Articles
Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial

https://doi.org/10.1016/S2468-1253(19)30040-8Get rights and content

Summary

Background

Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma. We assessed the intravenous perfusion of doxorubicin-loaded nanoparticles in patients with hepatocellular carcinoma in whom previous sorafenib therapy had failed.

Methods

We did a multicentre, open-label, randomised, controlled phase 3 trial at 70 sites in 11 countries. Patients with hepatocellular carcinoma with one or more previous systemic therapies, including sorafenib, were randomly assigned to receive 30 mg/m2 doxorubicin-loaded nanoparticles (30 mg/m2 group), 20 mg/m2 doxorubicin-loaded nanoparticles (20 mg/m2 group), or standard care using a computer-generated randomisation list prepared by the funder and stratified by geographic region. Patients in the experimental groups received perfusion of the drug every 4 weeks and those in the control group received any systemic anticancer therapy (except sorafenib) as per investigator decision. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01655693.

Findings

Between June 15, 2012, and Jan 27, 2017, 541 patients were screened, of whom 144 were excluded and 397 were randomly assigned to one of the groups (133 to the 30 mg/m2 group; 130 to the 20 mg/m2 group; and 134 to the control group). Median follow-up was 22·7 months (IQR 11·2–34·9). After pooling the doxorubicin groups for the efficacy analysis, median overall survival was 9·1 months (95% CI 8·1–10·4) in the pooled doxorubicin-loaded nanoparticles group and 9·0 months (7·1–11·8) in the control group (HR 1·00 [95% CI 0·78–1·28], two-sided p=0·99). 227 (94%) of 242 patients who received doxorubicin-loaded nanoparticles and 100 (75%) of 134 patients in the control group had at least one treatment-emergent adverse event. The most common drug-related grade 3 or 4 treatment-emergent adverse events were neutropenia (25 [10%] of 242 treated with doxorubicin-loaded nanoparticles and eight [6%] of 134 in the control group), asthenia (six [2%] and four [3%]), and thrombocytopenia (three [1%] and ten [7%]). Six (2%) patients treated with doxorubicin-loaded nanoparticles and one (1%) of those in the control group were deemed by investigators to have had a drug-related death. Serious adverse events occurred in 74 (31%) patients who received doxorubicin-loaded nanoparticles and 48 (36%) in the control group.

Interpretation

Doxorubicin-loaded nanoparticles did not improve overall survival for patients with hepatocellular carcinoma in whom previous sorafenib treatment had failed.

Funding

Onxeo.

Introduction

The treatment of hepatocellular carcinoma follows guidelines based on the Barcelona Clinic Liver Cancer (BCLC) staging system.1 Surgical resection, transplantation, and thermoablation are potential curative therapies for patients with early-stage hepatocellular carcinoma, whereas chemoembolisation is recommended as a palliative option for intermediate-stage hepatocellular carcinoma. For patients with advanced hepatocellular carcinoma, or with intermediate stage disease that is no longer a candidate for chemoembolisation, systemic strategies based on oral tyrosine kinase inhibitors such as sorafenib as first-line treatment2, 3 and regorafenib as second-line treatment4 provide a clinically significant improvement in overall survival. Lenvatinib is non-inferior to sorafenib as first-line treatment5 and cabozantinib is efficacious as second-line or third-line treatment.6 Ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor receptor 2, has shown efficacy in the subgroup of patients with hepatocellular carcinoma who have concentrations of alpha-fetoprotein of at least 400 ng/mL after sorafenib treatment failure,7 whereas ramucirumab did not show any significant benefit in non-selected patients with hepatocellular carcinoma.8 All other systemic drugs in phase 3 trials showed no efficacy in this population.9, 10, 11, 12, 13, 14, 15, 16 Further, radioembolisation with yttrium-90 has not shown superiority to sorafenib in a randomised phase 3 study in patients with advanced hepatocellular carcinoma or in those with intermediate hepatocellular carcinoma in whom chemoembolisation has failed.17, 18 The best observed overall survival in a systemic setting was for sorafenib followed by regorafenib (median 26·0 months [95% CI 22·6–28·1]).19 More effective systemic therapies are needed to increase overall survival of patients with advanced hepatocellular carcinoma.

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.

To date, no phase 3 trials of cytotoxic chemotherapy for hepatocellular carcinoma have shown signs of efficacy. Doxorubicin was a potential candidate, but the administration of free doxorubicin is associated with high morbidity in cirrhosis;20 it also did not show any additive or synergistic effects when added to sorafenib.21 Doxorubicin-loaded nanoparticles in the liver overwhelm the efflux pumps encoded by multiple drug resistance genes.22, 23 A phase 1–2 trial suggested a potential benefit of doxorubicin-loaded nanoparticles on overall survival of patients with hepatocellular carcinoma, although the trial was prematurely stopped because of lung toxicity associated with doxorubicin-loaded nanoparticles injected by the hepatic arterial route.24 Preclinical data from Wistar rats showed that this lung toxicity was reduced when doxorubicin-loaded nanoparticles were infused over 2 h.24 Thus, here, we assessed the efficiency of doxorubicin-loaded nanoparticles administered by a 6 h intravenous infusion in patients with hepatocellular carcinoma after failure of sorafenib therapy.

Section snippets

Study design

This multicentre, open-label, randomised, controlled phase 3 trial was done at 70 sites in 11 countries in Europe, the USA, the Middle East, and North Africa. The trial was approved by each centre's ethics committee or institutional review board and complied with Good Clinical Practice guidelines, the Declaration of Helsinki, and applicable local laws. The protocol is available online.

Patients

Eligibility criteria were age of at least 18 years; hepatocellular carcinoma confirmed by pathological or

Results

541 patients were screened between June 15, 2012, and Jan 27, 2017, and 144 were excluded because they did not meet eligibility criteria. 397 patients were randomly assigned to either the 30 mg/m2 group (n=133), the 20 mg/m2 group (n=130), or the control group (n=134) and included in ITT analysis (figure 1). 376 (95%) patients started treatment (120 in the 30 mg/m2 group, 122 in the 20 mg/m2 group, and 134 in the control group) and comprised the safety population. Of the patients who started

Discussion

The absence of more effective therapies for hepatocellular carcinoma is an unmet clinical need; however, chemotherapy has been clearly shown to be ineffective and toxic in patients with advanced disease. In this phase 3 trial assessing doxorubicin-loaded nanoparticles as subsequent-line treatment for patients in whom sorafenib has failed, no difference was detected between doxorubicin-loaded nanoparticles and control in terms of overall survival.

Survival in patients with hepatocellular

Data sharing

Data collected for this study (including individual participant data and a data dictionary defining each field in the set) will be made available to others after approval by the corresponding author. Additional, related documents will be also available (case report forms, statistical analysis plan, and informed consent forms) on request by the corresponding author and sponsor's approval. These data will be available after publication.

References (29)

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