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

This cohort study was approved by the Local Ethics Committee of West China Hospital, Sichuan University. A written informed consent was obtained from each patient after being informed of the purpose and investigational nature of the present study. This study was conducted according to the Declaration of Helsinki, and strictly adhered to the CONSORT guidelines. Participants were recruited from June 2014 to November 2016. Patients were stratified into two groups according to their willingness (Fig. 1). These patients were followed up until the date of analysis in January 2017. Among these patients, 31 patients received TACE plus intraarterial ethanol embolization (treatment group), while 57 patients received TACE only (control group).

All these patients were preoperatively evaluated by abdominal ultrasonography and thoracoabdominal dynamic computer tomography (CT)/magnetic resonance imaging (MRI), while some patients underwent abdominal angiography. The extent of the tumor thrombus to the portal vein was accurately assessed through these imaging techniques.

All TACE and intra-arterial ethanol embolization procedures were performed by two operators using the same angiographic system (Allura Xper FD20, Philips Healthcare). Prophylactic antibiotic treatment was not given. The treatment procedure was performed under local anesthesia with 3–5 mL of 1% lidocaine (Lidocaine Hydrochloride Injection, Taiji, Chongqing, China) administered at the groin, and started with hepatic arteriography to identify the tumor. Intra-arterial ethanol embolization procedures were performed using a 2-F tip microcatheter (Progreat α; Terumo Clinical Supply, Gifu, Japan) through a 4F catheter, in order to identify the potential PVTT-feeding artery under digital subtraction angiography (DSA). Furthermore, an angiographic unit with a 38 × 30 cm² flat panel detector (FPD) was used to obtain CACT images and confirm the PVTT-feeding artery. For each CACT scan, 312 projection images with X-ray parameters of 120 kV and 200-300 mAs were acquired with the motorized C-arm, covering a 200° clockwise arc at a rotation speed of 20° per second. Then, 6-20 mL of contrast material (370 mg I/mL; Omnipaque, Bracco-Sine, Shanghai, China) were injected under 100-300 MPa over 6-10 s with a 2-s delay. After confirmation of the PVTT-feeding artery and before delivery of the ethiodized oil–ethanol solution, 1 mL of 1% lidocaine was instilled intra-arterially through the microcatheter at each site of the solution administration for pain control. Lipiodol-ethanol mixture (1:1 ratio by volume up to 15 mL) was injected at a rate of 0.5-1 ml/min until the PVTT-feeding artery was nearly occluded, followed by embolization with 0.2-0.5-mm gelatin-sponge particles (Gelfoam; Fukangseng, Guilin, China) using a three-way stopcock valve and two 2.5-mL syringes. The agents were delivered under fluoroscopic control until the vasculature of all tumors was entirely filed, as shown by the fluoroscopic evidence of intraarterial flow stasis or until the maximum dose was reached. In case of acute severe abdominal pain, the procedure was temporarily suspended or stopped.

It was observed that repeating the treatment at 3-4 weeks after the first treatment was often necessary to achieve good results, since achieving complete intra-arterial ethanol embolization in a single session was difficult in most patients. Further treatment sessions were administered when there was CT evidence of residual tumors or occurrence of new hepatic tumors. There was no limit on the total number of treatment sessions.

Intra-arterial embolization was performed in most patients to treat the PVTT-feeding artery. The lipiodol-ethanol mixture was slowly injected in the feeding-artery, followed by a gelatin sponge mixed with contrast material. If the patient experienced acute intense pain, further injection was stopped or delayed. Two advantages of using a gelatin sponge were observed. First, it avoids lipiodol-ethanol mixture regurgitation, and decreases the rate of cholecystitis and bile leakage. Second, it stays within the target tissue for a long time and at a higher concentration, accounting for better lipiodol deposition on post-procedure CT scan. Then, an epirubicin-lipiodol mixture was injected into the intrahepatic lesions through TACE with a mixture of lipiodol (10 ml) and epirubicin (50 mg; Pfizer, Wuxi, China), followed by a gelatin sponge mixed with contrast material, until the vasculature of all tumors was entirely filed, as shown by fluoroscopic evidence of intra-arterial flow stasis.

Some patients with PVTT had several small tortuous feeding-arteries (Fig. 2, A1-A3). Hence, it was difficult to directly insert the microcatheter into the feeding-artery due to anatomical variations in its location. In our technique, for this type of PVTT, TACE was first performed in intrahepatic lesions until stasis distal to small tortuous feeding arteries. Then, the lipiodol-ethanol mixture was injected in the nearby PVTT-feeding artery, followed by a gelatin sponge. Throught this method, high concentrations of lipiodol-ethanol mixture flowing through the PVTT-feeding artery could be achieved.

In patients with large arteriovenous fistulas, after measuring the diameter of the vessel, the distal outflow vessel was embolized using a larger diameter gelatin sponge before injecting the lipiodol-ethanol mixture (Fig. 2, B1-B3), avoiding the mixture from flowing out too fast. This helped to maintain the high lipiodol-ethanol mixture concentration in the feeding-artery for a longer time, providing enough time for diffusion to the PVTT.

TACE with a mixture of lipiodol and epirubicin (50 mg of epirubicin; Pfizer, Wuxi, China) was performed for intrahepatic lesions, followed by gelatin-sponge embolization under DSA without CACT scan. Before the catheter was removed from the artery, diluted heparin was injected (50 IU/ml, 10 ml).

