This was a single-center, open-label, prospective, randomized controlled trial conducted between December 2013 and September 2017 with follow-up until November 2018. The study totally included 117 patients aged ≥ 18 years with histologically or clinically diagnosed advanced HCC with portal vein invasion or extrahepatic metastasis (BCLC stage C). Clinical diagnosis of HCC was based on the American Association for the Study of Liver Diseases guideline criteria[29]. Eligible patients were also required to have Child-Pugh class A or B liver function, an Eastern Cooperative Oncology Group performance status of 0 to 1, at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, life expectancy ≥ 12 wk, adequate organ function (hemoglobin ≥ 90 g/L, white blood cell count ≥ 3.0 × 10⁹/L, absolute neutrophil count ≥ 1.5 × 10⁹/L, platelet count ≥ 60 × 10⁹/L, serum albumin level > 20 g/L, aspartate transaminase and alanine transaminase < 5 times the upper limit of normal, total bilirubin serum levels < 3 times the upper limit of normal, creatinine clearance rate ≤ 1.5 times the upper limit of normal, and international normalized ratio < 2.3 or partial prothrombin time < 1.5 times the upper limit of normal), and not previously received TACE, HAIC or chemotherapy. Key exclusion criteria were early- or middle-stage HCC, any contraindication to TACE (poor liver function, portal obstruction of at least three segmental branches), advanced cardiac or pulmonary disease and severe renal function impairment, a known medical history of human immunodeficiency virus infection, other invasive malignant diseases and pregnant or breastfeeding women. All recruited patients with hepatitis B virus-related HCC received pre-emptive antiviral therapy.

Written, informed consent was obtained from all participants before entering the study. The clinical trial protocol was approved by the Ethics Committee of our hospital, and the trial was conducted according to Good Clinical Practice guidelines and the Declaration of Helsinki.

Participants were randomized 1:1 to receive TACE followed by oxaliplatin-based HAIC plus oral S-1 (TACE/HAIC + S-1) or TACE followed by oxaliplatin-based HAIC (TACE/HAIC). Random assignment was generated by a statistician from our hospital via a computer-generated randomization sequence and without stratification. Treatments were applied every 6 wk until disease progression, death or intolerable toxicity was observed.

Each patient underwent angiography via the femoral artery using Seldinger’s technique. Arteriography was routinely performed to collect information about the number, type and location of the tumors and feeding arteries, as well as the presence of vascular anatomic variations. After visualization of the arterial distribution and the portal system in the reflux phase for each individual patient, the most appropriate TACE procedure was selected. The feeding arteries to the lesion were catheterized as selectively as possible by using a highly flexible coaxial catheter (Renegade Hi Flo, Boston Scientific, Boston, MA, United States/Stride ASAHI INTECC, Seto, Japan). The chemoembolization procedure comprised injection of iodized oil (Lipiodol; Laboratoire Andre Guerbet, Aulnay-sous-Bois, France) mixed with 20–40 mg epirubicin hydrochloride (Main Luck Pharmaceutical, Shenzhen, China) as an emulsion into segmental or subsegmental tumor-feeding arteries. For patients with a hepatic arteriovenous fistula, sponge particles (Jinling, Nanjing, China) were used to block the fistula before the infusion of iodized oil.

HAIC was performed via a catheter. The coaxial catheter was retained in the proper hepatic artery or the left or right hepatic arterial branch following TACE. Oxaliplatin (Eloxatin^®; Sanofi S.A., Paris, France) 85 mg/m² was continuously infused over 4 hours via arterial pumping on day 1. After HAIC was completed, the catheter and sheath were removed. Repeated catheterization was performed in the next treatment cycle.

S-1 (TS-1^®; Taiho Pharmaceutical, Tokyo, Japan) 60 mg was given orally twice daily on days 2–15, initiated from the 2^nd d after HAIC, and then patients were allowed to rest for 1 wk. Depending on the TACE and HAIC interval, every 3 wk constituted a course.

The primary endpoint was initially designed to be time-to-progression (TTP). However, during the study a large proportion of patients died from liver function failure before tumor progression occurred and not enough progression events were observed for a meaningful estimate of TTP. Therefore, the primary endpoint was changed to progression-free survival (PFS). Progression was defined as progressive disease by an independent radiologic review according to modified RECIST or death from any cause. PFS was defined as the interval between the first TACE treatment and progression or death resulting from any cause.

Secondary endpoints included overall survival (OS), tumor objective response rate (ORR) defined as the proportion of patients achieving a complete (CR) or partial response (PR), disease control rate (DCR) defined as the proportion of patients achieving CR, PR or stable disease (SD) and safety. OS was defined as the interval between the first TACE treatment and death or final follow-up. All tumor response rates were evaluated according to modified RECIST criteria. Adverse reactions were evaluated and graded according to the National Cancer Institute Common Toxicity Criteria (version 4.0). Peripheral neuropathy was graded according to a modified Levi scale.

