Doxorubicin Plus Sorafenib vs Doxorubicin Alone in Patients With Advanced Hepatocellular Carcinoma

Abstract

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, 8.9not 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.

Risk of venous thromboembolic events associated with VEGFR‐TKIs: A systematic review and meta‐analysis

“…Figure 1 outlined the selection process in detail. These trials represented three studies with sorafenib, 21,31,32 three with sunitinib, 20,33,34 three with vandetanib [35][36][37] and five with pazopanib. 2,[38][39][40][41] The characteristics of each included trial were presented in Table 2.…”

“…No VTEs were observed in one trial. 31 When stratified by each VEGFR-TKIs, the incidence was 5.5% (95%CI: 1.4-19%) for sorafenib, 0.5% (0.2-1.6%) for sunitinib, 2.2% (95%CI: 1.4-3.6%) for vandetanib, and 4.7% (95%CI, 2.5-8.7%) for pazopanib (Fig. 2).…”

Hepatocellular carcinoma (HCC): beyond sorafenib—chemotherapy

“…Therefore, the combination can increase area under the curve (AUC) of doxorubicin without worsening toxicities (71). In a doubleblind phase II study, sorafenib plus doxorubicin resulted in prolonged PFS (median PFS: 6.0 vs. 2.7 months, P=0.006) and OS (median OS: 13.7 vs. 6.5 months, P=0.006) compared with doxorubicin monotherapy (72). Based on the promising results of the phase II study, Cancer and Leukemia Group B (CALGB) conducted a phase III trial randomizing sorafenib plus doxorubicin compared to sorafenib alone.…”

Schedule-Dependent Effects of Kappa-Selenocarrageenan in Combination with Epirubicin on Hepatocellular Carcinoma

“…However, high doses of these drugs lead to severe toxicities, which have a negative effect on patients' survival (Berk et al, 2013). The use of less toxic doses in combination with other anti-proliferative agents would be desirable (Lee et al, 2004;Abou-Alfa et al, 2010). Genistein could reinforce the inhibitory effect of cisplatin on HCC cell proliferation and tumour recurrence and metastasis after curative hepatectomy in nude mice, possibly through mitigation of cisplatin-induced MMP-2 upregulation .…”