Elsevier

The Lancet Oncology

Volume 11, Issue 1, January 2010, Pages 38-47
The Lancet Oncology

Articles
Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial

https://doi.org/10.1016/S1470-2045(09)70330-4Get rights and content

Summary

Background

Neoadjuvant chemotherapy for unresectable colorectal liver metastases can downsize tumours for curative resection. We assessed the effectiveness of cetuximab combined with chemotherapy in this setting.

Methods

Between Dec 2, 2004, and March 27, 2008, 114 patients were enrolled from 17 centres in Germany and Austria; three patients receiving FOLFOX6 alone were excluded from the analysis. Patients with non-resectable liver metastases (technically non-resectable or ≥5 metastases) were randomly assigned to receive cetuximab with either FOLFOX6 (oxaliplatin, fluorouracil, and folinic acid; group A) or FOLFIRI (irinotecan, fluorouracil, and folinic acid; group B). Randomisation was not blinded, and was stratified by technical resectability and number of metastases, use of PET staging, and EGFR expression status. They were assessed for response every 8 weeks by CT or MRI. A local multidisciplinary team reassessed resectability after 16 weeks, and then every 2 months up to 2 years. Patients with resectable disease were offered liver surgery within 4–6 weeks of the last treatment cycle. The primary endpoint was tumour response assessed by Response Evaluation Criteria In Solid Tumours (RECIST), analysed by modified intention to treat. A retrospective, blinded surgical review of patients with radiological images at both baseline and during treatment was done to assess objectively any changes in resectability. The study is registered with ClinicalTrials.gov, number NCT00153998.

Findings

56 patients were randomly assigned to group A and 55 to group B. One patient in each group were excluded from the analysis of the primary endpoint because they discontinued treatment before first full dose, one patient in group B was excluded because of early pulmonary embolism. A confirmed partial or complete response was noted in 36 (68%) of 53 patients in group A, and 30 (57%) of 53 patients in group B (difference 11%, 95% CI −8 to 30; odds ratio [OR] 1·62, 0·74–3·59; p=0·23). The most frequent grade 3 and 4 toxicities were skin toxicity (15 of 54 patients in group A, and 22 of 55 patients in group B), and neutropenia (13 of 54 patients in group A and 12 of 55 patients in group B). R0 resection was done in 20 (38%) of 53 patients in group A and 16 (30%) of 53 of patients in group B. In a retrospective analysis of response by KRAS status, a partial or complete response was noted in 47 (70%) of 67 patients with KRAS wild-type tumours versus 11 (41%) of 27 patients with KRAS-mutated tumours (OR 3·42, 1·35–8·66; p=0·0080). According to the retrospective review, resectability rates increased from 32% (22 of 68 patients) at baseline to 60% (41 of 68) after chemotherapy (p<0·0001).

Interpretation

Chemotherapy with cetuximab yields high response rates compared with historical controls, and leads to significantly increased resectability.

Funding

Merck-Serono, Sanofi-Aventis, and Pfizer.

Introduction

Over half of patients with colorectal cancer will develop metastatic disease, with a quarter having distant metastatic lesions at diagnosis,1 often in the liver. Surgical resection of colorectal liver metastases is a potentially curative option, with reported 5-year survival of 28–39%.2, 3, 4, 5 However, about 80% of patients with colorectal liver metastases have unresectable disease at presentation,5 and long-term survival is low. Decisions about whether to resect colorectal liver metastases are driven by technical considerations, including the volume of functional liver remnant following resection (>20–30%), and the involvement of non-resectable structures. Additionally, these decisions are affected by prognostic factors—ie, the number of liver metastases, primary tumour stage, disease-free interval, or the presence of extra-hepatic disease.2, 3, 6 In the EORTC 40983 trial for resectable liver metastases, resectability was defined as being technically resectable, and four liver metastases or fewer.7 Therefore, despite all definitions, there will be a subjective component in the decision-making process by the treating physicians in clinical practice.

Historically, patients with unresectable colorectal liver metastases have received mainly palliative chemotherapy. However, retrospective studies report the downsizing of colorectal liver metastases for rescue surgery following treatment with combinations of fluorouracil, with or without irinotecan or oxaliplatin, with resection of 12·5–28%8, 9 and 5-year survival of 33–50%.9, 10 These resection rates have been confirmed in prospective (phase 2) studies of neoadjuvant FOLFOX (oxaliplatin, fluorouracil, and folinic acid) or FOLFIRI (irinotecan, fluorouracil, and folinic acid) regimens in this setting.11, 12 In retrospective analysis, a direct correlation between tumour response rate and resection rate has been shown in studies investigating patients with unresectable colorectal liver metastases.13 Therefore, the goal of current medical treatment for unresectable CLM is to improve tumour response rates to maximise the rates of potentially curative resection.

Cetuximab, was initially approved for use in patients with epidermal growth factor receptor (EGFR)-detectable metastatic colorectal cancer who failed irinotecan therapy.14 Recently, randomised studies have shown that the addition of cetuximab to first-line chemotherapy (FOLFOX or FOLFIRI) significantly improves efficacy in patients without activating mutations of the KRAS gene in their tumours (KRAS wild-type tumours).15, 16 Activating mutations in the BRAF gene have also been shown to be associated with resistance to EGFR antibodies.17

To date, few studies have formally analysed tumour response and resection rates in a randomised trial. This multicentre study aimed to assess these endpoints in patients with clearly defined unresectable CLM receiving neoadjuvant cetuximab plus FOLFOX6 or FOLFIRI. Finally, to provide an objective assessment of changes in resectability, a formal retrospective review of radiological images taken at baseline and after treatment was done by surgeons blinded to clinical data.

Section snippets

Patients

This was an open, multicentre randomised phase 2 study that examined the effectiveness of cetuximab and either FOLFOX6 or FOLFIRI in neoadjuvant treatment of unresectable colorectal liver metastases (CELIM trial). The primary endpoint was response rate. Secondary endpoints included R0 resection rate, progression-free survival, overall survival, and safety, and an assessment of predictive molecular markers of response and toxicity.

A FOLFOX6-only group for patients with EGFR-undetectable tumours

Results

Between Dec 2, 2004, and March 27, 2008, 114 patients were enrolled from 17 centres in Germany and Austria; three patients receiving FOLFOX6 alone were excluded from the analysis (figure 1). Of 111 patients randomly assigned, two allocated to receive cetuximab plus FOLFOX6 (group A) did not receive treatment. Therefore, 109 patients were treated and assessed for toxicity. One patient in each group discontinued treatment before receiving the first full dose, and one patient in group B was not

Discussion

In our study of patients with colorectal liver metastases, high tumour-response rates were achieved with cetuximab and either FOLFIRI or FOLFOX6. This translated into a high rate of metastasectomy. In accordance with other studies in this setting, response rates were highest in KRAS wild-type tumours. An improved level of resectability was confirmed following a retrospective review of imaging scans. Treatment was generally found to be tolerable, with perioperative mortality in keeping with

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