Adding Cetuximab to Chemo Curbs Survival in Resectable Colorectal Liver Metastasis

By Davd Douglas

February 18, 2020

NEW YORK (Reuters Health) - The combination of chemotherapy and the epidermal-growth-factor receptor (EGFR) antibody cetuximab shortens survival compared with chemotherapy alone in certain patients with colorectal cancer, according to an open-label randomized trial.

"The long-term data from the New EPOC study has demonstrated that the addition of cetuximab to chemotherapy as neoadjuvant in patients with operable colorectal liver metastasis confers a significant survival detriment of over two years," Dr. John A. Bridgewater and Dr. John N. Primrose, who worked on the study, told Reuters Health in a joint email.

"This," they add, "suggests that RAS and RAF status may not be the only biomarkers we need to exclude treatment with EGFR inhibitors like cetuximab and that molecular therapies should be used with caution in epithelial cancers with complex molecular pathologies."

In a paper in The Lancet Oncology, Dr. Bridgewater of University College London and Dr. Primrose of the University of Southampton, also in the UK, and their colleagues note that the original EPOC study showed an improvement in progression-free survival with the addition of perioperative systemic chemotherapy to surgical resection for colorectal liver metastasis.

To assess possible further benefits with EGFR inhibition, in New EPOC a total of 257 patients were randomized to receive chemotherapy with or without the addition of cetuximab. Follow-up at a median of 67 months showed that progression-free survival was longer in those treated with chemotherapy alone (22.2 months vs. 15.5 months), although the difference was not statistically significant at P=0.3.

Median overall survival, however, was significantly longer in the chemotherapy-alone group (81.0 vs. 55.4 months, P=0.036).

Cetuximab administration was subsequently stopped, and treatment defaulted to the standard of care, which, for most patients, was continuation of chemotherapy alone.

The researchers conclude that although the addition of cetuximab to chemotherapy has shown benefit in some studies in patients with advanced, inoperable metastatic disease, "its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting."

In an accompanying editorial, Drs. Sepideh Gholami and Axel Grothey point out, "In New EPOC, no significant differences were observed in the distribution of RAS/RAF mutations between treatment groups, but this observation does not rule out imbalances in other molecular alterations that could have affected sensitivity to EGFR antibody therapy."

Dr. Gholami, of the University of California, Davis, in Sacramento, added in an email to Reuters Health, "The results of the study are quite complex and conflicting. We simply don't understand why cetuximab and cytotoxic therapy (FOLFOX) in resectable stage IV and III colorectal cancer has detrimental effects. It is clear however, that EGFR antibodies really should not be used as a component of neoadjuvant or perioperative therapy for resectable stage-IV colorectal cancer."

"This," Dr Gholami concluded, "calls for additional interdisciplinary randomized controlled trials to understand combination treatment strategies and the biology in this patient population."

SOURCE: and The Lancet Oncology, online January 31, 2020.