Previous communication has reported significant improvement in overall survival (OS) when using doxorubicin plus sorafenib in the treatment of advanced hepatocellular cancer (HCC).

To determine if doxorubicin added to sorafenib therapy improves OS, with stratification for locally advanced and metastatic disease.

This unblinded randomized phase 3 clinical trial was led by Alliance in collaboration with Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Canadian Cancer Trials Group, and Southwest Oncology Group. It was launched in February 2010 and completed in May 2015; data were also analyzed during this time frame. Patients with histologically proven advanced HCC, no prior systemic therapy, Child-Pugh grade A score, Eastern Cooperative Oncology Group performance status of 0 to 2 (later amended to 0-1), and adequate hematologic, hepatic, renal, and cardiac function were eligible. The OS primary end point had a final analysis planned with 364 events observed among 480 total patients with 90% power to detect a 37% increase in median OS.

Patients received either 60 mg/m2 of doxorubicin every 21 days plus 400 mg of sorafenib orally twice daily or the sorafenib alone, adjusted to half doses for patients with bilirubin levels of 1.3 to 3.0 mg/dL.

The primary end point was OS, and progression-free survival (PFS) was a secondary end point.

Of 356 patients included in the study, the mean (SD) age was 62 (10.1) years, and 306 (86.0%) were men. Although it was planned to include 480 patients, the study was halted after accrual of 356 patients (180 patients treated with doxorubicin plus sorafenib and 176 with sorafenib alone) with a futility boundary crossed at a planned interim analysis. Median OS was 9.3 months (95% CI, 7.3-10.8 months) in the doxorubicin plus sorafenib arm and 9.4 months (95% CI, 7.3-12.9 months) in the sorafenib alone arm (hazard ratio, 1.05; 95% CI, 0.83-1.31). The median PFS was 4.0 months (95% CI, 3.4-4.9 months) in the doxorubicin plus sorafenib arm and 3.7 months (95% CI, 2.9-4.5 months) in the sorafenib alone arm (hazard ratio, 0.93; 95% CI, 0.75-1.16). Grade 3 or 4 neutropenia and thrombocytopenia adverse events occurred in 61 (36.8%) and 29 (17.5%) patients, respectively, being treated with doxorubicin plus sorafenib vs 1 (0.6%) and 4 (2.4%) patients treated with sorafenib.

This multigroup study of the addition of doxorubicin to sorafenib therapy did not show improvement of OS or PFS in patients with HCC. identifier: NCT01015833.

JAMA oncology. 2019 Sep 05 [Epub ahead of print]

Ghassan K Abou-Alfa, Qian Shi, Jennifer J Knox, Andreas Kaubisch, Donna Niedzwiecki, James Posey, Benjamin R Tan, Petr Kavan, Rakesh Goel, Philip E Lammers, Tanios S Bekaii-Saab, Vincent C Tam, Lakshmi Rajdev, Robin K Kelley, Imane El Dika, Tyler Zemla, Ryan I Potaracke, Jennifer Balletti, Anthony B El-Khoueiry, James H Harding, Jennifer M Suga, Lawrence H Schwartz, Richard M Goldberg, Monica M Bertagnolli, Jeffrey Meyerhardt, Eileen M O’Reilly, Alan P Venook

Memorial Sloan Kettering Cancer Center, New York, New York., Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota., Princess Margaret Cancer Centre, Toronto, Ontario, Canada., Montefiore Medical Center, New York, New York., Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina., Thomas Jefferson University, Philadelphia, Pennsylvania., Washington University School of Medicine, St Louis, Missouri., McGill University, Montreal, Quebec, Canada., Ottawa Hospital, Ottawa, Ontario, Canada., Meharry Medical College, Nashville, Tennessee., Mayo Clinic, Scottsdale, Arizona., Tom Baker Cancer Centre, Calgary, Alberta, Canada., Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco., Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles., Kaiser Permanente Vallejo Medical Center, Vallejo, California., Columbia University Medical Center, New York-Presbyterian Hospital, New York, New York., West Virginia University Cancer Institute, Morgantown., Brigham and Women’s Hospital, Boston, Massachusetts., Dana-Farber Cancer Institute, Boston, Massachusetts.