HCC and portal venous invasion were diagnosed with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). Before treatment, patients were evaluated physical examination, laboratory tests including albumin, aspartate transaminase (AST), alanine transaminase (ALT), platelets, serum alpha-feto-pro- tein (AFP) and des-gamma-carboxy prothorombin (DCP). Advanced HCC patients were enrolled as below, who were not suitable for surgical resection, nonsurgical interventions such as percutaneous radiofrequency ablation (PRFA) or transcatheter arterial chemoembolization (TACE), and liver transplantation because of multiple HCCs involving both hepatic lobes and/or PVTT. The other inclusion criteria were as below: Child-Pugh class of A or B, preserved organ function (aminotransferase ≤4 times the institutional upper limit of normal and serum creatinine level ≤1.5 mg/dL), acceptable blood cell counts (neutrophil counts ≥1500/mm³, and platelet counts ≥30,000/mm³), and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1. Previous antitumor therapy was allowed if it was performed >8 weeks before enrollment in this study.

Patients were not eligible if they had another concurrent type of malignancy, latest upper gastrointestinal bleeding, or any other underlying critical medical problem that would disturb participation in the study. Patient disease stage was made using the TNM staging system and Japan Integrated Staging (JIS) [21] . The JIS score was obtained by the summation of the tumor stage score (stage I indicates a score of 0, stage II indicates a score of 1, stage III indicates a score of 2, and stage IV indicates a score of 3) and the Child-Pugh class (Child-Pugh class A indicates a score of 0, class B indicates a score of 1, and class C indicates a score of 2).

Informed consent was obtained from each patient or responsible family member after the feasible complications of implanted port system and HAIC had been fully accounted. This study was certified by the Review Board of the Ethics Committee of Saiseikai Maebashi Hospital.

After injection of local anesthetic, the Seldinger technique was used to gain access to the femoral artery. Arteriography of the celiac trunk and superior mesenteric artery was performed to visualize the arterial vascularization of the liver and to evaluate portal vein patency. After detection of the HCC and its feeding artery, the tip of the catheter was placed at the common hepatic artery or proper hepatic artery under fluoroscopic guidance. The proximal end of the catheter was connected to a drug delivery system (Terumo Clinical Supply Co., Tokyo, Japan) implanted in the lower abdomen subcutaneously. To prevent the occlusion of catheter, 10 mL (10,000 units) of a heparin aqueous solution were injected by the implanted port system every 3 weeks and after each cycle of chemotherapy. Hepatic angiography via the port system was performed with every treatment.

After the infused port system had been implanted subcutaneously, patients were treated with HAIC via the port system. Patients underwent continuous hepatic arterial infusion of 5-FU (5-FU^R, Nippon Kayaku, Tokyo, Japan) at a dose of 500 mg/m² for 5 hours on Days 1 - 3 and a fine powder formation of cisplatin (IAcall^R, Nippon Kayaku, Tokyo, Japan) at a dose of 50 mg that was suspended with 5 mL of warmed Lip (10 mg/mL) as a bolus injection on Day 2 (Figure 1). Lip was warmed to 45˚C before suspension. IA-call has been developed as a fine powder formulation of cisplatin, and the concentration of IA-call is three times that of water soluble cisplatin. The efficacy of cisplatin is concentration-dependent, and Lip, an oily contrast medium, is selectively retained in HCCs through hepatic arterial infusion. Therefore, 50 mg of IA-call was suspended with 5 mL of warmed Lip to increase the concentration (20 times that of water soluble cisplatin) and retention of cisplatin.

All patients were given 5-HT [3] antagonists before HAIC as preventive antiemetic treatment. The treatment was repeated every 4 to 10 weeks until confirmation of disease progression, intolerable toxicity, or patient denies continuing treatment. Dosage modulation was made according to the degree of toxicity with each chemotherapeutic cycle. The following cycle of dosage was reduced by 20% in the case of grade 2 to 4 toxicity during the foregoing treatment. Therapeutic cycle was delayed until recovery from grade 3 or 4 toxicity.

The primary endpoint was the response rate (complete response [CR] plus partial response [PR]), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Imaging with contrast-en- hanced CT was evaluated within 4 weeks before the start of therapy. During 3-day FPL treatment, a physical examination (including laboratory tests, toxicity evaluation) was performed every week in each cycle. Contrast- enhanced CT was examined repeatedly every cycle to evaluate the response of treatment. The tumoral responses were determined by contrast-enhanced CT or MRI at the end of each chemotherapeutic cycle according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0 [22] . PFS was calculated from the time of study entry to disease progression. OS was calculated from the time of study entry to the death or the last fol-

low-up visit. Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE; version 4.0).

