Phase 1 Trial of Sorafenib and Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma

Purpose

To determine the maximally tolerated dose of sorafenib delivered before, during, and after stereotactic body radiation therapy (SBRT) in hepatocellular carinoma (HCC).

Methods and Materials

Eligible patients had locally advanced Child-Pugh class A HCC, showed Eastern Cooperative Oncology Group performance status 0-1, and were ineligible for standard local-regional therapies. Sorafenib was dose escalated in 2 strata: (1) low effective irradiated liver volume (veff) < 30% and (2) high veff 30%to 60%. Sorafenib (400 mg daily = dose level 1) was administered for 12 weeks, with 6 fractions SBRT delivered weeks 2 and 3, and escalation to full dose (400 mg twice daily) after 12 weeks as tolerated. Standard 3 + 3 cohorts with dose escalation of sorafenib were planned.

Results

Sixteen patients (4 low veff, median dose 51 Gy; 12 high veff, median dose 33 Gy) were treated at 2 sorafenib dose levels. Of those patients 75% were had Barcelona Clinic Liver Cancer stage C, and 63% had main branch portal vein invasion. In the low veff stratum, no dose-limiting toxicities (DLTs) were observed in 4 patients treated with SBRT and sorafenib 400 mg. Inb the high veff stratum: 2 of 3 evaluable patients treated with sorafenib 400 mg experienced DLT (grade 3 large bowel bleed and grade 4 bowel obstruction 51 and 27 days, respectively, after SBRT). One of 6 evaluable patients at dose level −1 (200 mg once daily) experienced a grade 3 tumor rupture at week 5. Median overall survival and in-field local progression have not been reached. Worsening of Child-Pugh liver function class was seen in 6 of 12 patients in the high veff stratum.

Conclusions

Significant toxicity was observed in the high veff stratum, and concurrent SBRT with sorafenib is not recommended outside a clinical trial.

Introduction

Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide and a rapidly growing cause of cancer death in the United States 1, 2. Many HCC patients present with locally advanced disease and are not suitable for standard local-regional therapies.

Stereotactic body radiation therapy (SBRT) has demonstrated efficacy for patients with locally advanced HCC. With SBRT alone (6 fractions every other day), we previously described 102 patients with locally advanced HCC (55% vascular invasion), with 1-year survival and local control rates of 55% and 87%, respectively (3), comparable to those in other series 4, 5. Although some degree of liver toxicity is relatively common after SBRT for HCC (predominantly worsening of Child-Pugh score occurring in 10% to 30% of patients 3 months after SBRT), luminal gastrointestinal (GI) toxicity is uncommon (6), and severe luminal or liver toxicity is rare (2% and 3%, respectively) (3). The majority of patients with locally advanced HCC experience progression outside the irradiated volume, providing a rationale for combining SBRT with sorafenib.

Sorafenib, a tyrosine kinase inhibitor with activity against the c-raf vascular endothelial growth factor (VEGF)fr2/3 and platelet-derived growth factor-α kinases, is the standard-of-care systemic treatment for HCC, increasing overall survival in comparison with best supportive care (Child-Pugh class A) from 7.9 to 10.7 months in the Sorafenib HCC Assessment Randomized Protocol Trial (SHARP) phase 3 trial (7). Preclinical data from studies combining sorafenib and radiation therapy have suggested improved efficacy on HCC cell lines in vitro and in vivo (8). A phase 1 study was conducted to evaluate the combination of SBRT and sorafenib in patients with HCC.