Resectable colorectal liver metastasis in KRAS exon 2 wild-type patients: systemic chemotherapy with Cetuximab associated with shorter progression-free survival

Surgery for colorectal liver metastases results in an overall survival of about 40% at 5 years. Progression-free survival is increased with the addition of Oxaliplatin ( Eloxatin ) and Fluorouracil ( 5-FU ) chemotherapy.
The addition of Cetuximab ( Erbitux ) to these chemotherapy regimens results in an overall survival advantage in patients with advanced disease who have the KRAS exon 2 wild-type tumour genotype.
A study has assessed the benefit of addition of Cetuximab to standard chemotherapy in patients with resectable colorectal liver metastasis.

Patients with KRAS exon 2 wild-type resectable or suboptimally resectable colorectal liver metastases were randomised in a 1:1 ratio to receive chemotherapy with or without Cetuximab before and after liver resection.
Randomisation was done using minimisation with factors of surgical centre, poor prognostic tumour ( one or more of: greater than or equal to 4 metastases, N2 disease, or poor differentiation of primary tumour ), and previous adjuvant treatment with Oxaliplatin.

Chemotherapy consisted of Oxaliplatin 85 mg/m2 intravenously over 2 h and Fluorouracil bolus 400 mg/m2 intravenously over 5 min, followed by a 46 h infusion of Fluorouracil 2400 mg/m2 repeated every 2 weeks ( regimen one ) or Oxaliplatin 130 mg/m2 intravenously over 2 h and oral Capecitabine ( Xeloda ) 1000 mg/m2 twice daily on days 1-14 repeated every 3 weeks ( regimen two ).
Patients who had received adjuvant Oxaliplatin could receive Irinotecan ( Campto, Camptosar ) 180 mg/m2 intravenously over 30 min with Fluorouracil instead of Oxaliplatin ( regimen three ). Cetuximab was given as an intravenous dose of 500 mg/m2 every 2 weeks with regimen one and three or a loading dose of 400 mg/m2 followed by a weekly infusion of 250 mg/m2 with regimen two.

The primary endpoint was progression-free survival.

This is an interim analysis, up to Nov 1, 2012, when the trial was closed, having met protocol-defined futility criteria.

128 KRAS exon 2 wild-type patients were randomised to chemotherapy alone and 129 to chemotherapy with Cetuximab during the period 2007-2012.
117 patients in the chemotherapy alone group and 119 in the chemotherapy plus cetuximab group were included in the primary analysis.
The median follow-up was 21.1 months in the chemotherapy alone group and 19.8 months in the chemotherapy plus Cetuximab group.

With an overall median follow-up of 20.7 months and 123 ( 58% ) of 212 required events observed, progression-free survival was significantly shorter in the chemotherapy plus Cetuximab group than in the chemotherapy alone group ( 14.1 months vs 20.5 months, hazard ratio, HR=1.48; p=0.030 ).

The most common grade 3 or 4 adverse events were low neutrophil count ( 11% preoperatively in the chemotherapy alone group vs 4% in the chemotherapy plus Cetuximab group; 4% vs 8% postoperatively ), embolic events ( 4% vs 6% preoperatively; 2% vs 3% postoperatively ), peripheral neuropathy ( 4% vs 1% preoperatively; 2% vs 4% postoperatively ), nausea or vomiting ( 3% vs 4% preoperatively; 4% vs 2% postoperatively ), and skin rash ( 1% vs 15% preoperatively; 0 vs 8% postoperatively ).

There were three deaths in the chemotherapy plus Cetuximab group ( one interstitial lung disease and pulmonary embolism, one bronchopneumonia, and one pulmonary embolism ) and one in the chemotherapy alone group ( heart failure ) that might have been treatment related.

In conclusion, the addition of Cetuximab to chemotherapy and surgery for operable colorectal liver metastases in KRAS exon 2 wild-type patients results in shorter progression-free survival.
Translational investigations to explore the molecular basis for this unexpected interaction are needed but at present the use of Cetuximab in this setting cannot be recommended. ( Xagena )

Primrose J et al, The Lancet Oncology 2014; 15: 601-611


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