Baseline data are expressed as means ± standard deviation or as median and range values. Survival time was defined as the time from the date of the first treatment to the date of death or the last date of follow-up. Survival curves were calculated by the Kaplan-Meier method, and the clinical characteristics and prognostic factors were evaluated by the log-rank test. Finally, a Cox proportional hazards model was used to determine the most significant variables related to survival. A P value <0.05 was considered significant. Statistical analyses were performed using Stat View Version 5.0 (SAS Institute, Cary, NC, USA).

A total of 30 patients (19 males, 11 females; median age, 68.2 years; age range, 49 - 86 years) were enrolled between October 2007 and October 2012 in Saiseikai Maebashi hospital. The baseline characteristics of the patients are summarized in Table 1. The etiology of the background liver disease was hepatitis C virus (HCV) in 24 patients, hepatitis B virus (HBV) in 2 patients, alcoholism in 1 patient, nonalcoholic steatohepatitis (NASH) in 1 patient, and non HBV non HCV (NBNC) in 2 patients. All 30 patients had the portal vein invasion in Vp2-4 (the second branch to the main trunk). Twenty-eight patients (93.3%) had stage IV-A disease. Fourteen patients had ≥50% of their liver replaced by the tumor. The median serum AFP was 3527 ng/mL (4.0 - 50,000 ng/mL), and the median DCP was 671.1 mAU/ml (10.0 - 5180 mAU/mL).

Data are number of patients or mean ± standard deviation. HCV: hepatitis C virus; HBV: hepatitis B virus; NASH: non alcoholic steatohepatitis. PVTT: portal vein tumor thrombosis; AFP: alpha-fetoprotein; DCP: des-gamma-carboxy prothorombin; AST: aspartate aminotransferase; ALT: alanine aminotransferase.

A total of 73 courses of HAIC were administered with a median of 3 courses per patient (range, 1-7 courses). Of the 30 patients, 4 (13.3%) achieved a CR, 8 (26.7%) experienced a PR, and 7 (23.3%) experienced SD, 11 patients (36.7%) experienced PD. Consequently, the response rate was 40.0%, and 19 patients (63.3%) achieved successful disease control (SDC) with this protocol.

The Kaplan-Meier analysis was used to calculate the median PFS at 198 days and the median OS at 452 days. The 1, 2, and 3-year cumulative PFS rates were 28.6%, 10.5%, and 10.5%, respectively (Figure 2). The 1, 2, and 5-year cumulative OS rates were 53.3%, 31.1%, and 23.3%, respectively (Figure 3). The OS rate was significantly longer in the DC group (CR + PR + SD) than in the PD group (P < 0.0001) (Figure 4). The one-year survival rate was 82.1% in the DC group and 36.8% in the PD group. The duration of survival demonstrated a close correlation with disease control after chemotherapy.

The prognostic factors affecting patient survival were analyzed by evaluating the potential parameters (Table 2 and Table 3). Univariate analysis showed that four significant prognostic factors were correlated with survival: age (P = 0.05), tumor size (P = 0.001), PT activity (P = 0.05), and therapeutic effect (P = 0.001) (Table 2). Multivariate analysis showed that therapeutic effect was the only independent prognostic factor for survival (P = 0.01) (Table 3). Univariate analysis identified three significant prognostic factors that were correlated with PFS:

tumor size (P = 0.01), PT activity (P = 0.05), and therapeutic effect (P = 0.0001) (Table 4). Multivariate analysis revealed that therapeutic effect was the only independent prognostic factor for PFS (P = 0.02) (Table 5).

The patients were assessed for toxicities and complications related to HAIC. The major toxicities and complications associated with treatment are shown in Table 6. The hematologic toxicities were mild except in 1 patient (3.3%) with grade 4 thrombocytopenia, although there was no bleeding. Consequently, all toxicities were tolerable and transient, and they were favorably treated with conservative therapy. The major clinical problems were one case of hepatic failure and two of gastro-intestinal ulcers induced by HAIC. However, all of these cases also recovered without any problems by conservative treatment, and the hepatic failure case achieved CR with this treatment eventually.

The reason of hepatic failure was considered to be cisplatin or 5FU-related toxicity. However, this toxicity recovered to baseline levels within 1 month. In 3 patients, a hematoma occurred around the implanted port system. In all cases, the port systems were removed, and the patients reinitiated HAIC after the new implanted port system.

One of the patients who achieved a CR had previously been treated with sorafenib (case 1, 84 yrs male). Although he was 84 yrs and his HCC had progressed despite sorafenib treatment, his HCC decreased completely with 3-day FPL treatment (Figure 5). Similarly, a case of advanced HCC with inferior vena cava syndrome achieved CR (case 2, 63-yrs male); the vena cava syndrome and leg edema also decreased drastically (Figure 6).