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Lancet Oncol. 2014 Jul;15(8):862-73. doi: 10.1016/S1470-2045(14)70227-X. Epub 2014 Jun 11.

Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial.

Collaborators (326)

Thaler J, Greil R, Gaenzer J, Eisterer W, Tschmelitsch J, Keil F, Samonigg H, Zabernigg A, Schmid F, Steger G, Steinacher R, Andel J, Jagdt B, Lang A, Fridrik M, Függer R, Hofbauer F, Woell E, Geissler D, Lenauer A, Prager M, D'Haens G, Kerger J, Deboever G, Ghillebert G, Polus M, Van Cutsem E, Kalantari HR, Delaunoit T, Goeminne JC, Peters M, Vergauwe P, Houbiers G, Humblet Y, Janssens J, Schrijvers D, Vanderstraeten E, Van Laethem JL, Vermorken J, Van Daele D, Ferrante M, Forget F, Hendlisz A, Yilmaz M, Nielsen SE, Vestermark L, Larsen J, Zawadi MA, Bouche O, Mineur L, Bennouna-Louridi J, Dourthe LM, Ychou M, Boucher E, Taieb J, Pezet D, Desseigne F, Ducreux M, Texereau P, Miglianico L, Rougier P, Fratte S, Levache CB, Merrouche Y, Ellis S, Locher C, Ramee JF, Garnier C, Viret F, Chauffert B, Cojean-Zelek I, Michel P, Lecaille C, Borel C, Seitz JF, Smith D, Lombard-Bohas C, Andre T, Gornet JM, Fein F, Coulon-Sfairi MA, Kaminsky MC, Lagasse JP, Luet D, Etienne PL, Gasmi M, Vanoli A, Nguyen S, Lobry C, Perrier H, Stremsdoerfer N, Laplaige P, Arsene D, Auby D, Bedenne L, Cochin P, Denis B, Geoffroy P, Piot G, Becouarn Y, Bordes G, Deplanque G, Dupuis O, Fruge F, Guimbaud R, Lecomte T, Lledo G, Sobhani I, Asnacios C, Azzedine A, Desauw C, Galais MP, Gargot D, Lam YH, Abakar-Mahamat A, Berdah JF, Catteau S, Clavero-Fabri MC, Codoul JF, De Ledinghen V, Goldfain D, Guichard P, Verge DP, Provencal J, Provencal J, Vedrenne B, Brezault-Bonnet C, Cleau D, Desir JP, Fallik D, Garcia B, Gaspard MH, Genet D, Hartwig J, Krummel Y, Budnik TM, Palascak-Juif V, Randrianarivelo H, Rinaldi Y, Aleba A, Darut-Jouve A, Hamon H, Wendehenne F, Matzdorff A, Stahl MK, Schepp W, Burk M, Mueller L, Folprecht G, Geissler M, Mantovani-Loeffler L, Hoehler T, Asperger W, Asperger W, Kroening H, von Weikersthal LF, Fuxius S, Groschek M, Meiler J, Trarbach T, Rauh J, Ziegenhagen N, Kretzchmar A, Graeven U, Nusch A, von Wichert G, Hofheinz RD, Kleber G, Schmidt KH, Vehling-Kaiser U, Baum C, Schuette J, Haag GM, Holtkamp W, Potenberg J, Reiber T, Schliesser G, Schmoll HJ, Schneider-Kappus W, Abenhardt W, Denzlinger C, Henning J, Derigs HG, Lambertz H, Ingulf BB, Caca K, Constantin C, Decker T, Eschenburg H, Gabius S, Hebart H, Hoffmeister A, Heinz-August H, Kremers S, Leithaeuser M, Mueller S, Wagner S, Daum S, Schlegel F, Stauch M, Heinemann V, Maiello E, Latini L, Zaniboni A, Amadori D, Aprile G, Barni S, Mattioli R, Martoni A, Passalacqua R, Nicolini M, Pasquini E, Rabbi C, Aitini E, Ravaioli A, Barone C, Biasco G, Tamberi S, Gambi A, Verusio C, Marzola M, Lelli G, Boni C, Cascinu S, Bidoli P, Vaghi M, Cruciani G, Di Costanzo F, Sobrero A, Mini E, Petrioli R, Aglietta M, Alabiso O, Capuzzo F, Falcone A, Corsi DC, Labianca R, Salvagni S, Chiara S, Ciuffreda L, Ferraù F, Vincenzo T, Giuliani F, Lonardi S, Gebbia N, Mantovani G, Sanches E, Mellidez JC, Santos P, Freire J, Sarmento C, Costa L, Pinto AM, Barroso S, Santo JE, Guedes F, Monteiro A, Sa A, Furtado I, Salazar R, Aguilar EA, Herrero FR, Tabernero J, Valera JS, Ayerbes MV, Batlle AF, Gil S, Esteve AA, Garcia-Giron C, Vivanco GL, Salvia AS, Orduña VA, Garcia RV, Gallego J, Sureda BM, Remon J, Aguilera MJ, Nogueras LC, Merino BQ, Merino BQ, Castro CG, Martinez de Prado P, Pijaume Pericay C, Constenla Figueiras M, Guasch Jordan I, Gome Reina MJ, Lopez-Ladron Garcia A, Garcia-Ramos AA, Cervantes A, Fernandez Martos C, Marcuello Gaspar E, Cabezas Montero I, Escudero Emperador P, Leon Carbonero A, Gallen Castillo M, Garcia Garcia T, Garcia Lopez J, Gonzalez Flores E, Guillot Morales M, Llanos Muñoz M, López Martín A, Maurel J, Camara JC, Dueñas Garcia R, Salgado M, Hernandez Busquier I, Checa Ruiz T, Lacasta Muñoa A, Nogue Aliguer M, Ortiz de Taranco AV, Mendez Ureña M, Losa Gaspa F, Ponce JJ, Bosch Roig C, Valero Jimenez P, Galan Brotons A, Albiol Rodriquez S, Ales Martinez J, Canosa Ruiz L, Centelles Ruiz M, Bridgewater J, Glynne-Jones R, Tahir S, Hickish T, Cassidy J, Samuel L.

