Unexpected increased biliary toxicity when systemic bevacizumab is added to hepatic arterial infusion.

Abstract

3559 Background: Hepatic arterial infusion (HAI) with floxuridine + dexamethasone can be added safely and effectively to systemic (SYS) oxaliplatin + irinotecan in unresectable colorectal cancer liver metastases (CLM) and after CLM resection. HAI is also feasible in unresectable intrahepatic cholangiocarcinoma (primary liver, PL). Bevacizumab (Bev) is an active agent that was added to these HAI regimens to increase efficacy (disease-free survival) in CLM and PL. Methods: We combined Bev with HAI in 3 separate trials: (1) phase II trial of unresectable CLM with best SYS, (2) phase II trial in PL (no SYS), and (3) phase II randomized trial ± Bev after CLM resection with best SYS. The phase II trials of unresectable CLM and PL were compared to prior HAI trials (no Bev). The phase II trial after CLM resection compared two arms. Fisher's exact test was used to assess the association of clinicopathologic variables, e.g., Fong score, previous SYS, dose of HAI, KPS, blood tests, and toxicity data (grade 3-4 NCI CTCAEv3.0) with/without Bev. Bilirubin toxicity was reported as ≥ 2mg/dl. Multivariate analysis to further characterize risk of hepatic toxicity was not possible due to small numbers of events. Results: In all 3 trials patients exhibited similar characteristics. In univariate analyses, no clinicopathologic variable was significantly associated with increased risk of hepatic toxicity. Usual Bev toxicity (e.g., increased clotting and hypertension) was seen as expected. However, increased hepatic toxicity was also noted with the addition of Bev (Table). Conclusions: Although our analyses were limited by sample size, we found unexpected increased biliary toxicity with Bev+HAI±SYS resulting in increased biliary stenting. Impaired healing of HAI-induced biliary injury due to angiogenesis inhibition may be the mechanism of increased biliary toxicity. Efficacy data will be presented. Studies HAI ± SYS HAI ± SYS + BEV p value Colorectal adjuvant Stents 0 4 0.05 (n=73; 38 with Bev) Total bilirubin ≥ 2 0 5 0.02 SGOT 5 5 1.00 Colorectal unresectable Stents 0 3 0.06 (n=76; 30 with Bev) Total bilirubin ≥ 2 1 7 0.005 SGOT 6 0 0.08 Primary liver unresectable* Stents 0 2 0.15 (n=56; 22 with Bev) Total bilirubin ≥ 2 2 5 0.10 *No SYS SGOT 0 5 0.006 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Pfizer, sanofi-aventis