Tumor Hypervascularity and hand-foot-skin reaction predict better outcomes in combination treatment of TACE and Sorafenib for intermediate hepatocellular carcinoma

This retrospective study comprised 447 newly diagnosed HCC patients who were treated with combination therapy of TACE and sorafenib at our center between January 2010 and December 2014, according to the criteria from the European association for the study of liver disease/American association for the study of liver disease [6, 7]. The patients were eligible for treatment if they presented with unresectable HCC, an eastern cooperative oncology group (ECOG) performance status of ≤1, adequate hematologic and renal function. Excluding 183 patients who had macrovascular invasion, 69 patients with extrahepatic spread, and 3 patients with Child-Pugh score of greater than B8, 192 patients remained after that. Considering that short duration of exposure to sorafenib might impact the judgment of adverse events and the efficacy of combination treatment, 47 patients who were treated with sorafenib for less than 8 weeks were also excluded to rule out the potential time-dependent bias [25, 26]. And then 13 patients were additionally excluded for the interval time of > 60 days between the beginning of sorafenib treatment and the first TACE procedure. Finally, present study included 132 treatment naive patients with unresectable HCC treated by combination therapy of TACE and sorafenib with more than 8-week sorafenib administration. The study protocol conformed to the ethical guidelines of the 1975 declaration of Helsinki and was approved by the ethics committee of Xijing Hospital (Xi’an, China). A written informed consent about receiving treatment and providing their clinical data in following studies was given by all patients before receiving combination therapy according to the institutional guidelines.

Before the TACE procedure, digital subtraction angiography (DSA) of the hepatic artery was performed to assess the vascular anatomy and tumor vascularity. Hypervascular lesions were confirmed by two independent radiologists based on these characteristics: (1) tumor staining obviously; (2) vessels dilated and tortuous; (3) venous pooling; (4) “holding ball” sign; (5) clear boundary of the lesion. Otherwise were considered hypovascular. During the operation, tumor-feeding vessels were selected/super-selected whenever possible, and then infused by a mixture of lipiodol (2–20 mL) and doxorubicin (10–50 mg), followed by an embolization with gelatin sponge particles. The infusion continued until a stagnant flow was observed in the feeding vessels. After TACE procedure, lipiodol retention in DSA further verified the hypervascularity of the lesion. Tumor response was evaluated every 4–6 weeks with dynamic liver CT or magnetic resonance (MR) imaging, along with chest CT and/or bone scanning if applicable, according to the modified response evaluation criteria in solid tumors (mRECIST). For patients with residual viable lesions or local and/or distant intrahepatic recurrences over follow-up, on-demand repeated TACE sessions were carried out; and the TACE therapy was discontinued under the condition of liver function deterioration (Child-Pugh score more than 8), performance status worsening (ECOG score more than 2) and disease progression according to imaging assessments. As for the initiation of sorafenib, there were 74 (56.1%) patients initiating sorafenib before first TACE, while the remaining 58 (43.9%) patients received sorafenib after TACE. The median time interval between the initiation of TACE and sorafenib was − 2 (interquartile range [IQR] -3 to 3.25) days. Sorafenib was administered to the patients at a dosage of 400 mg twice daily without any planned interruption during TACE procedure. Despite does modification based on the presence of adverse events, patients were still encouraged to continue the sorafenib treatment if the toxicity was manageable. In this study, the prevention of sorafenib side effects is not applied; however, when the side effects reached severe or affect life quality, the patients would receive relevant treatment. Grade of adverse events were prospectively defined according to the national cancer institute common terminology criteria for adverse events (NCI-CTCAE) version 3.0. According to our previous studies, the development of a HFSR ≥ grade 2 within 60 days after sorafenib initiation as the optimal criterion to best discriminate responders with improved survival [31]; therefore, this study focused on this kind of AE. After the disease progression, combining therapy was used to these patients still in intermediated stage and sorafenib alone was recommended to those progressing to advanced stage.

The baseline demographic and clinical characteristics of patients are shown in Table 1. Among the 132 eligible patients, 112 patients (84.8%) were male with a mean age of 53 years; hepatitis B virus (HBV) was the most common underlying cause of liver disease (82.6%). There were 75 patients (56.8%) diagnosed at BCLC B stage, while 47 patients (35.6%) belonged to BCLC C stage only because of ECOG performance status of 1. 124 patients (93.9%) were in the Child-Pugh A class, and 15 patients had ascites. None of the 8 patients who were classified in the Child-Pugh B class had clinically overt jaundice or hepatic encephalopathy. The median diameter of the largest measurable lesion was 7.1 cm (IQR 5.2–9.8), and 69 patients (52.3%) had single lesion. The median number of TACE sessions was 3 (IQR, 1–4), and 24.2, 22.7, and 25.8% of the patients received 1, 2, or 3 TACE treatments, respectively. Eighty-nine patients (67.4%) received sorafenib treatment before TACE and 43 patients (32.6%) began sorafenib after TACE. For sorafenib therapy, the median duration of its administration was 16.5 (IQR 9.5–26.7) months. There were 23 (17.4%) patients with sorafenib dose reductions due to adverse events, and 32 (24.2%) patients with temporary dose interruptions occurred (17 for AEs, 11 for impairments in general condition or liver function and 4 for other non-disease-related reasons). Finally, 36 (27.3%) patients discontinued the sorafenib treatment because of disease progression (n = 12), deterioration of their liver function (n = 19) or other reasons (n = 5). None of the included patients permanently stopped sorafenib therapy owing to adverse events. For the whole cohort, the median TTP and OS reached 7.3 months and 21.4 months, respectively.

