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SAN FRANCISCO -- Patients with unresectable hepatocellular carcinoma (HCC) lived almost twice as long with treatable disease if they received transarterial chemoembolization (TACE) and sorafenib (Nexavar) compared with TACE alone, a randomized trial showed.

According to the trial's novel endpoint definition, patients had a median progression-free survival (PFS) of 25.2 with TACE and the VEGF inhibitor versus 13.5 months with TACE alone. The definition of PFS included the usual endpoints of disease progression and death but also the nonstandard definition of untreatable (un-TACEable) disease progression, according to Masatoshi Kudo, MD, PhD, of Kindai University in Osaka, Japan, and colleagues.

"This trial clearly showed that TACE, in combination with sorafenib, is a treatment option to improve clinical outcome and may be a standard of care in patients with intermediate-stage hepatocellular carcinoma," Kudo reported here at the Gastrointestinal Cancers Symposium (GICS).

"Longer sorafenib treatment duration -- 37.8 weeks -- may be the key to success of this trial, as compared with previous failed trials. New intrahepatic lesions should not be regarded as progressive disease or the stopping rule in a TACE combination trial."

A separate study reported at GICS showed that TACE plus radiotherapy significantly improved PFS and all other endpoints compared with sorafenib monotherapy in patients with advanced HCC and macroscopic vascular invasion (MVI).

The rationale for combining TACE and sorafenib came from observations that TACE causes a spike in intratumoral VEGF concentration. Individually, TACE and sorafenib have demonstrated ability to improve survival in patients with advanced HCC. Moreover, subgroup analyses of two randomized trials suggested that prolonged administration of sorafenib in combination with TACE might improve outcomes, Kudo noted.

Collectively, the evidence led to the , involving patients with unresectable HCC that is also considered not amenable to ablative strategies. Investigators at 33 Japanese centers randomized 156 patients to TACE alone or in combination with sorafenib. TACE procedures employed standard lipiodol emulsion containing epirubicin and miriplatin plus gelatin particles.

Patients randomized to sorafenib started treatment 2 to 3 weeks before the first TACE procedure and then daily thereafter. Sorafenib stopped 2 days before each subsequent TACE procedure and restarted 3 days afterward.

The primary endpoint was PFS, defined as progression to unTACEable status, TACE failure or refractory, and death. Overall survival was a co-primary endpoint. Secondary endpoints included time to unTACEable progression or TACE failure/refractoriness (TTUP), and time to (unTACEable) progression (TTP).

The primary analysis showed a statistically significant 11.7-month improvement in PFS with the combination therapy. The difference represented a 41% reduction in the hazard ratio (95% CI 0.41-0.87, P=0.006). Subgroup analysis showed a consistent benefit of as much as 75% in favor of combination therapy.

A preliminary survival analysis showed no difference between the groups. Kudo noted that the trial had reached 73.6% maturity for the protocol-specified analysis and that follow-up will continue until 100% maturity, when a final survival analysis will occur.

Analysis of the secondary endpoints also yielded significant advantages in favor of the combination: 26.7 versus 20.6 months for TTUP (HR 0.57, 95% CI 0.36-0.92, P=0.02) and 26.7 versus 16.4 months for TTP (HR 0.54, 95% CI 0.35-0.83, P=0.005).

Grade 3/4 adverse events that occurred more often in the combination arm included thrombocytopenia (12.8% versus 2.8%), hand-foot skin reaction (5.1% versus 0%), hypertension (10.3% versus 4.2%), increased lipase (15.4% versus 2.8%), increased amylase (7.7% versus 1.4%), neutropenia (5.1% versus 0%), fatigue (2.6% versus 0%), diarrhea (2.6% versus 0%), and erythema multiforme (2.6% versus 0%).

The randomized trial of TACE and sorafenib involved 90 patients with untreated advanced HCC and MVI. Patients randomized to TACE also received radiotherapy. The trial had a primary endpoint of PFS, said Sang Min Yoon, MD, of the University of Ulsan in Seoul, South Korea.

The primary endpoint was PFS at 12 weeks. Data analysis showed that the TACE-RT group had a 12-week PFS of 86.7% compared with 34.3% with sorafenib. The difference represented a 79% reduction in the hazard ratio in favor of TACE-RT (95% CI 0.12-0.37, P<0.001). The median PFS also favored TACE-RT (30.0 versus 11.3 weeks, HR 0.27, 95% CI 0.17-0.44, P<0.001).

Median time to progression was 31.0 versus 11.7 weeks in favor of TACE-RT (HR 0.28, 95% CI 0.17-0.46, P<0.001). Patients treated with TACE and RT lived about a year longer (55.0 versus 43.0 weeks, HR 0.61, 95% CI 0.38-0.98, P=0.04).