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.
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 > 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.
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).
Chemotherapy with cetuximab yields high response rates compared with historical controls,
and leads to significantly increased resectability.
Merck-Serono, Sanofi-Aventis, and Pfizer.
Copyright (c) 2010 Elsevier Ltd. All rights reserved.