Tolerability of the mTOR inhibitor rapamycin in cirrhotic patients with advanced hepatocellular carcinoma

Introduction: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. In the West, around 40% of patients are eligible for potential curative treatment (resection, transplantation or local ablative treatment) and 20% for chemoembolization. Sorafenib, a multikinase inhibitor, represents a breakthrough in the management of advanced hepatocellular carcinoma. A new therapeutic option for those patients would be inhibition of the PI3K/Akt/mTOR signalling pathway which is involved in multiple cellular functions including proliferation, differentiation, tumorgenesis, and apoptosis. Rapamycin (=Sirolimus; a specific mTOR inhibitor) leads to G(1) arrest of many malignant cell lines, and currently analogs of rapamycin are being investigated as a adjuvant to chemotherapy.

Aim: A pilot study was undertaken to investigate the side effects and tolerability of rapamycin treatment in cirrhotic patients with advanced hepatocellular carcinoma.

Methods: Between June 2005 and February 2007 patients with advanced hepatocellular carcinoma, uneligible for any established therapy, were included in the study. The initial rapamycin dosage was 1mg/day. Discontinuation was based on progression of disease and toxicity.

Results: 18 patients (female: 5, male: 13) with compensated liver cirrhosis (Child A n=11, Child B n=5, Child C n=2) and histologically proven HCC (G1 n=1, G2 n=14, G3 n=3) were included in this study. According to the BCLC staging system most of the patients enrolled had an advanced hepatocellular carcinoma: BCLC stage B: n=2, BCLC stage C: n=14, BCLC stage D: n=2. Overall, therapy with rapamycin was well tolerated, we did not observe any rapamycin-related infectious complication, and no treatment discontinuation was necessary due to side effects. Most common toxicities were thrombocytopenia and anemia. Two patients had stable disease over 3.0 months, the other 16 patients had progressive disease. The median overall survival was 6.7 months. Because of progression of disease 4 patients were switched to another treatment, the remaining 14 patients died before treatment could be changed.

Conclusion: The mTOR inhibitor rapamycin is well tolerated in cirrhotic patients with advanced hepatocellular carcinoma, but its therapeutic effect seems to be only marginal.