Phase I Study of Sorafenib and Whole-liver Radiation Therapy (WLRT) or Stereotactic Body Radiation Therapy (SBRT) for Liver Metastases

Abstract

SBRT has efficacy in selected patients with liver metastases but out-of-field progression is common despite local control. WLRT can palliate symptoms from diffuse liver metastases, but durable responses are rare. Sorafenib is a tyrosine kinase inhibitor that targets a number of kinases involved in angiogenesis including VEGFR-2/3 and PDGF-β. Preclinical data has suggested improved efficacy of RT in combination with VEGF axis inhibition. Thus, a phase I study evaluating sorafenib combined with SBRT and WLRT in patients with liver metastases was conducted. Eligible patients had metastases from solid cancers not suitable for standard local and systemic therapies, Child-Pugh A status, liver enzymes <5x normal, platelets >100,000. RT was delivered in 2 strata: (1) focal SBRT (with doses from 30 to 60 Gy in 6 fractions) and (2) diffuse WLRT (21.6 Gy in 6 fractions). Maximal permitted dose to luminal GI tract was 33 Gy. Sorafenib was dose escalated in each strata from 400 mg (200 mg po bid, level 1) to 600 mg (400 mg po q am and 200 mg po q pm, level 2) to 800 mg (400 mg po bid, level 3) over 4 weeks (pre-, during, and post-RT). Dose limiting toxicity (DLT) was defined as grade 3, 4, or 5 classic or nonclassic radiation induced liver disease (RILD) or any grade 4 or 5 RT-related toxicity. Evaluable patients received at least 75% of the study treatment and were followed for at least 3 months without liver PD. Fifty-three patients consented to participate in this study. Nineteen patients were screened ineligible, and 1 did not initiate therapy, leaving 33 eligible patients who initiated therapy (18 partial liver, 15 whole liver) with the most common diagnoses colon (10) and melanoma (7). In the partial liver SBRT cohort (doses 30 to 54 in 6 fractions, med dose: 42 Gy), no DLT was seen in 15 evaluable patients treated at level 1 (3), level 2 (6), and level 3 (6). One additional patient in level 2 was not evaluable due to discontinuation of sorafenib prior to RT due to sorafenib toxicity. Two other patients (1-level 2, 1-level 3) had sorafenib dose reductions to 200 mg daily due to sorafenib toxicity, without DLT. Three patients developed transient grade 3 chest wall pain (1-level 1, 2-level 2). Median survival was 14.0 months. In the WLRT strata, 2 grade 5 liver DLTs were seen: 1 of 6 evaluable patients at level 1, and 1 of 5 evaluable patients at level 2 (2 patients at 2-month follow-up). One grade 3 pneumonitis (level 2) and 1 chest wall pain (level 2) were also seen. Four additional WLRT patients died of other causes during RT (urosepsis, level 1) and at 3-3.5 months from progressive disease. Median survival of WLRT patients was 5.8 months. Full dose sorafenib can be combined safely with SBRT, although chest wall toxicity is increased. Serious toxicity was seen following low dose sorafenib combined with whole liver RT at 21.6 Gy.