Primary outcomes were the overall response of PVTT to therapy and OS. Adverse events were considered as secondary outcomes. The latest version of the Response Evaluation Criteria In Solid Tumors (RECIST) guidelines (version 1.1) were used to assess the tumor response of intrahepatic lesions to therapy [17]. Considering that the tissue organization of postoperative residual thrombi without viability can be persistent for months or years, and that PVTT is always accompanied by benign thrombus [18], the investigators decided not to adopt the RECIST guidelines in assessing the efficiency on PVTT. Therefore, the following four grades were proposed to classify PVTT response to therapy: grade 3, recanalization of the portal vein trunk or, right or left portal vein; grade 2, decreased PVTT diameter without recanalization of any branch of the portal vein; grade 1, neither shrinkage to qualify for grade 2 nor increase to qualify for grade 0; grade 0, PVTT diameter increased by 20%. Regression of PVTT to grade3/grade2 and complete/partial response of intrahepatic lesions based on the modified RECIST criteria were considered as significant responses to interventional therapy. At 2-7 days after the procedure, CT scan revealed lipiodol deposits within PVTT (Fig. 3, C1-D1). Enhanced CT/MRI images, which were evaluated by two experienced radiologists, were repeated at 4 weeks after the procedure, in order to assess the response. OS was defined as the period from the date of first treatment to the date of death, or censorship at the date of last follow-up if the patient is still alive. Repeated TACE was performed if lesion diameter increased or new lesions were found. Repeated intra-arterial ethanol embolization was suspended if PVTT diameters did not increase, or complete embolization of the visible PVTT-feeding artery was achieved.

Continuous baseline characteristic variables were compared by Student t-test, ranked data was compared by rank-sum test, and categorical variables were compared by χ ² -test. Survival curves were estimated using the Kaplan-Meier method. Data were analyzed with SPSS version 20.0 (SPSS Inc., Chicago, IL, USA). All statistical tests used were two-sided, and P < 0.05 was considered statistically significant.

In the treatment group, the mean age of patients (n = 31) was 54.3 ± 11.9 years old. These patients received TACE with 50 mg of epirubicin dissolved in 10 ml of lipiodol for intrahepatic lesions combined with intra-arterial ethanol embolization (alcohol/lipiodol, 7.8 ± 3.9 ml) for PVTT (Fig. 3). In the control group, the mean age patients (n = 57) was 54.2 ± 13.4 years old. These patients received TACE with 50 mg epirubicin alone (Table 1). The mean course of procedures in the treatment and control groups was 2.4 ± 1.7 and 1.9 ± 1.0, respectively (P = 0.18). Results related to the end-points of the present study are summarized in Table 2.

Thirty-eight patients died during follow-up: 14 patients in the treatment group and 24 patients in the control group. Median survival was 10.5 months and mean survival was 11.5 ± 8.5 months (95% CI: 8.6-15.3) in the treatment group, while median survival was 3.8 months and mean survival was 5.0 ± 4.0 months (95% CI: 4-6) in the control group (Fig. 4). Probabilities of survival at 3, 6 and 12 months were significantly higher in the treatment group than in the control group (90.3% vs. 59.6%, 64.5% vs. 29.8%, and 41.9% vs. 10.6%) (P = 0.001, Table 2). The mean survival of patients classified as Vp3 and Vp4 in the treatment and control group was 16.4 ± 10.8 vs. 9.2 ± 6.1 (P = 0.004) and 5.9 ± 4.7 vs. 4.3 ± 3.7 (P < 0.001). The mean survival of patients classified as Child-Pugh A and Child-Pugh B in the treatment and control groups was 13.2 ± 12.6 vs. 4.0 ± 3.0 (P < 0.001) and 11.0 ± 9.4 vs. 5.2 ± 4.4 (P = 0.003), respectively.

Ninety complications occurred in the treatment group, while 125 complications occurred in the control group. The duration of the procedure was significantly longer in the treatment group than in the control group (1.9 ± 0.6 h vs. 0.6 ± 0.2 h, respectively; P < 0.001). No treatment-related death, pulmonary embolism, renal damage, renal failure, respiratory failure, cholecystitis, or cholangitis were observed during follow-up in both groups. The other main adverse events are presented in Table 3.

Complete response/partial response/stable/progressive disease of intrahepatic lesions at 1 month was observed in 7%, 31%, 41.3% and 20.7% of patients in the treatment group, compared to 11.3%, 9.4%, 66.1%, and 13.2% of patients in the control group, respectively (P = 0.61, Table 2). PVTT radiographic response rate to therapy was significantly higher in the treatment group (37.9%), compared with the control group (13.2%) (P < 0.001, Table 2).

The main limitations of the present study are small sample size, non-randomized controls, relatively short follow-up, and a single center experience. Therefore, performing prospective randomized studies are warranted to confirm these results. Any new treatment should ideally be compared with the reference standard for the disease at that stage. The evidence based standard of care for locally advanced HCC is sorafenib. However, few Chinese people able to bear the high cost, especially in developing countries [31]. Moreover, there is no standard treatment for patients with treatment failure with sorafenib. A recent study [32] demonstrated that patients with PVTT (Vp3), who received TACE or sorafenib, had a poor 1-year OS (35.7 vs. 26.5 months). Hence, for this group of patients, we propose TACE treatment. Although, there was no statistical significance between the compared groups in terms of treatment courses, more number of courses of repeated TACE in HCC provided better results in the treatment group. Clearly, a higher proportion of Child-Pugh A patients in the treatment group may contribute to explain the longer OS.