Doxorubicin Combined With Sorafenib Fails to Improve Survival in Patients With Advanced HCC

Doxorubicin Combined With Sorafenib Fails to Improve Survival in Patients With Advanced HCC

The addition of doxorubicin to sorafenib for the first-line treatment of patients with advanced hepatocellular carcinoma (HCC) did not improve overall survival (OS) and was associated with increased toxicity, according to the results of the phase III CALGB 80802 (Alliance) trial (Abstract 4003). The lack of benefit of combining doxorubicin with sorafenib, a tyrosine-kinase inhibitor, could mark the beginning of the end for the use of chemotherapy in the treatment of HCC.

Dr. Ghassan K. Abou-Alfa

The results of CALGB 80802 were presented by Ghassan K. Abou-Alfa, MD, of Memorial Sloan Kettering Cancer Center, during the “Gastrointestinal (Noncolorectal) Cancer” Oral Abstract Session held June 6. It was followed by a discussion of the implications of the trial, and why the results may contradict those of a phase II trial that had suggested a survival benefit with the combination.1

No Survival Benefit With Combination Doxorubicin and Sorafenib

The CALGB 80802 trial randomly assigned 356 patients with advanced, inoperable HCC to receive six cycles of doxorubicin followed by sorafenib or sorafenib alone. Participants were predominantly male, and 14% were Asian. Dr. Abou-Alfa noted that the majority of participants had American Joint Committee on Cancer (AJCC) stage IV disease, indicating that the cancer had spread to the lymph nodes or other organs.

The trial found no significant difference in either OS or progression-free survival (PFS) between the two arms. The median OS was 8.9 months in the sorafenib plus doxorubicin arm and 10.5 months in the sorafenib arm, and the median PFS was 4.0 months and 3.9 months, respectively. In contrast, the earlier phase II trial found a significant improvement in OS in the sorafenib plus doxorubicin arm of 13.7 months compared with 6.5 months in the doxorubicin arm.1

Analyses of adverse events revealed that hypertension was more common in the sorafenib arm than in the sorafenib plus doxorubicin arm, occurring in 13% and 3% of patients, respectively. However, the sorafenib plus doxorubicin arm had higher rates of hematologic adverse events. Fourteen percent of patients in this arm had reduced platelet counts compared with 1% of patients in the sorafenib alone arm.

Dr. Stephen Lam Chan
The study involved one interim analysis for PFS and five interim analyses for OS. By the fifth interim analysis, the data and safety monitoring board for the trial recommended ending the trial. Research is still ongoing to determine the effect that hepatitis B and C infections may have had on the outcomes, Dr. Abou-Alfa said. Sixteen percent and 34% of the participants in both arms had hepatitis B or C, respectively.

Is There Still a Role for Chemotherapy in Advanced HCC?

The results of CALGB 80802 are surprising, considering the phase II trial that preceded it found an important survival benefit with the addition of sorafenib to doxorubicin, said Stephen Lam Chan, MD, FRCP, of The Chinese University of Hong Kong, China.

However, a closer consideration of the phase II and III trials could explain the differences in the findings. There were important differences in the patient populations, with the phase III trial including a more realistic group of patients who were sicker with more extrahepatic disease, Dr. Chan said. In addition, there is precedent in other cancers, with phase III trials failing to support the benefits found in preceding phase II trials that combined chemotherapy with anti-angiogenic tyrosine-kinase inhibitors.

Given the lack of data to support the inclusion chemotherapy in first-line treatment of advanced HCC, Dr. Chan asked, “Is it the end of chemotherapy? I would say close.”

–Carina Storrs, PhD