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


RESULTS
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).


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


BACKGROUND
Merck-Serono, Sanofi-Aventis, and Pfizer.
Folprecht
Gunnar
G
University Hospital Carl Gustav Carus, Medical Department I/University Cancer Center, Dresden, Germany. Gunnar.Folprecht@uniklinikum-dresden.de
Gruenberger
Thomas
T
Bechstein
Wolf O
WO
Raab
Hans-Rudolf
HR
Lordick
Florian
F
Hartmann
Jörg T
JT
Lang
Hauke
H
Frilling
Andrea
A
Stoehlmacher
Jan
J
Weitz
Jürgen
J
Konopke
Ralf
R
Stroszczynski
Christian
C
Liersch
Torsten
T
Ockert
Detlev
D
Herrmann
Thomas
T
Goekkurt
Eray
E
Parisi
Fabio
F
Köhne
Claus-Henning
CH
D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001317:Austria; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D000068818:Cetuximab; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000473:pathology*; D066246:ErbB Receptors / Q000032:analysis; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use; D005858:Germany; D006498:Hepatectomy; D006801:Humans; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use; D016014:Linear Models; D008113:Liver Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary / Q000601:surgery*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020360:Neoadjuvant Therapy; D016017:Odds Ratio; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D018570:Risk Assessment; D013997:Time Factors; D036542:Tomography, Spiral Computed; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin