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Combination treatment with intrahepatic arterial infusion and intratumoral injection chemotherapy in patients with far-advanced hepatocellular carcinoma and arterioportal or arteriovenous shunts: preliminary results

Background/Aims Combination treatment consisting of hepatic arterial infusion chemotherapy with epirubicin and cisplatin (HAIC-EC) and systemic infusion of low-dose 5-fluorouracil (5-FU) are sometimes effective against advanced hepatocellular carcinoma (HCC). However, there is no effective treatment for advanced HCCs with arterioportal shunts (APS) or arteriovenous shunts (AVS). Methods We investigated a response and adverse events of a new combination protocol of repeated HAIC-EC and percutaneous intratumoral injection chemotherapy with a mixture of recombinant interferon-gamma (IFN-γ) and 5-FU (PIC-IF) in patients with far-advanced HCCs with large APSs or AVSs. Results There was a complete response (CR) for the large vascular shunts in all three patients and for all tumor burdens in two patients. Significant side effects were flu-like symptoms (grade 2) and bone marrow suppression (grade 2 or 3) after each cycle, but these were well-tolerated. Conclusions These results suggest that the combination of HAIC-EC and PIC-IF is a new and promising approach for advanced HCC accompanied by a large APS or AVS.


INTRODUCTION
Hepatocellular carcinoma (HCC) is the 5th most common malignancy worldwide and the 3rd most common cause of cancer mortality. 1 Because a majority of patients present at an advanced stage, which does not consistently respond to any chemotherapeutic protocols, the prognosis of HCC is generally very poor. Only a small proportion of cases with HCC diagnosed at an early stage as a result of close surveillance, and with serial imaging studies, could be eligible for and receive curative treatments, such as liver transplantation and surgical resection, resulting in a favorable long-term outcome. 2 The Barcelona Clinic Liver Cancer (BCLC) staging classification system, which reflects liver functional status and characteristic features of HCC staging, is a clinically useful algorithm for selecting proper management and predicting the prognosis of HCC patients. 2,3 The management of patients with advanced BCLC stages (BCLC stage C) is a complex issue, as the degree of vascular invasion, tumor size and number, extrahepatic metastasis, HCC-associated complications, liver functional reserve, and the performance status of the patient must be taken into account. Systemic chemotherapy, radiation therapy, and transarterial infusion chemotherapy via implantable drug delivery systems rarely offer survival benefits, such as select patients with well-preserved liver function and a good performance status. 4

Eligibility
The eligibility criteria for chemotherapy were as follows: (1) 18 The length of admission was usually from 4-7 days.
Laboratory tests were usually performed 3 times during the admission (before and 1 day after treatment, and prior to discharge). Additional laboratory tests were performed from 7-10 days after discharge in the outpatient clinic to evaluate  Each clinical course is described in detail below (Table 1).

Patient 1
A 60-year-old man was admitted due to variceal bleeding.
Dynamic CT scan showed a massive infiltrative type of HCC with a maximum diameter ≥12 cm and the main portal vein tumor thrombosis with a massive APS in the right lobe.
The baseline blood tests were as follows: white blood cell  (Fig. 3, 4). Co. Ltd, Seoul Korea), both serological HCC biomarkers normalized again (Fig. 3). The patient is alive without any An ill-defined huge mass mainly involving the right lobe (white arrow) and tumor thrombosis along the right portal system (black arrow) and inferior vena cava were markedly decreased after treatment. Pulmonary metastatic lesions had also completely disappeared (dotted arrow). Hepatic arteriography (C, before treatment; D, after treatment) showed an ill-defined huge mass mainly involving the right lobe and tumor thrombosis along the right portal system and inferior vena cava, together with a large APS at the time of initial treatment. All of the lesions had markedly improved after the treatment.

Patient 3
A 66-year-old man who had anorexia and nausea for 1 month was found to have liver cirrhosis and far advanced Intrahepatic HCC lesions with a large AVS showed a complete response to the treatment protocol, but extrahepatic metastatic lesions showed only a partial response early in the treatment course. However, elevation of the AFP and PIVKA-II levels and multiple metastases in both lungs and adrenal gland were aggravated without intrahepatic recurrence of HCC late in the treatment course.
identified. The initial laboratory tests were as follows: A massive HCC in the right hepatic lobe with right portal vein invasion and multiple lung metastases were noted, but initial MRI revealed no lesions in the adrenal gland. After the treatment protocol the intrahepatic tumor lesions were markedly improved (white arrow), but the left adrenal metastasis (dotted arrow) and pulmonary metastatic nodules (black arrow) were aggravated. Hepatic arteriography (C, before treatment; D, after treatment) showed a huge hypervascular HCC in the right hepatic lobe and a large AVS (white arrow). Both the HCC lesion and AVS shunt had disappeared after the treatment protocol.
showed better treatment responses than shunt embolization with the use of coils and/or gelatin-sponge particles. 10 In