This study received approval from the ethics committee of our institution, and all provided written informed consent before participating.
The institutional database used in this study was compiled using data from HCC patients with PVTT who underwent endovascular 125I seed-strip implantation followed by TACE-S (PVS-125I-TACE-S) or TACE-S from May 2014 to July 2018. For all patients, attending physicians had recommended TACE, sorafenib, TACE-S, or PVS-125I-TACE-S treatment, with final treatment approaches having been selected by the individual patients. Study inclusion criteria were as follows: 1) diagnosis with HCC and either type II or type III PVTT; 2) no previous local treatment for PVTT lesions; 3) An Eastern Cooperative Oncology Group (ECOG) performance of 0-2; 4) Child-Pugh Class A or B. Study exclusion criteria were as follows: 1) complete portal vein occlusion with a lack of collateral circulation; 2) bleeding of the esophagus or gastric fundus; 3) intractable coagulation disorders; 4) macroscopic hepatic vein tumor thrombi or extrahepatic tumor metastasis; 5) a lack of baseline imaging results.
A total of 64 consecutive HCC patients with PVTT were identified, including 7 patients that underwent simple TACE, and 1 patient treated with only sorafenib. In addition, preoperative enhanced CT/MRI scan results were not available for 2 patients, and 1 patient was lost to follow up. These patients were excluded from the study, leaving a final study population of 53 patients. A total of 28 of these patients were treated via PVS-125I-TACE-S (group A), while the remaining 25 patients were treated via TACE-S alone (group B).
In all patients, HCC diagnosis was confirmed either via histology or by a combination of two imaging approaches and elevated α-fetoprotein, as per the American Association guidelines [17]. Magnetic resonance imaging (MRI) or computed tomography CT) was used to diagnose PVTT based on the presence of a low attenuation intraluminal mass that partially or fully occluded the portal vein or filled a portal vein defect [18]. Patients were stratified into Type I - IV PVTT according to Cheng's PVTT classification system based on the following criteria: Type I, tumor thrombi locating at or above portal vein segmental branches (second-order branches); Type II, tumor thrombi extending so as to involve the right or left portal vein (first-order branches); Type III, thrombi involving the main trunk of the portal vein; Type IV, invasion of the superior mesenteric vein or inferior vena cava [4].
PVS combined with endovascular 125I seed-strip implantation
The required number (N) of 125I seeds was determined based upon the length (L) of the obstructed portal vein segment in mm per the formula N = L/4.5 + 2 (Shanghai GMS Pharmaceutical Co. Ltd) [13]. The 125I seeds used in this study were 0.8 mm in diameter, and 4.5 ± 0.5 mm long, with 25.9 MBq of radioactivity and a 59.4-day half-life, primarily emitting 27.4 and 31.4 keV X-rays and 35.5 keV 𝛾-rays. Given the local tissue half-value thickness of 17 mm, these seeds were associated with an initial dose rate of 7 cGy/h. Prior to implantation, these seeds were loaded in a linear arrangement in a 4 Fr flexible stiffening cannula (Boston Scientific Co., Ltd). With ultrasonic guidance, a Neff Percutaneous Access Set (Cook, Inc., IN, USA) was then used to puncture the patent second-order portal vein branch, after which both a vascular stent (diameter: 12-14 mm; length: 60-100 mm; Bard Peripheral Vascular Inc., AZ, USA) and 125I seed-strip were implanted in succession. After this, a 3-3 spring coil (Cook, Inc., Bloomington, Indiana) was used for blocking the intrahepatic puncture, and subcutaneous low-molecular-weight heparin (4100 IU; Hebei Changshan Biochemical Pharmaceutical Co, Ltd) was administered twice daily for a 5 day period, after which warfarin (Shanghai Sine Pharmaceutical Laboratories Co., Ltd) was administered orally in order to achieve the international normalized ratio of 2.0–2.5.
TACE procedure
In group A patients, TACE was conducted 3 - 7 days after PVS and seed implantation, whereas in group B patients this procedure was conducted directly. A 5-Fr hepatic-curve catheter (Terumo Corporation, Japanese) was placed into the celiac artery and then hepatic arterial angiography and indirect portography were performed. Next, a 2.7 Fr microcatheter (Progreat™, Terumo, Tokyo, Japan) was placed into tumor-feeding arteries, and 5–20 mL lipiodol (Beijing Wh-Medical Apparatus and Instruments Co. Ltd) mixed with 50–75 mg/m2 doxorubicin hydrochloride (Shanghai Hisun Pfizer Pharmaceutical Co. Ltd) were injected into these arteries. If the entire 20 mL volume was administered without substantially impairing blood flow in these vessels, polyvinyl alcohol (PVA) particles (Hangzhou ALICON Pharmaceutical Science and Technology Co. Ltd) were used for vessel embolization, being administered until only a limited slow flow was evident. For those with arterioportal shunts, initial embolization using 350-1000 μm PVA particles was conducted prior to lipiodol/doxorubicin infusion in order to ensure shunt occlusion. TACE treatment was guided by imaging results.
Sorafenib
Three to seven days after TACE treatment, when liver function had stabilized, patients were administered 400 mg sorafenib (Nexavar®, Bayer HealthCare, Leverkusen, Germany) twice per day. In many patients suffering from grade 1 or 2 adverse events (AEs), or with serum bilirubin > 34.2 μmol/L, sorafenib doses were reduced. In patients suffering grade 3 AEs or hyperbilirubinemia (serum bilirubin > 51.3 μmol/L) events, sorafenib treatment was temporarily halted and was only resumed if AE grades and serum bilirubin levels fell back within the acceptable treatment ranges. Patients were continuously administered sorafenib tablets until it was no longer possible to do so, even when disease progression was noted, or until death.
Follow-up and treatment evaluation
At 1 and 3 months post-operatively, patient follow-up was conducted, and it was then performed every three months thereafter. During follow-up, patients underwent physical examination, laboratory analyses, as well as contrast-enhanced abdominal MRI or CT. The Common Terminology Criteria for Adverse Events (CTCAE) v4.0 assessment was used to gauge any complications associated with treatment [8]. Albumin-Bilirubin (ALBI) scores were used as an objective means of gauging liver function, with scores being calculated solely based upon albumin and bilirubin levels [ALBI score=log10 bilirubin (μmol/L) ×0.66) + (albumin (g/L) ×−0.0852)] [17]. The modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria for HCC were used to gauge tumor responses, with possible responses including complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) (Fig. 1). A disease control rate (DCR) after 6 months of treatment was then calculated based on the formula: (CR+PR+SD)/total cases×100% [19]. OS was the study endpoint and was defined as the period of time between treatment and either death or last follow-up.
Statistical analyses
SPSS 21.0 (SPSS Inc., Chicago, IL, USA) was utilize for all testing. Quantitative results are given as means ± standard deviation, and t-tests was used to compare these values. Qualitative results are given as a number (%), and Pearson Chi-Squared tests or Fisher's exact tests were employed for comparing these results as appropriate. Paired sample t-tests were used for comparison of ALBI scores and pre- and post-operative portal venous pressure in group A patients. Survival was analyzed via the Kaplan–Meier approach and through log-rank tests. P<0.05 was the significance threshold. Cox univariate regression analyses were used to assess the relationship between specific factors and treatment outcomes. Multivariate logistic regression analyses were conducted based on the variables in the univariate analysis (P<0.10).