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Systemic chemotherapy typically converts previously unresectable liver metastases (LM) from colorectal cancer to curative intent resection in ∼15% of patients. This European multicenter phase II trial tested whether hepatic artery infusion (HAI) with triplet chemotherapy and systemic cetuximab could increase this rate to 30% in previously treated patients.Participants had unresectable LM from wt KRAS colorectal cancer. Main non-inclusion criteria were advanced extra hepatic disease, prior HAI and grade 3 neuropathy. Irinotecan (180 mg/m2), oxaliplatin (85 mg/m2) and 5-fluorouracil (2800 mg/m2) were delivered via an implanted HAI access port and combined with i.v. cetuximab (500 mg/m2) every 14 days. Multidisciplinary decisions to resect LM were taken after every three courses. The rate of macroscopic complete resections (R0 + R1) of LM, progression-free survival (PFS) and overall survival (OS) were computed according to intent to treat.The patient population consisted of 42 men and 22 women, aged 33–76 years, with a median of 10 LM involving a median of six segments. Up to 3 extrahepatic lesions of <1 cm were found in 41% of the patients. A median of six courses was delivered. The primary end point was met, with R0–R1 hepatectomy for 19 of the 64 previously treated patients, 29.7% (95% confidence interval 18.5–40.9). Grade 3–4 neutropenia (42.6%), abdominal pain (26.2%), fatigue (18%) and diarrhea (16.4%) were frequent. Objective response rate was 40.6% (28.6–52.3). Median PFS and OS reached 9.3 (7.8–10.9) and 25.5 months (18.8–32.1) respectively. Those with R0-R1 hepatectomy had a median OS of 35.2 months (32.6–37.8), with 37.4% (23.6–51.2) alive at 4 years.The coordination of liver-specific intensive chemotherapy and surgery had a high curative intent potential that deserves upfront randomized testing.EUDRACT 2007-004632-24, NCT00852228.