Addition of cetuximab to chemotherapy increases tumour shrinkage leading to more curative surgery in advanced colorectal cancer

Adding cetuximab to neoadjuvant chemotherapy can shrink tumours leading to increased potentially curative surgery in patients who have colorectal cancer with inoperable metastatic liver lesions, finds research published in The Lancet Oncology.

Over half of all patients with colorectal cancer develop metastatic disease, most commonly in the liver. Surgical removal of colorectal liver metastases (CLM) is potentially curative, but about 80% of patients with CLM have inoperable disease and poor prognosis at presentation. However, previous research suggests that neoadjuvant treatment with irinotecan or oxaliplatin-based chemotherapy can shrink tumours and consequently make surgery viable.

Most colorectal cancers express epidermal growth factor receptor (EGFR), high levels of which are linked to more metastases and poorer outcome. Cetuximab is a monoclonal antibody that targets and disables EGFR and has been shown to prevent cancer cell growth, and might increase the effectiveness of chemotherapy in patients with CLM.

Gunnar Folprecht, from University Hospital Carl Gustav Carus, Dresden, Germany, and colleagues from Germany and Austria did the CELIM randomised trial to examine the effectiveness of adding cetuximab to neoadjuvant chemotherapy to improve tumour response and maximise rates of potentially curable surgery in patients with CLM.

109 patients were randomly assigned to treatment with cetuximab plus FOLFOX6 (oxaliplatin, fluorouracil, and folinic acid—group A) or cetuximab plus FOLFIRI (irinotecan, fluorouracil, and folinic acid—group B). Tumour response and suitability for surgery were assessed every 4 cycles (8 weeks) using CT or MRI. Patients with resectable disease after assessment were offered liver surgery. The authors also did a blinded surgical review of MRI and CT scans to provide an objective assessment of how suitability for surgery changed during treatment.

Findings showed that treatment with cetuximab resulted in high tumour response rates and a significant increase (28%) in the proportion of tumours that were amenable to surgery compared with at the start of the study.

Partial or complete tumour response was shown in 68% of patients in group A and 57% of patients in group B. Tumour response was higher in patients with KRAS wild-type tumours (70%) compared with patients with KRAS tumour mutations (41%), consistent with results of previous studies which have shown that this mutation confers resistance to cetuximab.

Overall, surgery was achieved in 36 of 106 patients (34%). Importantly, the blinded review found that treatment with cetuximab significantly increased the proportion of tumours that were amenable to surgery, with 60% (41 of 68 patients) of tumours judged to be resectable after treatment compared with 32% (22 of 68 patients) at the start of the study.

The treatment was generally well tolerated. Grade 3 toxicity occurred in 72% of patients, the most common toxicities being skin reactions and neutropenia (an abnormally low number of white blood cells).

The authors conclude: “Our data suggest that treatment with cetuximab and chemotherapy results in high confirmed tumour response rates...leading to…increased resectability…In the light of recent studies in metastatic colorectal cancer the value of further treatment intensification will be investigated.”