Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced
hepatocellular carcinoma: a randomized trial.
Author(s): Abou-Alfa GK, Johnson P, Knox JJ, Capanu M, Davidenko I, Lacava J, Leung T,
Gansukh B, Saltz LB.
Affiliation(s): Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave,
New York, NY 10065, USA. abou-alg@mskcc.org
Publication date & source: 2010, JAMA. , 304(19):2154-60
CONTEXT: In a randomized phase 3 trial, 400 mg of sorafenib twice daily prolonged
overall survival of patients with advanced hepatocellular carcinoma (HCC) and
Child-Pugh A disease. In a phase 1 study, sorafenib combined with doxorubicin, 60
mg/m(2), was well tolerated by patients with refractory solid tumors. The
combination of sorafenib and doxorubicin in patients with advanced HCC has not
been evaluated in a phase 2 or 3 trial.
OBJECTIVE: To evaluate the efficacy and safety of doxorubicin plus sorafenib
compared with doxorubicin alone in patients with advanced HCC and Child-Pugh A
disease.
DESIGN, SETTING, AND PATIENTS: In a double-blind phase 2 multinational study,
conducted from April 2005 to October 2006, 96 patients (76% male; median age, 65
years [range, 38-82 years]) with advanced HCC, Eastern Cooperative Oncology Group
performance status 0 to 2, Child-Pugh A status, and no prior systemic therapy
were randomly assigned to receive 60 mg/m(2) of doxorubicin intravenously every
21 days plus either 400 mg of sorafenib or placebo orally twice a day. The date
of the last patient's follow-up was April 2008.
MAIN OUTCOME MEASURE: Time to progression as determined by independent review.
RESULTS: Following complete accrual, an unplanned early analysis for efficacy was
performed by the independent data monitoring committee, so the trial was halted.
The 2 patients remaining in the placebo group at that time were offered
sorafenib. Based on 51 progressions, 63 deaths, and 70 events for
progression-free survival, median time to progression was 6.4 months in the
sorafenib-doxorubicin group (95% confidence interval [CI], 4.8-9.2), and 2.8
months (95% CI, 1.6-5) in the doxorubicin-placebo monotherapy group (P = .02).
Median overall survival was 13.7 months (95% CI, 8.9--not reached) and 6.5 months
(95% CI, 4.5-9.9; P = .006), and progression-free survival was 6.0 months (95%
CI, 4.6-8.6) and 2.7 months (95% CI, 1.4-2.8) in these groups, respectively (P =
.006). Toxicity profiles were similar to those for the single agents.
CONCLUSIONS: Among patients with advanced HCC, treatment with sorafenib plus
doxorubicin compared with doxorubicin monotherapy resulted in greater median time
to progression, overall survival, and progression-free survival. The degree to
which this improvement may represent synergism between sorafenib and doxorubicin
remains to be defined. The combination of sorafenib and doxorubicin is not yet
indicated for routine clinical use.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00108953.
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