Effective Salvage Therapy Of Liver-Only Colorectal Cancer Metastases With Chronomodulated Irinotecan-Fluorouracil-Oxaliplatin Via Hepatic Artery Infusion.

3585 Background: Cell cycle and pharmacology genes are controlled by the molecular clock in normal liver but not in tumors (Filipski et al. JNCI 2005). As a result, circadian-based hepatic artery infusions of 3 main active drugs (ChronoHAI) could improve both tolerability and efficacy in patients (pts) with liver metastases from colorectal cancer. Methods: The therapeutic potential of 3-drug chronoHAI was evaluated in 28 heavily pretreated non hospitalized pts with metastatic colorectal cancer (MCC). They received 5-day (d) q21 d courses (c) with d1 irinotecan (160 mg/m2 from 2 to 8 am, peak at 5 am) and d2–5 oxaliplatin (20 mg/m2/d from 10 am to 10 pm, peak at 4 pm) and 5-fluorouracil (600 mg/m2/d from 10 pm to 10 am, peak at 4 am). 149 courses (c) were given (median, 5 ; 1–15) using a multichannel pump (Mélodie, Aguettant, F). Toxicity was assessed q21 d and response q3 c with CT scan. Results: Pt characteristics: prior chemotherapy lines 1/2/3/4+: 3/4/8/13 pts; WHO Performance Status 0/1/2/3 : 12/9/6/1 pts; median age: 63 years (32–73); liver only: 21 pts; liver and lung: 7 pts. Treatment was withdrawn for thrombosis (6 pts) and/or Grade (gr) 3 abdominal pain (3 pts). Grade 3–4 diarrhea and vomiting respectively occurred in 6 pts (21%) and 4 pts (14%) and were the main toxicities. Leucopenia, anemia and thrombocytopenia were respectively encountered in 5, 2 and 1 pt (< 18%). NCIC gr 3 sensory neuropathy occurred in 4 pts and alopecia in 3 pts. Of 25 pts with measurable lesions, disease progressed in 11 pts (exclusively outside the liver for 3 pts) and was controlled in 14 pts (56%), including 8 objective responses - 32% [95% C.L. 13.4 to 50.6]. Partial hepatectomy was performed in 3 pts with measurable disease (12%): R0 (2 PR) and R1 (1 SD). Median Progression free survival is 5 months [2.5 to 7.5] and median survival is 18.4 mo [10.5 to 26.3]. Five pts are alive at 2 to 51 mo. Conclusions: 3-drug chronoHAI is safe in heavily pretreated pts and achieves consistent activity against colorectal cancer liver metastases despite prior failure to oxaliplatin, irinotecan and fluorouracil. The addition of systemic molecular targeted therapy could be useful for preventing extra hepatic dissemination. Supported by ARTBC, Hôpital P. Brousse, Villejuif, France No significant financial relationships to disclose.