Physical, clinical, enhanced computed tomography or magnetic resonance imaging and laboratory tests were performed at baseline and at the start of each treatment cycle during the treatment phase. All patients were followed every 2 mo until death or until their final follow-up visit.

The study sample size was calculated based on the assumption that the median TTP in patients with advanced HCC receiving TACE followed by HAIC would be 4.0 mo and that adding S-1 would improve the median TTP to 6.5 mo. To detect this difference with 70% power and a 2-sided α of 0.05, 100 participants would be required, with an enrollment period of 24 mo and a follow-up period of 12 mo. Based on an estimated dropout rate of 5%, the target enrollment was set at 110 participants (55 per group).

For all statistical tests, P values < 0.05 were considered significant. Depending on data normality, two-independent-samples t tests or Mann-Whitney U tests were used to assess differences in continuous variables between the groups. The χ² test was used to assess between group differences in categorical variables. Tumor response rates were compared using the two-sided Fisher’s exact test. The Kaplan-Meier method was used to calculate estimates of PFS and OS, and data were compared using the log-rank test.

Exploratory univariate and multivariate analyses were conducted to investigate the association between patient demographic and baseline characteristics and survival outcomes (PFS and OS). Any factors that were statistically significant at a P value < 0.10 in the univariate analysis were candidates for entry into the multivariate model. All statistical analyses were performed using SPSS software (version 22; IBM SPSS Statistics, Armonk, NY, United States). The statistical methods of this study were reviewed by Xiao-Ting Li from our hospital.

Between December 2013 and September 2017, 230 patients were screened, and 117 were randomly assigned to TACE/HAIC + S-1 (n = 56) or TACE/HAIC (n = 61) (Figure 1). Two participants withdrew consent before receiving treatment (one patient in each treatment group) and were therefore excluded from final analysis. Baseline characteristics were comparable between the two treatment groups (Table 1). Overall, participants were predominantly male and infected with HBV, and all participants had portal vein invasion or extrahepatic metastasis; 76/115 (66.1%) patients had portal vein invasion, 79/115 (68.7%) patients had extrahepatic metastasis and 40/115 (34.8%) patients had both portal vein invasion and extrahepatic metastasis. Extrahepatic metastasis sites included retroperitoneal lymph nodes (50 patients), lungs (18 patients), adrenal glands (10 patients), bones (8 patients) and other sites (6 patients). Ten patients had at least two sites of extrahepatic metastases.

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Figure 1 CONSORT flow diagram. TACE: Transarterial chemoembolization; HAIC: Hepatic arterial infusion chemotherapy.

The total number of cycles of treatment received was 150 and 163 for patients in the TACE/HAIC + S-1 and TACE/HAIC groups, respectively. Patients in both groups received a median of two cycles (1−9cycles) of TACE and HAIC. Curative surgical resection was conducted for 1/55 (1.8%) patient in the TACE/HAIC + S-1 group and 2/60 (3.3%) patients in the TACE/HAIC group following downstaging. TACE combined with local ablation was conducted for 8/55 (14.5%) patients in the TACE/HAIC + S-1 group and 9/60 (15.0%) patients in the TACE/HAIC group. TACE combined with radioactive particle implantation was conducted for 1/60 (1.7%) patient in the TACE/HAIC group.

Numerically higher ORR and DCR were observed for patients receiving TACE/HAIC + S-1 than those receiving TACE/HAIC (30.9% vs 18.4%, P = 0.176 and 72.7% vs 56.7%, P = 0.109, respectively). Rates of CR, PR, SD and progressive disease in the TACE/HAIC + S-1 group were 7.3%, 23.6%, 41.8%, 27.3%, respectively, and in the TACE/HAIC group were 6.7%, 11.7%, 38.3%, 43.3%, respectively (Table 2).

After a median follow-up period of 8.3 mo (0.4–58.6 mo), the median PFS for patients receiving TACE/HAIC + S-1 and TACE/HAIC was similar: 5.0 mo (0.4−58.6 mo; 95% confidence interval (CI): 3.82 to 6.18) and 4.4 mo (1.1−54.4 mo; 95%CI: 2.50 to 6.30) (P = 0.585) (Figure 2A). The median OS was also similar between the two groups: 8.4 mo (0.4−58.6 mo; 95%CI: 7.03 to 9.76) and 8.3 mo (1.4−54.4 mo; 95%CI: 6.00 to 10.60) (P = 0.985), respectively (Figure 2B). The PFS rates at 3, 6, 9 and 12 mo were 67.3%, 41.8%, 23.6% and 19.7%, respectively, in the TACE/HAIC + S-1 group and 65.0%, 41.7%, 18.7% and 11.2%, respectively, in the TACE/HAIC group. The OS rates at 3, 6, 9 and 12 mo were 85.5%, 63.6%, 41.8% and 32.5%, respectively, in the TACE/HAIC + S-1 group and 83.1%, 64.5%, 45.3% and 36.6%, respectively, in the TACE/HAIC group.