Among the whole cohort, tumors of 99 patients (75.0%) were stained obviously in DSA. Majority (122, 92.4%) of tumor feeding vessels were dilated and tortuous. The venous pooling and “holding ball” sign were found in 56 (42.4%) and 65 patients (49.2%), respectively. Clear tumor boundary was seen in 87 patients (65.9%), and finally 88 patients (66.7%) with homogeneous lipiodol retention were confirmed as those with hypervascularity (Additional file 1: Figure S1). In 131 patients with at least once imaging evaluation, the median time to evaluate initial response was 31 (IQR 27–35) days following first TACE treatment. Regarding the early imaging response, the complete response (CR), partial response (PR), stable disease (SD), and progression disease (PD) were in 39 (29.8%), 32 (24.4%), 46 (35.1%) and 14 (10.7%) patients, respectively, with an object response rate (CR and PR) of 54.2% (Fig. 1). Mann-Whitney analysis showed that hypervascular lesions responded better than hypovascular ones to combination treatment of TACE and sorafenib (U = 842.0, p < 0.001). Besides, patients with hypervascular tumors benefit more in TTP (10.2 vs 3.7 months, HR 0.38, p < 0.001) and OS (25.1 vs 15.0 month, HR 0.50, P = 0.002) than those with hypovascular lesions (Fig. 2 a and b).

Overall, 123 patients (93.2%) presented at least one adverse event during that time. The most common sorafenib-related adverse events were HFSR (107, 81.1%), alopecia (96, 72.7%), and rash (63, 47.7%). Nevertheless, majority of them were mild (62.8%) or moderate (27.8%) (Additional file 2: Table S1). For HFSR, more than half of them were severe or moderate and considered as clinical significant HFSR. In addition, 93.5% of the clinically significant HFSR appeared within 60 days after the sorafenib initiation. According to our previous definition, the development of ≥2 grade of HFSR within 60 days of sorafenib initiation as HFSR-response were observed in 72 patients, and otherwise as HFSR-nonresponse in 60 patients. Besides, patients with HFSR-response were superior to those with HFSR-nonresponse in TTP (9.1 vs 5.4 months, HR 0.63, p = 0.018) and OS (25.1 vs 15.0 month, HR 0.56, P = 0.004) (Fig. 3 a and b).

Hypervascularity and the HFSR-response were favorable predictors for combination therapy, which divided patients into four distinct groups: group A included patients with both hypervascularity and HFSR-response (52 patients); group B represented patients with hypervascularity but HFSR-nonresponse (36 patients); group C included patients with hypovascularity but HFSR-response (20 patients); group D consisted of those with hypovascularity and HFSR-nonresponse (24 patients). Median TTP of group A, B, C and D were 12.2, 7.8, 4.9 and 2.9 months, respectively; and median OS of them were 29.1, 16.5, 15.9 and 11.9 months (Fig. 4 a and b). Because of the similarity in TTP and OS (p = 0.066 and p = 0.794), patients of group B and group C comprised a same stratification, group BC. Median TTP and OS of such group BC (patients with either hypervascularity or HFSR-respond) were 6.0 and 16.5 months, which were better than group D (patients with hypovascularity and HFSR-nonresponse) of 2.9 months in TTP (HR 1.99, p = 0.009) and 11.9 in OS (HR 1.85, p = 0.024). Group A of patients (with both hypervascularity and HFSR-response) achieved median TTP of 12.2 months and OS of 29.1 months, which were better than those of group BC (HR 1.74, p = 0.012; HR 1.73, p = 0.021) (Fig. 4 C and D).

Although the vascularity, HFSR-response, and the stratification based on them were significant predictors for TTP and OS, they hadn’t yet adjusted by other prognostic factors in multivariate analysis. Consequently, vascularity and HFSR-response, as well as the stratification, were included in four different multivariate analysis of TTP and OS (Table 2 and Table 3). The univariate analysis showed that the prognostic factors for TTP were tumor size ≥7 cm (HR 1.65, p = 0.011), hypovascularity (HR 2.64, p < 0.001) and HFSR-nonresponse (HR 1.59, p = 0.018), and they remained significant in multivariate analysis (HR 1.90, p = 0.001; HR 2.81, p < 0.001; HR 1.50, p = 0.043). Multivariate analysis for OS indicated AST ≥ 40 U/L (HR 1.86, p = 0.006), Child-Pugh score (HR 1.90, p = 0.012), multiple lesions (HR 1.75, p = 0.012), hypovascularity (HR 2.10, p = 0.001) and HFSR-nonresponse (HR 1.96, p = 0.002) were independent risk factors. When tumor vascularity and HFSR-response were replaced with the stratification in another two multivariate analyses, group A patients still survived group BC and group D obviously (HR 1.91, p = 0.010; HR 4.15, p < 0.001), and remained better in TTP (HR 1.87, p = 0.005; HR 4.11, p < 0.001).