Treatment with all-trans retinoic acid plus tamoxifen and vitamin E in advanced hepatocellular carcinoma.

Background: Low serum retinol and hepatic tocopherol levels correlate with hepatocellular carcinoma (HCC) risk. Antiestrogen tamoxifen seems useful in HCC patients. A pilot study was performed to evaluate the effect of all-trans retinoic acid associated with tamoxifen and vitamin E on patients with advanced HCC. Patients and Methods: Fifteen consecutive patients with advanced HCC were included in the study. Patients were evaluated for survival, quality of life, liver function, tumor mass, toxicity related to the treatment and retinoid receptors in liver biopsies. Results: The median survival of our patients was 22 months. Pain and asthenia were improved in the majority of patients. Every patient with baseline elevated liver enzymes showed an improvement in liver function. RAR-·, RXR-·, RAR-‚ and RAR- A receptors were demonstrated in 100%, 73%, 47% and 40%, respectively. Conclusion: A combination therapy of all-trans retinoic acid, tamoxifen and vitamin E increases the survival rate and ameliorates the clinical outcome in patients with inoperable HCC. Hepatocellular carcinoma (HCC) is one of the ten most common cancers in the world (1), with an estimated annual incidence of about 1,000,000 cases (2,3). Treatments of HCC are disappointing, especially in patients with cirrhosis whose prognosis is determined not only by the characteristics of the liver cancer but also by the underlying liver disease and the degree of liver failure. When the early symptoms are recognized, most of the patients have inoperable HCC (4). The median survival of HCC untreated patients with an Okuda II stage and with a Cancer Liver Italian Program Investigation (CLIP) score of 2-3 was about 7 months. In patients with Okuda stage III and CLIP scores of 4-6 it was 3 months (5,6). Chemotherapy with doxorubicine, epirubicine, tegatur or cisplatin did not increase the survival and induced fatal toxicity in 25% of the patients (7). Lipiodol chemoembolization reduced tumor growth but often caused acute liver failure and did not significantly improve survival (8). The presence of estrogen receptor in the liver and the supposed causative relationship between sex steroids and liver tumors (9,10) suggested the possibility of using the antiestrogen tamoxifen for the treatment of HCC. Tamoxifen may reduce the cytosolic and nuclear estrogen receptor-independent mechanism of tumor growth, as suggested by the absence of detectable estrogen receptor in several tamoxifen-sensitive hepatoma cell lines (11). Consistent with this view, in vitro and in vivo preclinical evidence shows that all-trans retinoic acid, an analog of vitamin A, was able to inhibit proliferation and induce apoptosis in human hepatoma cells (Hep3b) and suppress tumorigenicity in a nude mice model (12,13). Moreover, 13-cis retinoic acid reduces the incidence of 3'- methyl-4-dimethylaminobenzene-induced hepatic tumors, while retinyl acetate has a protective effect against spontaneous hepatic adenoma in mice (14,15). Epidemiological evidence showed that low serum retinol and hepatic tocopherol levels correlate with HCC risk (16,17), suggesting a potential role of retinoids for the