Intra-arterial ethanol embolization augments response to TACE for treatment of HCC with portal venous tumor thrombus

Hepatocellular carcinoma (HCC) is the fifth most frequently diagnosed cancer worldwide and the third most frequent cause of cancer death [1, 2]. Unfortunately, HCC has a propensity to invade the portal vein and cause portal vein tumor thrombus (PVTT) [3], and this can be detected in 30-62% of patients with HCC [4]. PVTT is considered as an adverse prognosis factor [3]. Although liver resection and liver transplantation are accepted as the only potential curative treatment for HCC patients, HCC with PVTT has been considered a contraindication to surgery due to poor prognosis and high surgical risk [5]. Both percutaneous ethanol injection (PEI) and radiofrequency ablation have not been shown to improve survival in cases of HCC with neoplastic involvement of major branches of the portal vein or main portal trunk (Vp3/Vp4), and median survival ranged from 2.4 to 4.8 months [6]. For patients with PVTT, sorafenib is suggested as the standard therapy of care in the Barcelona Clinic Liver Cancer (BCLC) staging system [7, 8]. However, the median overall survival (OS) gain with sorafenib is 5.6 months, and better treatment modalities are clearly required [9]. Yamada et al. [10] performed TACE in nine patients with PVTT (Vp4), and 1-month mortality was 55.5%. Among those patients, 33% of patients died of hepatic insufficiency. Based on this study, they concluded that TACE was contraindicated in HCC patients with PVTT (Vp4). Recently, two studies have indicated that transarterial chemoembolization (TACE) could be safely performed in such patients with no increase in morbidity or mortality [11, 12]. Most importantly, all methods described in these studies are targeting intrahepatic lesions, and none of these focused on treating PVTT itself. In addition to treating intrahepatic lesions, it is our hypothesis that a therapeutic approach including the treatment of the portal vein thrombus itself could provide benefits in terms of OS.

Ethanol can produce an embolization effect by causing endothelial damage and thrombus of the arteriolar lumen of tumor feeder vessels and tumor vasculature, thereby leading to tumor infarction [13]. Intra-arterial lipiodol-ethanol mixture embolization has been shown to be effective for treating HCC [14, 15]. Si et al. [16] revealed that the feeding vessels of PVTT are complex. However, in their study, 92.3% of PVTT had the same blood supply characteristics as intrahepatic lesions, indicating that most nutrient vessels of PVTT correspond to liver arteries. C-arm cone beam computed tomography (CACT) angiography could be helpful to identify the PVTT-feeding artery and embolize the PVTT by lipiodol-ethanol mixture. In addition, CACT provides a good method for evaluating iodized oil deposition during the procedure. Based on these data, we considered that intraarterial ethanol embolization for PVTT could be feasible and effective. In the present study, we present a new lipiodol-ethanol mixture technique, wherein, intraarterial ethanol embolization and TACE are combined to treat HCC patients with PVTT (Vp3/Vp4).

PVTT is an independent prognostic factor for patients with HCC. The reported median survival for untreated HCC patients with PVTT (Vp3/Vp4) was 2.7 months, whereas survival in patients without PVTT was 24.4 months [3]. Intra-arterial ethanol embolization has been used in HCC cases in a similar approach to TACE, which has exhibited a higher 1-year OS rate (93.3% vs. 73.3%) and greater lipiodol retention (89.5% vs. 47.5%); but its specific impact on PVTT has not been previously studied [19]. The present study demonstrated that our therapeutic approach may be more effective than TACE in HCC patients with PVTT (Vp3/Vp4). The percentage of patients with more than three nodes or diffused tumors, or huge tumors in the treatment group was higher than in the control group. This selection bias may be due to the patient’s decision, and may have lessened the possibility to evaluate the advantages in the treatment group. Despite this limitation, there was a significant trend toward OS improvement vs. the control group. We found that occluding the arterial supply to PVTT with the help of intraarterial ethanol embolization not only resulted in the recanalization of the portal vein, but also significantly improved survival in this patient group. In the treatment group, patients had more complications compared with those in the control group, which was possibly correlated to the destruction of the PVTT-feeding artery induced by ethanol. The potential risk of thrombus at the infusion port was higher due to longer procedure time in the treatment group. This is why some blood was extracted from both the infusion port and connected catheter before removing the needle from the infusion port, followed by flushing with diluted heparin. The duration of post-procedure abdominal pain was longer in the treatment group than in the control group, which was possibly due to the ethanol itself.

