blood flow and the overall survival (OS) of HCC patients after the initiation of sorafenib therapy. Patients and Methods: Therapeutic responses of 158 advanced HCC patients with hypervascular tumors who had received sorafenib for more than 1 month were analyzed. To assess their therapeutic response, patients underwent radiological evaluation before and every 4-6 weeks after the initiation of sorafenib treatment. After the classification of patients into three groups based on the change in arterial enhancement during treatment (no change, decrease and disappearance), the OS of each group was compared using the Kaplan-Meier method. Results: Statistically significant differences in OS were observed among the three groups (p < 0.001). A decrease or disappearance of arterial enhancement was significantly associated with improved OS compared to patients with no change in arterial enhancement; the median OS was 19.9 months (95% confidence interval, CI, 16.4-24.5 months) and 6.0 months (95% CI, 4.0-8.8 months), respectively (p < 0.001). However, there was no difference in OS between the decrease and disappearance groups (p = 0.88). Conclusion: We conclude that decreased arterial enhancement during sorafenib treatment was associated with the longest OS and could therefore reflect an effective response.

Advances in Hypoxia-Mediated Mechanisms in Hepatocellular Carcinoma

“…The overall survival (OS) of patients with higher peak blood flow in their tumors is significantly improved, suggesting that hypoxia is an adverse factor for HCC patient survival. Similar results were also reported from studies using perfusion computerized tomography (CT) detection (Arizumi et al, 2014;Bayraktutan et al, 2014;Guo and Yu, 2014). Owing to the abnormal vessel structure or function, acute/intermittent perfusion hypoxia is common in HCC.…”

Fever within 2 Weeks of Sorafenib Therapy Predicts Favorable Treatment Efficacy in Patients with Advanced Hepatocellular Carcinoma

“…Disappearance of intratumor blood flow is often observed after sorafenib therapy and might be a marker of good antitumor efficiency [9,13]. In our previous study [9], we reported that the disappearance of arterial tumor enhancement on CE-CT after 2 weeks of sorafenib therapy was a significant predictor of better survival.…”

Early Clinical Response after 2 Weeks of Sorafenib Therapy Predicts Outcomes and Anti-Tumor Response in Patients with Advanced Hepatocellular Carcinoma

“…Reductions in intra-tumor blood flow are often observed after sorafenib therapy without measurable change in tumor size [ 3 , 15 , 20 ]. Some reports have documented that OS is better reflected by the modified RECIST based on tumor viability measurement than by the conventional RECIST based on tumor burden measurement for patients receiving sorafenib therapy [ 29 , 30 ].…”

“…Third, we investigated only whether or not there was disappearance of arterial tumor enhancement on CE-CT at 2 weeks post-dose in order to evaluate the changes in intra-tumor blood flow, because only the disappearance of arterial tumor enhancement is taken into consideration in the modified RECIST. However, in clinical practice, a disappearance or a decrease of arterial tumor enhancement is often observed, and one report documented that patients with either disappearance or a decrease in tumor enhancement showed better OS than patients without disappearance or a decrease in tumor enhancement [ 15 ]. Therefore, it may be preferable to investigate changes in intra-tumor blood flow as a continuous variable by using changes in quantitative enhancement on CE-CT rather than evaluating this parameter as a dichotomous variable.…”

“…Several studies have investigated prognostic factors and serum biomarkers to predict treatment outcomes for patients treated with sorafenib [ 10 – 14 ]. Disappearance of tumor staining on contrast-enhanced computed tomography (CE-CT) [ 15 ] or on contrast-enhanced ultrasound [ 16 , 17 ], decrease in alpha-fetoprotein (AFP) level [ 18 – 21 ] and decrease in vascular endothelial growth factor level [ 22 ] have been reported as indicators of good prognosis and the anti-tumor effect in the early post-dose period of sorafenib therapy.…”