Bhattacharya, Satyajit; (1995) Iodised oil in the management of hepatocellular carcinoma: An experimental and clinical investigation. Masters thesis (M.Phil), UCL (University College London).

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Abstract

Lipiodol (iodised poppyseed oil) administered into the hepatic artery is selectively retained by primary hepatocellular carcinomas (HCCs) for prolonged periods, and targeted therapy with Lipiodol conjugated to a cytotoxic drug or radioisotope has been used to treat these tumours. The mechanism of Lipiodol retention has remained unclear so far. A clear understanding of why Lipiodol is retained by tumours is essential to improving the efficacy of Lipiodol-targeted therapies. To investigate any cellular role in this process, the interaction of Lipiodol with tumour and endothelial cells was studied in vitro in cell cultures and in vivo in human HCCs. Cultures of HepG2 (a human liver tumour cell line) and HUVECs (human umbilical vein endothelial cells, which share phenotypic markers with the endothelium in HCCs) were exposed to 1%, 2% and 4% Lipiodol in culture medium for 4, 8, 24 and 32 hours. Cell monolayers were stained for Lipiodol by a selective silver nitrate impregnation technique. All tumour and endothelial cultures demonstrated incorporation of Lipiodol into the cells. Intracellular Lipiodol uptake was quantitated by computer-assisted image analysis of the optical density of silver-stained monolayers. A significant increase in optical density was noted with every concentration of Lipiodol (n=10; p<0.05, Wilcoxon Signed Rank test). HepG2 cells demonstrated a slow rate of uptake initially, followed by progressive intracellular accumulation. On the other hand, HUVECs demonstrated rapid initial uptake, but subsequently the optical densities diminished, indicating that the Lipiodol had been excreted or metabolised by the cells. Electron microscopy of HepG2 cells demonstrated membrane-bound lipid vesicles in the cytoplasm, suggestive of uptake by pinocytosis. The effect of Lipiodol on tumour cells was assessed with respect to cell viability (Trypan Blue exclusion and media Lactate Dehydrogenase levels), cell numbers and protein synthesis (3H-labelled Leucine incorporation). Lipiodol had no significant effect on any of these parameters. Histologic assessment of Lipiodol retention in HCCs was performed on surgically resected tumours (n = 8) administered pre-operative arterial Lipiodol-Epirubicin and incidental HCCs (n = 15) discovered in cirrhotic livers removed at orthotopic liver transplantation, wherein Lipiodol had been arterially administered at prior angiography. All tumour sections were stained by silver nitrate impregnation. Light and electron microscopy confirmed Lipiodol incorporation by tumour cells and by endothelial cells lining tumour vessels. Intracellular Lipiodol was also demonstrated in one incidental HCC perfused with Lipiodol ex vivo immediately after removal from the body, which would suggest that cellular incorporation of Lipiodol occurs rapidly after administration. In the clinical context, it is as yet unclear which is the ideal therapeutic agent for conjugation to Lipiodol. There have been few comparative studies of the available cytotoxic drug regimens, and no reported comparisons of Lipiodol-targeted chemotherapy with Lipiodol-targeted radiotherapy. This study assessed 95 patients with unresectable HCC confined to the liver. Sixty-nine were treated with Lipiodol-Epirubicin emulsion [median age 61 yrs; Cirrhotics - Child's grade A27, B27, C7; Tumour stage (Okuda) I 14, II 37, HI 18; Epirubicin dose 75 mg/m2] and 26 received Lipiodol-131I [median age 64 yrs; Cirrhotics - Child's grade A13, B5, C0; Tumour stage I 6, II19, III 1; Dose 750-1050 MBq]. The last 28 patients (17 Epirubicin, 11 131I) were treated within a prospective randomised trial. Bolus drug or isotope was injected into the hepatic artery by transfemoral cannulation. Lipiodol and 131I uptake were gauged by 10th day CT and 48-hr scintiscan. Tumour size at 2 months remained static or diminished partially in 21/38 Epirubicin recipients (55%) and 15/22 recipients (68%). Treatments were repeated 2 monthly when clinically indicated. Cumulative survival at 6, 12 and 24 mths was 40%, 25% and 6% with Epirubicin, and 58%, 25% and 0% with 131I; 30-days mortality was 11% and 15% respectively. Comparison with historical controls indicated a survival benefit in Stage I/II disease. Similar findings were recorded in the subset of 28 patients in the randomised controlled trial. In conclusion, liver tumour cells and endothelial cells exposed to Lipiodol in vitro incorporate it, possibly by pinocytosis, without suffering obvious adverse effects. Similar mechanisms may operate in vivo. Clinically, patients with Stage I/II HCC receiving Lipiodol-Epirubicin or Lipiodol-131I show good localisation, acceptable toxicity, and comparable survival benefit at 6 and 12 months with either modality.

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