Phase I trial of radiation therapy and sorafenib in unresectable liver metastases.

Abstract

To determine maximum tolerated dose (MTD) and toxicities of sorafenib combined with stereotactic radiotherapy (SBRT) or whole liver radiotherapy (WLRT) in patients with liver metastases. Eligible patients had unresectable liver metastases. Sorafenib dose was escalated in 2 strata: I - SBRT: effective liver volume irradiated (V_eff)<80% (30-60Gy in 6 fractions); II - WLRT: V_eff>80% (21.6Gy in 6 fractions). Four weeks of sorafenib, with radiotherapy during weeks 2-3, was delivered at 3 escalating dose levels (200-400mg twice daily). Dose limiting toxicity was defined as any grade 3+ liver toxicity, or grade 4+ treatment-related toxicity. Thirty-three patients were treated: 18 in stratum I (median dose 42Gy), 15 in stratum II. The MTD was not reached. Grade 3+ toxicity was seen in 33% of patients, at a median of 10days. Two deaths from non-classic liver toxicity occurred post WLRT in stratum II. The median overall survival was 22.3 and 5.7months for strata I and II respectively. Sorafenib and 21.6Gy in 6 fraction WLRT resulted in unacceptably high rates of liver toxicity. Although sorafenib combined with SBRT was tolerable, the observed efficacy does not merit further clinical evaluation.