AIM: To determine significant indicators for the efficacy of sorafenib in patients with advanced hepatocellular carcinoma (HCC).

METHODS: A total of 46 patients with Barcelona Clinic Liver Cancer stage C who received sorafenib for more than 30 d at the Iizuka Hospital from June 2009 to December 2012 were enrolled in this study. Multivariate and univariate analyses were performed to evaluate the associations of hepatic function according to Child-Pugh grade, location and size of the largest tumor and adverse events of sorafenib treatment, such as hand-foot syndrome (HFS), hypertension, diarrhea, and alopecia, with the efficacy of treatment, as measured by overall survival (OS) and time to progression (TTP).

RESULTS: Patients included 39 men and 7 women whose ages ranged from 48 to 85 years (70.6 ± 9.6 years). HCC was classified according to etiology as follows: hepatitis C virus (n = 26), hepatitis B virus (n = 9), and other (n = 11). Liver function in patients was categorized as Child-Pugh grade A (n = 30) or B (n = 16). Tumors were categorized by size [< 5 cm (n = 33) or >5 cm (n = 13)] and the location of the largest tumor was used to categorize patients with intrahepatic (n = 28) or extrahepatic (n = 18) HCC. HFS, hypertension, diarrhea, and alopecia were present in 22 (47.8%), 19 (41.3%), 15 (32.6%) and 7 patients (15.2%), respectively. The median OS of all patients was 373 d and the median TTP was 112 d. The etiology of HCC did not correlate with the median OS and TPP. The median OS of patients with tumors < 5 cm was significantly longer than those with larger tumors (496 vs 245 d; HR = 0.19, 95%CI: 0.07-0.48; P < 0.01). According to the results of a multivariate analysis, the size of the largest tumor affected OS (HR = 0.22, 95%CI: 0.08-0.59; P < 0.01). The median TTP was significantly longer in patients with extrahepatic compared to intrahepatic major HCC (224 vs 98 d; HR = 0.32; 95%CI: 0.14-0.67; P < 0.01). The median TTP of patients with HFS was significantly longer than those without it (195 d vs 83 d; HR = 0.41, 95%CI: 0.20-0.82; P < 0.05), and the median TTP was significantly longer in patients with hypertension (195 d vs 84 d; HR = 0.43, 95%CI: 0.21-0.84; P < 0.05). According to the results of the multivariate analysis, extrahepatic major HCC (HR = 0.36, P < 0.01) and HFS (HR = 0.44, P < 0.05) prolonged TTP.

CONCLUSION: Extrahepatic major HCC and HFS are associated with prolonged TTP and are useful indicators for judging the efficacy of sorafenib treatment.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, developing in more than one million new patients each year worldwide, and is the fifth most common cancer and the third most common cause of cancer-related death[1]. The Barcelona Clinic Liver Cancer staging system (BCLC)[2] is widely used to assist in the selection of HCC treatment, which is determined by the tumor characteristics, such as size, number, and presence of vascular invasion or extrahepatic metastasis, as well as by the patient’s hepatic function and performance status. Curative treatments, including surgical resection and radiofrequency ablation, are considered for patients with early stage HCC (solitary tumor < 5 cm or as many as three nodules < 3 cm in diameter) and well-preserved hepatic function[3,4]. Advanced HCC can be treated with sorafenib, an orally administered inhibitor of multiple protein kinases, such as c-Raf, B-Raf, mitogen-activated protein kinase kinase, extracellular signal regulated kinase, and vascular endothelial growth factor[5,6]. Sorafenib induces apoptosis of tumor cells and inhibits tumor angiogenesis[7]. The phase III Sorafenib HCC Assessment Randomized Protocol (SHARP) trial demonstrated that median overall survival (OS) and time to progression (TTP) of patients with advanced HCC is improved with sorafenib compared with placebo[8]. Sorafenib is therefore the recommended first-line treatment for patients with BCLC stage C HCC[3,4].

