Cetuximab and neoadjuvant chemotherapy may decrease survival in liver metastasis

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1. The addition of cetuximab to chemotherapy before and after surgery decreases survival in colorectal cancer with resectable liver metastases.

2. The negative effect of cetuximab was most significant in tumors with normally more favorable prognostic factors.

Evidence rating: 1 (Excellent)

Study Rundown:  The EGFR inhibitor, cetuximab, has been previously shown to increase survival in advanced colorectal cancer when combined with chemotherapy.  While cetuximab’s advantage only pertains to the 60% of tumors that express wild-type KRAS gene, it may also play a similar role in increasing survival when combined with surgery for colorectal carcinoma with liver metastasis.  In the EPOC trial, investigators studied the effect of adding cetuximab to standard chemotherapy regimens before and after surgery for colorectal cancer with resectable liver metastasis.  Only tumors with confirmed wild-type KRAS alleles were included in the study.  The chemotherapy backbone was oxaliplatin, in addition to three permutations of fluorouracil and capecitabine.  117 patients were randomized to chemotherapy alone and 119 were randomized to chemotherapy plus cetuximab; all patients underwent surgery.  This trial was stopped once futility criteria showed that progression-free survival was significantly less in the group treated with cetuximab.  Interestingly, the adverse effect of cetuximab was most pronounced in subgroups with a more favorable baseline prognosis (i.e. well differentiated primary tumor, fewer metastases, and absence of nodal disease).  While safety is always prioritized in large trials, one limitation of this study was that only 58% of the events required to reach the predetermined statistical power of the study occurred.

Click to read the study in Lancet Oncology

Relevant reading: Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer

In Depth [randomized controlled trial]: In this randomized controlled trial, chemotherapy-naïve patients with wild-type KRAS colorectal cancer with resectable liver metastases were identified.  117 patients were randomized to 6 weeks of neoadjuvant chemotherapy alone, followed by surgery four weeks later, and the same regimen for six weeks after.  119 patients were randomized to the same regimen, with the addition of cetuximab.  The two treatment arms were well matched in terms of both demographics and disease burden.  The primary endpoint of the trial was progression free survival, which was defined as time from randomization to death, disease recurrence, or disease progression.  Median follow-up was 21.1 months.  Median progression free survival for the standard chemotherapy group was 20.5 months compared to 14.1 months for the chemotherapy plus cetuximab (Hazard ratio 1.48, 95% confidence interval: 1.04-2.12, p=0.03).   The trial was declared futile and terminated after 56 events in the chemotherapy group and 67 events in the chemotherapy plus cetuximab group.  Comparisons of survival were done using Cox proportional-hazards regression and Kaplan-Meier curves.

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