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Original Investigation
September 5, 2019

Assessment of Treatment With Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients With Advanced Hepatocellular Carcinoma: Phase 3 CALGB 80802 Randomized Clinical Trial

Author Affiliations
  • 1Memorial Sloan Kettering Cancer Center, New York, New York
  • 2Weill Cornell Medical College, Cornell University, New York, New York
  • 3Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota
  • 4Princess Margaret Cancer Centre, Toronto, Ontario, Canada
  • 5Montefiore Medical Center, New York, New York
  • 6Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina
  • 7Thomas Jefferson University, Philadelphia, Pennsylvania
  • 8Washington University School of Medicine, St Louis, Missouri
  • 9McGill University, Montreal, Quebec, Canada
  • 10Ottawa Hospital, Ottawa, Ontario, Canada
  • 11Meharry Medical College, Nashville, Tennessee
  • 12Mayo Clinic, Scottsdale, Arizona
  • 13Tom Baker Cancer Centre, Calgary, Alberta, Canada
  • 14Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco
  • 15Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles
  • 16Kaiser Permanente Vallejo Medical Center, Vallejo, California
  • 17Columbia University Medical Center, New York–Presbyterian Hospital, New York, New York
  • 18West Virginia University Cancer Institute, Morgantown
  • 19Brigham and Women's Hospital, Boston, Massachusetts
  • 20Dana-Farber Cancer Institute, Boston, Massachusetts
JAMA Oncol. Published online September 5, 2019. doi:10.1001/jamaoncol.2019.2792
Key Points

Question  Does adding doxorubicin to sorafenib therapy improve overall survival in patients with advanced hepatocellular cancer?

Findings  This phase 3 clinical trial randomized 356 eligible patients to treatment with doxorubicin plus sorafenib vs sorafenib alone. Results demonstrated no difference in median overall survival (9.3 months for the doxorubicin plus sorafenib arm and 9.4 months for the sorafenib arm).

Meaning  The addition of doxorubicin to sorafenib therapy did not improve overall survival and resulted in higher toxicity; the combination of doxorubicin and sorafenib should not be used for the treatment of advanced hepatocellular cancer.


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

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

Design, Setting, and Participants  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.

Interventions or Exposures  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.

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

Results  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.

Conclusions and Relevance  This multigroup study of the addition of doxorubicin to sorafenib therapy did not show improvement of OS or PFS in patients with HCC.

Trial Registration  ClinicalTrials.gov identifier: NCT01015833