Cetuximab and Chemotherapy for Patients with Unresectable CRC Liver Metastasis: Are We Changing the Natural Course of the Disease?

Delaunoit et al. evaluated the secondary resection rate among 795 patients treated within the Intergroup Study N9741 this being a more unselected setting in the context of a large cooperative group [10]. 24 patients (3.3%) underwent secondary resections: 2 patients treated with IFL, 11 with FOLFOX4, and 11 with IROX. The median survival was not reached in the resected group at the time of the publication, whereas patients who achieved a partial response but who did not undergo resection had a median survival of 21 months. Globally, these data show that neoadjuvant chemotherapy can potentially render some peviously unresectable patients resectable, with the possibility of prolonged survival. Further improvements in treatment are likely to be facilitated by the use of rationally selected therapeutic agents that target functionally important proteins in tumour cells, such as the epidermal growth factor receptor (EGFR), expressed in 75–89% of CRCs [11]. Cetuximab (Erbitux®, Merck Pharma GmbH, Darmstadt, Germany), an IgG1 monoclonal antibody (MAb) directed to the ectodomain of the EGFR, has demonstrated clear activity, both as a single agent and when combined with irinotecan in mCRC patients who have failed irinotecan-based therapy [12]. Furthermore, the combination of cetuximab with different irinotecan/5-FU/LV regimens has shown an acceptable safety profile and promising RR (43–67%) in the first-line setting [13–16]. In this issue of the journal, Min et al. [17] present the results of a phase II clinical trial designed to investigate the ability of the combination of cetuximab with the chemotherapy schedule of irinotecan, and 5-FU/LV (FOLFIRI) in downsizing initially unresectable mCRC patients with liver metastases. Of the 23 patients enrolled in the study, 9 patients presented an objective response, the RR being 39.1%. Potentially curative resection of liver metastases could be performed in 7 out of the 23 patients included, the secondary hepatic resection rate being 30.4%. Colorectal cancer (CRC) is the second most frequent cause of cancer-related death in Europe [1]. Liver metastases are the main cause of death in this patient population. Approximately 20% of patients have liver metastases at the time the primary tumour is diagnosed, and 25% more will develop metastatic lesions in the follow-up after they undergo resection of their primary tumour. For selected patients who have recurrent disease that is confined to the liver, surgical resection of the metastases is the treatment of choice, with a 5-year survival rate of approximately 40% reported in the recent literature [2, 3]. Although there have been substantial advances in the treatment of metastatic CRC (mCRC) median survival remains below 2 years and less than 5% of patients survive for more than 5 years [4–6]. However, chemotherapy can render previously unresectable liver metastases operable, conferring the possibility of curative surgery. The original experience from the Paul Brousse Hospital in France reported by Bismuth and Giacchetti in patients with initially unresectable mCRC treated with oxaliplatin/5-Fluorouracil (5-FU)/Leucovorin (LV) showed a salvage hepatic resection rate between 16 and 38% [7, 8]. The 5-year survival rate after liver resection in the report by Bismuth et al. was 40%, and the median survival in the report by Giacchetti et al. was 48 months for the patients who underwent resection and 15.5 months in the patients who did not undergo resection. Subsequent trials confirmed the ability of neoadjuvant chemotherapy to render patients resectable. Alberts et al. reported a 62% response rate (RR) in 42 patients with initially unresectable liver metastasis treated with FOLFOX4 and secondary resection was possible in 17 patients (41%). The median survival for the global population of the study was 31.4 months [9]. The encouraging results mentioned above are obtained in these much selected populations of patients with mCRC predominantly with liver metastasis only treated at highly qualified centres with devoted hepatic surgery teams.