A multi-center phase II trial of bevacizumab (B) pre- and post-transarterial chemoembolization (TACE) treatment for patients with localized unresectable HCC: interim safety report

Abstract

BACKGROUND: TACE prolongs survival for selected patients with unresectable HCC. However, the outcome remains modest with low response rates and frequent disease progression (PD). A significantly elevated circulating VEGF level, which contributed to neovascularization and tumor re-growth, was reported following TACE (Schwartz et al., 2006). VEGF has a fundamental role in tumor angiogenesis and is targeted by the humanized mAb bevacizumab (B). Given the short half-life of B (1.4 days) and a peak circulating VEGF level days after TACE, this trial was initiated to investigate the feasibility and tolerability of adjunctive B pre- (within 24–48h) and post-TACE (2-weekly) for optimized inhibition of tumor angiogenesis. METHODS: Untreated pts with localized unresectable HCC received standard TACE (8–10 weekly) and B (5mg/kg 2-weekly iv). B was given 24–48h prior to each TACE. Both TACE and B were continued until PD or unacceptable toxicity. Screening esophagogastroduodenoscopy was used to exclude significant varices. Tumor response was monitored by MRI. The primary endpoint was PFS by RECIST. Other endpoints were OS, ORR, tumor necrosis rate and safety. Blood samples were collected to monitor circulating EPC and VEGF. RESULTS: 29 Asian pts were enrolled between Feb08 and Feb10. Baseline characteristics were: median age 62 years (range 43–78); 86% male; Child-Pugh A/B: n=27/2; BCLC A/B/C: n=7/18/4; etiology HBV/HCV/ALD/HCV&ALD: n=24/3/1/1; 1/2/multifocal tumor lesions: n=7/6/16; tumor size (largest nodule) <3cm/3–5cm/>5cm: n=4/11/14; vascular invasion yes/no: n=3/26; median platelet count 154x109/L (range 62–393x109); median bilirubin 11.9μmol/L (range 3.7–32.5); median albumin 38g/L (range 30–46); and grade 1/2 varices (no red sign): n=9. Up to the time of this report, pts have received a median of 3 TACE sessions (range 1–10) and a median of 12 B cycles (range 1–41).12 pts remained on the study. Most treatment-related toxicities (TRTs) were grade 1 or 2; grade 3/4 TRTs were hypertension (n=4), tumor rupture (n=2), and chest discomfort, right groin pseudoaneurysm, AST elevation, malaise, hyperbilirubinaemia, thrombocytopenia and abdominal pain (all n=1); no grade 5 TRTs. Neither tumor rupture was major; both had tumors in a subcapsular location; one was an internal rupture and one responded well to TACE. No variceal bleeding was observed. 6 deaths occurred mostly due to advanced disease, but none due to TRT. CONCLUSIONS: The current data suggests that it is safe to use B as an adjunctive agent pre- and post-TACE. Further trials should be considered to compare the survival of inoperable HCC patients undergoing TACE with and without adjunctive B.