Hepatocellular carcinoma, with portal thrombus after viral eradication, disappeared by 5-fluorouracil and interferon

Abstract

Hepatocarcinogenesis after a sustained virological response (SVR) in type C chronic hepatitis and cirrhosis is an important issue in endemic areas; hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) therapy is especially very hard. We herein report a first case in which combination therapy with interferon-α and continuous intra-arterial infusion of 5-fluorouracil (designated as FAIT) provided a complete response in HCC with PVTT after SVR. Therefore, we think that FAIT is a good option to treat HCC with or without PVTT, even after SVR.

Key Words: Hepatocellular carcinoma, Portal vein tumor thrombus, Sustained virological response, 5-Fluorouracil intra-arterial infusion

INTRODUCTION

Hepatocarcinogenesis after a sustained virological response (SVR) in type C chronic hepatitis and cirrhosis is an important issue in endemic areas. On the other hand, hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) therapy is especially known to be very hard. There has never been a sufficient therapeutic option in PVTT without a miserable prognosis. We herein report a first case in which combination therapy with interferon-α and continuous intra-arterial infusion of 5-fluorouracil (designated as FAIT) provided a complete response in HCC with PVTT after SVR.

CASE REPORT

A 69-year-old man was having a periodical check-up for chronic hepatitis C in our outpatient clinic. In 2006, a SVR was achieved by pegylated interferon α-2b with ribavirin for 48 wk. HCC 17 mm in size occurred in the caudate lobe 18 mo after SVR and a caudate lobectomy was performed. The extirpated lobe contained hepatocellular carcinoma, Edmondson’s grade III, pT3N0M0. Liver histology was macronodular cirrhosis. Adjuvant chemotherapy was recommended since the surgical margin was positive for cancer cells. However, he rejected our proposal and thus, he chose just periodical check-ups in our outpatient clinic.

Six months after surgery, HCC recurred at the resection margin with PVTT that extended to the major trunk (Vp4) in computed tomography (CT) (Figure 1A). His preserved liver function was Child-Pugh score 5, thus classified as grade A.

Figure 1 Abdominal computed tomography. A: Portal vein tumor thrombus (PVTT) extends to the major trunk (arrows) before intra-arterial infusion of 5-FU (FAIT); B: After four courses of FAIT, PVTT clearly disappeared and the portal vein becomes vacant.

He was treated with combination therapy with interferon (IFN)-α and continuous intra-arterial infusion of 5-FU (FAIT). IFN-α (6 × 10⁶ U) was self-injected intramuscularly on day 1, 3 and 5 in each week. Five-FU (500 mg/m² per day for 2 wk) was continuously infused through the proper hepatic artery via a catheter connected to a subcutaneously implanted drug delivery system every 4 wk[1,2]. A severe adverse event of grade 3 oral mucositis (according to the Common Terminology Criteria for Adverse Events v3.0) appeared. Thus, 5-FU was reduced to 350 mg/m² per day in the second course with no severe adverse events thereafter. Elevated tumor markers (AFP and PIVKA-II) fell under the upper normal limit after three courses and CT showed neither HCC nor PVTT after four courses of FAIT (Figure 1B). He is now having subsequent courses of FAIT without recurrence.

DISCUSSION

Chronic hepatitis C is now a curative disease by IFN therapy with ribavirin. The effects of IFN are summarized as follows: (1) elimination of HCV; (2) reduction of hepatic inflammation; (3) improvement in liver fibrosis; and (4) reduction in hepatocarcinogenesis[3,4].

Recently, a new issue, hepatocarcinogenesis after SVR, is emerging. In fact, it is reported that the hepatocarcinogenesis after SVR occurs in 1.5%, 2.4% and 4.1% at 5, 10 and 15 years respectively[5]. Cirrhosis, age over 50 and male are risk factors for hepatocarcinogenesis[5]. The present case had all three.

HCC is now treated according to the guideline[6]. Nevertheless, HCC with PVTT has a poor prognosis. Even in such circumstances, FAIT is effective in cases[1] and also as adjuvant chemotherapy[2]. The rationale of FAIT therapy includes: (1) IFN-α stimulates the metabolic activation of 5-FU[7]; and (2) the combination of IFN-α and 5-FU induces tumor cell apoptosis more than 5-FU alone[8]. IFN-α/β receptor[9] and type 1 interferon receptor[10] are correlated with the sensitivity to FAIT. Insulin-like growth factor-binding protein 7 (IGFBP7)[11], vascular endothelial growth factor (VEGF) signaling[12] and Wnt/β-catenin signaling pathway[13] are reported to be correlated with both the sensitivity and the antitumor effects. FAIT is a relatively novel therapeutic strategy. There is a clinical question whether HCC even after SVR maintains the sensitivity to IFN. On the other hand, the therapeutic strategy for HCC with PVTT after SVR has not been discussed enough in previous studies[1,2,10,14-18]. Hence the accumulation of related cases, clinical trials and the elucidation of more detailed mechanisms of actions in anti-tumor agents are needed in the near future.

In conclusion, FAIT showed a complete response for a case with HCC with PVTT after SVR. No previous report is currently available concerning this issue. HCC developed after SVR is now increasing in number and FAIT may be an option to treat HCC with or without PVTT, even after SVR, although further study is still needed.