Research in context
Evidence before this study
We searched PubMed for phase 3 randomised controlled studies of advanced inoperable hepatocellular carcinoma, published between Jan 1, 2000, and Feb 4, 2018, and in English. We used the search terms “hepatocellular carcinoma” AND “randomized trial” AND “chemotherapy” OR “doxorubicin”. Our search showed that no cytotoxic chemotherapy has improved survival in a previous randomised controlled phase 3 trial in patients with advanced hepatocellular carcinoma, except the small study published by Lai and colleagues in 1988. However, although free doxorubicin was shown to be effective in terms of overall survival, this drug has never become the standard of care for advanced hepatocellular carcinoma because of the weak evidence (small sample size) and the high toxicity in patients with cirrhosis (sepsis, mucositis, and cardiotoxicity).
Added value of this study
The results of RELIVE show that treatment with doxorubicin-loaded nanoparticles, which overrides multiple mechanisms of drug resistance-related chemoresistance, did not result in a significant improvement in overall survival compared with best standard of care in patients with disease progression on sorafenib alone or with other subsequent systemic treatment lines. The secondary endpoints of progression-free survival, time to progression, disease control, and overall tumour response also showed no improvement.
Implications of all the available evidence
This phase 3 trial of doxorubicin-loaded nanoparticles demonstrates the absence of a benefit in overall survival for patients with advanced hepatocellular carcinoma in whom sorafenib treatment had failed. These findings are in contrast with preclinical and phase 1 or 2 clinical studies that had positive results with this treatment for hepatocellular carcinoma. The absence of more effective therapies is an unmet clinical need, but so far, chemotherapy has been clearly demonstrated to be ineffective and toxic in these patients.