Optimal control of liver metastases with intravenous cetuximab and hepatic artery infusion of three-drug chemotherapy in patients with liver-only metastases from colorectal cancer: A European multicenter phase II trial.
TPS198 Background: Circadian clocks control drug metabolism and cell cycle over the 24 h in healthy liver and are disrupted in cancer cells (Lévi et al. Annu Rev Pharm. Toxicol 2010). Hepatic artery infusion (HAI) of chronomodulated (chrono) irinotecan, 5-FU and oxaliplatin offered a first proof of principle of improved therapeutic index in patients (pts) with liver metastases from colorectal cancer (mCRC) failing 3 prior chemotherapy (chemo) lines (Bouchahda et al. Cancer 2009). Intravenous cetuximab (iv cetux) addition could further enhance efficacy of HAI in pts with predominantly hepatic mCRC with wt K-Ras, through allowing complete macroscopic resections of metastases. Methods: This is among the first international trials specifically targeting liver mCRC for enhancing the rate of complete macroscopic resections. It is an open label nonrandomized strategic phase II study of iv cetux and HAI of irinotecan (180 mg/m2), 5-FU (2,800 mg/m2), and oxaliplatin (85 mg/m2) q 2-wks. The primary objective_is to increase from 15% to 30% the complete macroscopic resection rate of liver mCRC. Chemo is given as chrono or conventional infusion, according to institution. Secondary endpoints include the rates of pathologic complete responses, and relapses, and usual efficacy (RECIST) and toxicity (NCIC v3.0) criteria. Eligible patients received 1-3 prior chemo lines for mCRC, deemed as non resectable with curative intent in multidisciplinary staff meeting (<30% estimated residual liver after resection; prior progressive disease). Pts undergo partial hepatectomy after 3-9 courses whenever possible. Translational studies include a pharmacokinetic analysis of all drugs during 1st course (16 pts), a monitoring of cytokines and rest-activity rhythm at baseline, and during 1st and 4th course, and a genetic study in host and tumor cells for assessing clock and pharmacology gene determinants. Current status:21 of 60 expected pts are registered at 6 centers. Adequate safety in the initial 6 pts on each schedule led the French Agency (AFSSAPS) to let the trial proceed. Efficacy data are expected in March 2011.