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Figure 2 Kaplan-Meier curves. A: Curves of progression-free survival; B: Curves of overall survival. Group A indicates hepatic arterial infusion chemotherapy after transarterial chemoembolization plus S-1. Group B indicates hepatic arterial infusion chemotherapy after transarterial chemoembolization. HR: Hazard ratio.

By the last follow-up, 20 patients were alive (9 patients in the TACE/HAIC + S-1 group and 11 patients in the TACE/HAIC group). In the TACE/HAIC + S-1 group, 3 patients received other treatments after progression, 3 patients were lost to follow-up, and 3 patients achieved a CR. In the TACE/HAIC group, 3 patients received sorafenib, 2 received other treatments after progression, 2 patients were lost to follow-up, 3 patients achieved a CR and 1 patient achieved a PR.

Univariable and multivariable Cox regression analyses (Table 3 and Table 4) showed that the number of tumors and gamma-glutamyl transferase were predictive factors for PFS, and the number of tumors, gamma-glutamyl transferase and the tumor response were predictive factors for OS. However, age, sex, tumor size, portal vein invasion, extrahepatic metastasis, S-1 treatment and target treatment showed no significance as predictive factors.

In both treatment groups the most common AEs were transient liver injury (including elevation of serum liver enzymes and bilirubin), vomiting, abdominal nonspecific pain and fever (Table 5). Abdominal pain occurred frequently during HAIC and 2–3 d after TACE. This pain was adequately controlled by temporarily stopping the infusion of oxaliplatin or by the application of analgesics. Hematologic AEs observed included leukopenia, thrombocytopenia and anemia, and rates of theses AEs were also similar between the two treatment groups. One patient in the TACE/HAIC group experienced cerebral lipiodol embolism, however, they recovered after symptomatic treatment. The main AE related to S-1 was tolerable nausea. No incidences of neuropathy were observed in either group and no treatment-related death was observed.

The prognosis for patients with advanced hepatocellular carcinoma (HCC) characterized by vascular tumor invasion and/or extrahepatic metastasis is almost always very poor. Systemic therapy with sorafenib was the only recommended first-line therapy for these patients at the beginning of this study. Transarterial chemoembolization (TACE) is recommended for the treatment of patients with intermediate stage HCC, although it has been investigated in patients with more advanced disease with equivocal results. Hepatic arterial infusion chemotherapy (HAIC) has shown promising local benefits for advanced HCC. S-1 has proven to be a convenient oral chemotherapeutic agent with definite efficacy against advanced HCC.

Sorafenib had shown limited benefit and was not easily accessible for many patients due to high cost. Other therapeutic approaches such as TACE and HAIC have been investigated in clinical practice, particularly in the Asia Pacific region. However, equivocal data mean that these approaches remain controversial in patients with advanced HCC. Novel treatment strategies are therefore being sought, and TACE followed by HAIC with oxaliplatin has shown promising preliminary results.

To evaluate the efficacy and safety of treatment with TACE followed by oxaliplatin-based HAIC, with or without oral S-1, in advanced-stage HCC with portal vein invasion and/or extrahepatic metastasis, we use progression-free survival (PFS) as the primary endpoint and overall survival (OS), objective response rate, disease control rate and safety as the secondary endpoints.

In this single-center, open-label, randomized, controlled trial, patients with advanced HCC were randomized (1:1) to receive TACE (epirubicin 20-40 mg) followed by oxaliplatin-based HAIC (oxaliplatin 85 mg/m²) either with (TACE/HAIC + S-1) or without (TACE/HAIC) oral S-1 60 mg twice daily.

Our results showed that the addition of oral S-1 to TACE followed by HAIC with oxaliplatin did not lengthen PFS and OS, although numerically higher objective response rate and disease control rate were observed for TACE/HAIC with S-1 vs without S-1 (30.9% vs 18.4% and 72.7% vs 56.7%). Both treatment regimens were similarly well tolerated by patients.

In conclusion, TACE combined with HAIC was an effective and safe treatment for patients with advanced HCC with portal vein invasion and/or extrahepatic metastasis, although the addition of S-1 to sequential TACE and oxaliplatin-based HAIC did not lead to improved PFS or OS.

Given that systemic therapy has only limited benefit and is inaccessible for patients with advanced HCC in many countries, and based on the promising results achieved with TACE and HAIC, identifying a strategy to derive the optimal benefit from these approaches remains an unmet need.