Despite the success of sorafenib for the treatment of advanced HCC[9-11], significant predictive factors for its efficacy are not available. Sorafenib treatment induces adverse events such as diarrhea, hand-foot syndrome (HFS) and hypertension[8,12]. Moreover, early skin reactions correlate with tumor control[13]. Although some adverse events may predict efficacy or indicate a need for dose adjustment, there are no standard guidelines to follow[8-13]. The aim of the present study was to determine the factors that influence the efficacy of sorafenib according to the Child-Pugh tumor grade[14] at the beginning of treatment, the location and the size of the largest tumor, and common adverse events such as HFS, hypertension, diarrhea, and alopecia.

Results of the SHARP trial demonstrated that sorafenib was the first agent to improve the median OS and TTP of patients with advanced HCC[8]. The present study evaluated the impact of clinical factors on the efficacy of sorafenib for treating patients with BCLC stage C HCC. The median OS of patients was 373 d, which is comparable to the median OS of 10.5 mo reported in the SHARP trial. Multivariate analysis showed that the size of the largest tumor was the only factor that correlated significantly with OS, though CP-A was associated with a prolonged OS according to a univariate analysis. Hepatic function affects OS[16], consistent with untreated or nonsurgical HCC[17]. In contrast to OS, Child-Pugh grade was not associated with TTP, suggesting that hepatic function at the beginning of treatment did not determine the effect of sorafenib.

As previous reports indicated that the health-related quality of life (HRQoL) of patients with HCC gradually worsens because of the development of new symptoms as the disease progresses[18-20], this study focused on factors that might influence TTP. The results suggest that sorafenib is more effective in patients with extrahepatic major HCC than in those with intrahepatic major HCC. It is possible that different mechanisms of angiogenesis are involved in the progression of intrahepatic lesions and extrahepatic metastases. For example, many intrahepatic lesions are adequately supplied with blood by the hepatic arterial system, which primarily feeds liver tissue. However, vigorous de novo angiogenesis is required for the growth of metastatic tumors[21]. Thus, the progression of extrahepatic metastases likely requires greater angiogenic activity to provide sufficient blood flow, allowing for a more evident anti-angiogenic effect of sorafenib. Moreover, patients with intrahepatic major HCC had larger intrahepatic tumors and more frequent portal invasion than those with extrahepatic major HCC. As a result, hepatic arterial blood flow may have been increased, attenuating the efficacy of sorafenib.

Univariate analyses of the adverse events caused by sorafenib indicated that HFS and hypertension correlated significantly with TTP. Moreover, HFS was found to significantly affect TTP by a multivariate analysis. HFS is a frequent and typical form of dermatologic toxicity associated with multi-targeted kinase inhibitors (MKIs) such as sorafenib and sunitinib[22-24]. Although the precise mechanism by which MKIs cause HFS is unknown, the anti-angiogenic activity of MKIs may inhibit vascular repair mechanisms in high-pressure areas such as the palms and soles, which are repeatedly exposed to subclinical trauma[25]. These observations provide a possible rationale for concluding that HFS predicts a good response to the anti-angiogenic activity of sorafenib. Although the severe symptoms of HFS are not life-threatening, they diminish the HRQoL of patients receiving sorafenib[25,26]. As the results of this study show that the dose of sorafenib did not affect the median TTP, we recommend careful monitoring of the patient for signs of HFS, and adjusting the dose of sorafenib accordingly.

The progression of HCC causes symptoms of liver failure such as jaundice, refractory ascites, hepatic encephalopathy, and gastrointestinal bleeding, as well as intractable pain and cachexia. Therefore, extending the TTP can delay the appearance of symptoms of advanced HCC. This study shows that sorafenib was more effective in extending TTP in patients with extrahepatic major HCC. Moreover, HFS significantly correlated with increased TTP and is therefore a useful indicator for adjusting the dose of sorafenib. Sorafenib treatment should be individualized to improve its effectiveness and the HRQoL of patients with advanced HCC.

We are grateful to Y. Ishibashi for assistance with manuscript preparation.