Addition of Doxorubicin to Sorafenib in Advanced Hepatocellular Carcinoma

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As reported in JAMA Oncology by Ghassan K. Abou-Alfa, MD, and colleagues, the phase III Alliance/CALGB 80802 trial has shown no progression-free or overall survival benefit with the addition of doxorubicin to sorafenib in patients with advanced hepatocellular carcinoma. The study was stopped early due to futility.

Ghassan K. Abou-Alfa, MD

Ghassan K. Abou-Alfa, MD

Study Details

In the open-label, Alliance-led National Clinical Trials Network multigroup trial, 356 patients with advanced disease who had received no prior systemic therapy were randomly assigned to receive the combination (n = 180) of doxorubicin 60 mg/m2 (30 mg/m2 in those with bilirubin of 1.3–3.0 mg/dL) every 21 days to a maximum total dose of 360 mg/m2 plus sorafenib 400 mg twice daily (400 mg once daily in those with bilirubin of 1.3–3.0 mg/dL) or sorafenib alone (n = 176).

The primary endpoint was overall survival.

Survival Outcomes

Enrollment began in February 2010, with a target enrollment of 480 patients. The trial was stopped in May 2015 on the recommendation of the data and safety monitoring board after the fifth interim analysis showed low probability (futility boundary crossed) that overall survival in the combination group would surpass that in the sorafenib group.

Median follow-up was 36.1 months. Median overall survival was 9.3 months in the combination group vs 9.4 months in the sorafenib group (hazard ratio [HR] = 1.05, 95% confidence interval [CI] = 0.83–1.31, P = .68). Median progression-free survival was 4.0 months vs 3.7 months (HR = 0.93, 95% CI = 0.75–1.16, P = .54). Median time to progression was 4.7 vs 4.2 months (HR = 0.92, 95% CI = 0.71–1.18, P = .49).


  • The trial was stopped early due to futility.
  • The addition of doxorubicin to sorafenib did not improve overall or progression-free survival.

Adverse Events

Grade 3 or 4 neutropenia (36.8% vs 0.6%) and thrombocytopenia (17.5% vs 2.4%) were more common in the combination vs sorafenib groups. Grade 3 or 4 cardiac toxic events occurred only in the combination group, including left ventricular systolic dysfunction in 3.0% of patients and decreased ejection fraction in 4.8%. Death considered possibly related to study treatment occurred in seven patients in the combination group and three patients in the sorafenib group.

The investigators concluded, “This multigroup study of the addition of doxorubicin to sorafenib therapy did not show improvement of [overall survival] or [progression-free survival] in patients with hepatocellular carcinoma.”

Dr. Abou-Alfa, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the JAMA Oncology article.

Disclosure: The research was supported by grants from the National Cancer Institute and by Bristol-Myers Squibb and Sanofi. For full disclosures of the study authors, visit

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