Yamada et al. [10] first reported that HCC patients with Vp3/Vp4 PVTT treated with TACE had a 28.6% 1-year survival rate. Recently, Chung et al. [20] reported a 30% 1-year survival rate and 28.2% PVTT response rate. Georgiades et al. [12] and Takayasu et al. [21] reported a 25% and 35% 1-year survival rate, respectively. Peng et al. [11] reported that PVTT had a 36.1% 1-year survival rate. In contrast, in the present study, the 1-year survival rate was 41.9% for patients in the treatment group vs. 10.6% for patients in the control group, which show that patients in the treatment group had a higher OS rate than those reported in literature [11, 12]. In the present study, PVTT response rate was higher than those were reported by Yamada et al. [10]. Percutaneous ethanol injection has been reported to be efficient for treating PVTT on the basis that ethanol is diffused within cells [22]. Nevertheless, ethanol in PEI is limited both in terms of diffusion and of adapting the ethanol dose. In contrast, intra-arterial ethanol embolization, a method based on the infusion of ethanol into the artery, can achieve a more efficient diffusion without damaging the normal liver parenchyma, and allows the ethanol dose to be easier controlled according to the pain degree of the patient or the distribution of ethanol.

Diagnosing PVTT remains difficult. Percutaneous puncture biopsy is invasive, and is associated with a high risk of tumor seeding along the needle track. Color Doppler sonography (CDS) has been widely used with the method of pulsatile flow. PVTT has been diagnosed in approximately 62% of patients using the presence of a pulsatile flow as its diagnostic criterion [23]. DSA together with CACT combines the advantages of DSA and contrast-enhanced CT, which can provide slice imaging and dynamic flow information. Wallace et al. [24] reported that 60% of CACT images contain information that were not found in DSA, and influenced the treatment procedure in 19% of cases. CACT detects HCC with greater accuracy and sensitivity than both DSA and CT [25]. In addition, CACT data sets can be viewed in three-dimension and slice-images. These information provides a more effective therapy by delivering an increased amount of lipiodol-ethanol mixture to the target, while sparing uninvolved parenchyma exposure from toxic agents such as the gallbladder.

In an animal experiment carried out by Kan et al. [13] and the use of absolute ethanol, the endothelial cell was denuded from the vascular wall, its protoplasm precipitated and a fracture in the vascular wall to the level of the internal elastic lamina was formed, followed by the shrinking of lesions. Hence, ethanol has been widely used for vascular malformations [16]. Ethanol is a better embolic agent than lipiodol, and can lead to vascular endothelial destruction. However, ethanol is not radio-opaque, and its flow and speed are difficult to visualize. In contrast, lipiodol-ethanol mixture (in a 1:1 ratio) is visible during injection. At the same time, it maintains the potency of absolute ethanol in the target vasculature, and is not diluted by aqueous solutions; which are necessary to avoid regurgitation and ectopic embolization [15]. From the fluoroscopic observation on an animal model, dual embolization could be induced by the slow infusion of an insoluble substance such as the lipiodol-ethanol mixture, which appears as small droplets passing through the hepatic sinusoids and to the portal vein [14]. This achieves complete embolization in both arteries that supply the tumor and its adjacent parenchymal portal veins [14]. The long-lasting embolization of both the arterioles and portal venules is highly effective in causing infarction of the whole tumor including the tumor border, which is commonly supplied by portal venules [26]. The treatment group, unlike a gelatin sponge, not only induces tumor ischemia and hypoxia, but also diffuses within tumor cells [15, 27, 28]. Ischemia and hypoxia may be potent stimulators of angiogenesis and carcinogenesis, which promote collateral circulation and the restoration of tumor blood supply; and these may eventually lead to tumor proliferation and recurrence [29, 30].

Although intra-arterial ethanol embolization combined with TACE does not represent a cure for HCC with PVTT, the principal goals of significant safety, effectiveness and OS could be achieved. In the present pilot study, considering the higher survival rate for TACE plus intra-arterial ethanol embolization compared with TACE alone, this therapeutic approach may be the treatment of choice for HCC patients with PVTT (Vp3/Vp4). However further prospective studies are needed to confirm the present data.