Hepatic arterial injection chemotherapy for hepatocellular carcinoma with epirubicin aqueous solution as numerous vesicles in iodinated poppy-seed oil microdroplets: clinical application of water-in-oil-in-water emulsion prepared using a membrane emulsification technique

Abstract

Iodinated poppy-seed oil (IPSO) accumulates selectively in hepatocellular carcinoma (HCC) when injected into the hepatic artery. This virtue has been applied to the hepatic arterial injection chemotherapy for the disease. We invented a new water-in-oil-in-water emulsion (W/O/W), in which IPSO microdroplets, 70 μm in diameter, were suspended in physiological saline enclosing numerous vesicles of an aqueous solution of epirubicin with remarkable stability. After hepatic arterial injection, the microdroplets accumulated only in HCC tissue and remained in the tissue for more than 3 weeks affecting tumor cells. Efficacy of the W/O/W has been fully proved clinically; the 6-year cumulative survival rate for 24 patients bearing HCC nodules recurrent after hepatectomy, including even 12 patients with four or more nodules, though prognosis of these patients is recognized very poor, was 24%.

Introduction

Hepatocellular carcinoma (HCC) is the malignant neoplasm which arises from the hepatocytes affected by long-term infection with hepatitis B or C virus [1]. Its prevalence is dominant in Africa and Asia. In the areas with a moderately high incidence of HCC including Japan and southern Europe, hepatitis C viral infection is the main cause of the disease. Recently, patients bearing the disease are increasing even in countries such as UK or US because of a tendency of massive transfusion during invasive surgeries or large scale immigration from the areas contaminated with the virus.

Until the late 1970s, treatment of HCC was restricted to hepatic resection, though up to 80% of patients with HCC were excluded because of impaired functional reserve of the liver. Even in patients undergoing partial hepatectomy, intrahepatic recurrence due to cell spreading or multicentric carcinogenesis was inevitable. For the aid of surgery, hepatic arterial injection chemotherapy using anthracyclines such as doxorubicin or epirubicin was selected [2] after the fact that HCC is supplied mainly with hepatic arterial blood flow. In spite of several modifications, its therapeutic effect was poor because of severe myelosuppression compared with its antitumor effect [3].

In 1966, Idezuki et al. [4] first reported clinical application of iodinated poppy-seed oil (iodinated ethyl esters of fatty acids obtained by hydrolysis of poppy-seed oil, IPSO) for the diagnosis of HCC. (They injected the oil, which had been used as a contrast medium for lymphangiography or hysterosalpingography, into the portal vein of patients bearing small HCC nodules. On a plain X-ray film taken after the injection, they found a diffuse positive stain in non-tumorous area of the liver emerging negative shadows corresponding to the tumors.) After that, they incidentally found that IPSO accumulates selectively in HCC tissue when injected into the hepatic artery.

After a more than 10-year complete blank, Nakakuma et al. applied IPSO to the treatment for HCC [5] by injecting a mixture of IPSO and an oily anticancer drug into the hepatic artery. This method made a great impact on many oncologists, although it was lamentable that ordinary water soluble anticancer drugs could not be used in the system.

Its modification was reported by Kanematsu et al. [6]. In their method, IPSO was mixed with a solution of a hydrophilic anticancer drug in a hydrophilic contrast medium, urografin, forming an emulsion in which IPSO was dispersed as numerous microdroplets with multifarious diameter. The method must be a monumental work because almost all anticancer drugs for HCC are hydrophilic. Nevertheless, the emulsion prepared was not stable; the aqueous solution tended to separate from the oil within an hour. The clinical effect of the emulsion was inadequate [7]. Radiologists began to inject embolic substances such as gelatin sponge particles simultaneously. The use of embolic substances induced unexpected liver-tissue injury [8]. We therefore invented a water-in-oil-in-water emulsion (W/O/W) using membrane emulsification technique.