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

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. HardingJennifer M. Suga, Lawrence H. Schwartz, Richard M. Goldberg, Monica M. Bertagnolli, Jeffrey Meyerhardt, Eileen M. O'Reilly, Alan P. Venook

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalJAMA Oncology
DOIs
StateAccepted/In press - Jan 1 2019

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Doxorubicin
Hepatocellular Carcinoma
Randomized Controlled Trials
Survival
Therapeutics
Liver Neoplasms
Disease-Free Survival
sorafenib
Medical Futility
Phase III Clinical Trials
Neutropenia
Bilirubin
Radiology
Communication
Outcome Assessment (Health Care)
Kidney

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Assessment of Treatment with Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients with Advanced Hepatocellular Carcinoma : Phase 3 CALGB 80802 Randomized Clinical Trial. / Abou-Alfa, Ghassan K.; Shi, Qian; Knox, Jennifer J.; Kaubisch, Andreas; Niedzwiecki, Donna; Posey, James; Tan, Benjamin R.; Kavan, Petr; Goel, Rakesh; Lammers, Philip E.; Bekaii-Saab, Tanios S.; Tam, Vincent C.; Rajdev, Lakshmi; Kelley, Robin K.; El Dika, Imane; Zemla, Tyler; Potaracke, Ryan I.; Balletti, Jennifer; El-Khoueiry, Anthony B.; Harding, James H.; Suga, Jennifer M.; Schwartz, Lawrence H.; Goldberg, Richard M.; Bertagnolli, Monica M.; Meyerhardt, Jeffrey; O'Reilly, Eileen M.; Venook, Alan P.

In: JAMA Oncology, 01.01.2019.

Research output: Contribution to journalArticle

Abou-Alfa, GK, Shi, Q, Knox, JJ, Kaubisch, A, Niedzwiecki, D, Posey, J, Tan, BR, Kavan, P, Goel, R, Lammers, PE, Bekaii-Saab, TS, Tam, VC, Rajdev, L, Kelley, RK, El Dika, I, Zemla, T, Potaracke, RI, Balletti, J, El-Khoueiry, AB, Harding, JH, Suga, JM, Schwartz, LH, Goldberg, RM, Bertagnolli, MM, Meyerhardt, J, O'Reilly, EM & Venook, AP 2019, 'Assessment of Treatment with Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients with Advanced Hepatocellular Carcinoma: Phase 3 CALGB 80802 Randomized Clinical Trial', JAMA Oncology. https://doi.org/10.1001/jamaoncol.2019.2792
Abou-Alfa, Ghassan K. ; Shi, Qian ; Knox, Jennifer J. ; Kaubisch, Andreas ; Niedzwiecki, Donna ; Posey, James ; Tan, Benjamin R. ; Kavan, Petr ; Goel, Rakesh ; Lammers, Philip E. ; Bekaii-Saab, Tanios S. ; Tam, Vincent C. ; Rajdev, Lakshmi ; Kelley, Robin K. ; El Dika, Imane ; Zemla, Tyler ; Potaracke, Ryan I. ; Balletti, Jennifer ; El-Khoueiry, Anthony B. ; Harding, James H. ; Suga, Jennifer M. ; Schwartz, Lawrence H. ; Goldberg, Richard M. ; Bertagnolli, Monica M. ; Meyerhardt, Jeffrey ; O'Reilly, Eileen M. ; Venook, Alan P. / Assessment of Treatment with Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients with Advanced Hepatocellular Carcinoma : Phase 3 CALGB 80802 Randomized Clinical Trial. In: JAMA Oncology. 2019.
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title = "Assessment of Treatment with Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients with Advanced Hepatocellular Carcinoma: Phase 3 CALGB 80802 Randomized Clinical Trial",
abstract = "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.",
author = "Abou-Alfa, {Ghassan K.} and Qian Shi and Knox, {Jennifer J.} and Andreas Kaubisch and Donna Niedzwiecki and James Posey and Tan, {Benjamin R.} and Petr Kavan and Rakesh Goel and Lammers, {Philip E.} and Bekaii-Saab, {Tanios S.} and Tam, {Vincent C.} and Lakshmi Rajdev and Kelley, {Robin K.} and {El Dika}, Imane and Tyler Zemla and Potaracke, {Ryan I.} and Jennifer Balletti and El-Khoueiry, {Anthony B.} and Harding, {James H.} and Suga, {Jennifer M.} and Schwartz, {Lawrence H.} and Goldberg, {Richard M.} and Bertagnolli, {Monica M.} and Jeffrey Meyerhardt and O'Reilly, {Eileen M.} and Venook, {Alan P.}",
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month = "1",
day = "1",
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journal = "JAMA oncology",
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TY - JOUR

T1 - Assessment of Treatment with Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients with Advanced Hepatocellular Carcinoma

T2 - Phase 3 CALGB 80802 Randomized Clinical Trial

AU - Abou-Alfa, Ghassan K.

AU - Shi, Qian

AU - Knox, Jennifer J.

AU - Kaubisch, Andreas

AU - Niedzwiecki, Donna

AU - Posey, James

AU - Tan, Benjamin R.

AU - Kavan, Petr

AU - Goel, Rakesh

AU - Lammers, Philip E.

AU - Bekaii-Saab, Tanios S.

AU - Tam, Vincent C.

AU - Rajdev, Lakshmi

AU - Kelley, Robin K.

AU - El Dika, Imane

AU - Zemla, Tyler

AU - Potaracke, Ryan I.

AU - Balletti, Jennifer

AU - El-Khoueiry, Anthony B.

AU - Harding, James H.

AU - Suga, Jennifer M.

AU - Schwartz, Lawrence H.

AU - Goldberg, Richard M.

AU - Bertagnolli, Monica M.

AU - Meyerhardt, Jeffrey

AU - O'Reilly, Eileen M.

AU - Venook, Alan P.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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