Early prediction of response to sorafenib in patients with advanced hepatocellular carcinoma: The role of dynamic contrast enhanced ultrasound

Background & Aims

Sorafenib has become the standard first-line treatment for patients with advanced HCC and acts by inducing alterations in tumor vascularity. We wanted to evaluate the feasibility of dynamic CEUS (D-CEUS) as a predictor of early tumor response to sorafenib and to correlate functional parameters with clinical efficacy end points.

Methods

Twenty-eight HCC patients treated with sorafenib 400 mg bid were prospectively enrolled. CEUS was performed at baseline (T0) and after 15 (T1) and 30 (T2) days of treatment. Tumor vasculature was assessed in a specific harmonic mode associated with a perfusion and quantification software (Q-Lab, Philips). Variations between T1/T2 and T0 were calculated for five D-CEUS functional parameters (peak intensity, PI; time to PI, T_P; area under the curve, AUC; slope of wash in, P_w; mean transit time, MTT) and were compared for responders and non-responders. The correlation between D-CEUS parameters, overall survival (OS), and progression-free survival (PFS) was also assessed. A p value <0.05 was considered statistically significant.

Results

The percentage variation at T1 significantly correlated with response in three D-CEUS parameters (AUC, PI and P_w; p = 0.002, <0.001, and 0.003, respectively). A decrease of AUC (p = 0.045) and an increased/unchanged value of T_P (p = 0.029) and MTT (p = 0.010) were associated with longer survival. Three D-CEUS parameters (AUC, T_P, P_w) were significantly associated with PFS.

Conclusions

D-CEUS provides a reliable and early measure of efficacy for anti-angiogenic therapies and could be an excellent tool for selecting patients who will benefit from treatment.

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer-related death [1]. Unfortunately, most patients with HCC have advanced disease at the time of diagnosis with no curative treatment available [2].

In the last years, accumulated understanding of the molecular mechanisms regulating cancer progression has led to novel development of molecularly targeted therapies with cytostatic agents. Among them, the oral multikinase inhibitor, sorafenib, has been clearly proved to prolong the overall survival [3] and has been established as a standard agent for systemic chemotherapy in patients with advanced HCC [4], [5], [6]. Different responses were obtained in terms of safety and efficacy: although sorafenib is usually well tolerated, some patients show severe adverse events or very short survival [7]. Early functional evaluation of therapeutic response is of major importance because it will allow selecting patients that should be treated, sparing unnecessary toxicity and costs.

There is some evidence to suggest that this molecularly targeted treatment induces changes in tumor structure (such as decreased tumor vascularity or necrosis) that are consistent with a therapeutic response before a change in tumor size is observed [8], [9], [10]. For this reason, the traditional response criteria based on tumor size (Response Evaluation Criteria In Solid Tumors, RECIST) were recently amended by a panel of experts in order to take into account tumor necrosis induced by treatment [11].

Among different contrast enhanced imaging techniques, dynamic contrast-enhanced ultrasonography (D-CEUS) has emerged as a versatile tool for monitoring anti-angiogenetic treatments since it is a non-invasive method that easily allows repeated examinations. The setting up of perfusion software has improved the technique further.

Mathematical models applied to signal intensity vs. time representing the kinetics of microbubble flow through the tumor are used to characterize tumor vascular density and perfusion. This has promising clinical potential for depicting changes in tumor perfusion occurring with the application of therapies targeting tumor vessels [12], [13], and D-CEUS is currently under evaluation in a broad range of tumors, including hepatocellular carcinoma, to establish the optimal perfusion parameters and timing for quantitative anticancer efficacy assessments [14], [15], [16], [17], [18].

An early reduction in tumor vascularity was shown to correlate with response and was predictive of progression-free survival and overall survival in different settings [16], [19]. A recent prospective study confirmed that D-CEUS is a simple, accurate and non-invasive measure of tumor vascularity in patients with renal cell carcinoma treated with sorafenib [20]. Similarly, this technique has been proved able to detect early and to quantify post therapeutic changes in tumor perfusion after bevacizumab administration in patients with advanced HCC [21]. D-CEUS imaging of tumour vascularization could therefore be an excellent tool for predicting the efficacy of sorafenib in patients with HCC.

The purpose of this study was to investigate whether early changes in tumor perfusion parameters measured by D-CEUS were predictive of tumor response in patients with advanced HCC treated with sorafenib. The secondary aim was to correlate these functional parameters with clinical efficacy end points such as overall survival (OS) and progression-free survival (PFS).