Author information

1
Department of Gastroenterology and Digestive Oncology, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France. Electronic address: jtaieb75@gmail.com.
2
Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain.
3
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
4
Francophone Federation of Digestive Oncology, Cedex Dijon, France; University of Lyon, Lyon, France; Laboratoire de Biométrie et Biologie Evolutive, Villeurbanne, France; Hospices Civils de Lyon, Service de Biostatistique, Lyon, France.
5
1st Medical Department, University Hospital Carl Gustav Carus, Dresden, Germany.
6
Department of Gastroenterology, Hôpital Universitaire Erasme, Brussels, Belgium.
7
Department of Internal Medicine IV, Klinikum Kreuzschwestern Wels, Austria.
8
UCL Cancer Institute, University College London, London, UK.
9
Department of Oncology, Rigshospitalet, København, Denmark.
10
Université Paris Descartes, Sorbonne Paris Cité, France; Assistance Publique Hôpitaux de Paris, Department of Biology, Hôpital Européen Georges Pompidou, Paris, France; UMR-S775, INSERM, Centre Universitaire des Saints Pères, Paris, France.
11
Statistics Department, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium.
12
Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium.
13
Department of Gastroenterology and Digestive Oncology, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France.
14
Catalan Institute of Oncology (IDIBELL), Barcelona, Spain.
15
Hepato-Gastroenterology Department Dijon University Hospital and INSERM U 866, France.
16
EA4340 and Pathology Department, Versailles University and Ambroise Paré Hospital APHP, Boulogne, France.
17
Université Paris Descartes Sorbonne Paris Cité France; UMR-S775, INSERM, Bases Moléculaires de la Réponse aux Xénobiotiques, Paris France; Assistance Publique Hôpitaux de Paris, Department of Biology, Hôpital Européen Georges Pompidou, Paris, France.

Abstract

BACKGROUND:

Since the 1990s, fluorouracil-based adjuvant chemotherapy has significantly reduced the risk of tumour recurrence in patients with stage III colon cancer. We aimed to assess whether the addition of cetuximab to standard adjuvant oxaliplatin, fluorouracil, and leucovorin chemotherapy (FOLFOX4) in patients with stage III colon cancer improved disease-free survival (DFS).

METHODS:

For this open-label, randomised phase 3 study done in nine European countries, we enrolled patients through an interactive voice response system to the central randomisation centre, with a central stratified permuted block randomisation procedure. We randomly assigned patients with resected (R0) stage III disease (1:1) to receive 12 cycles of FOLFOX4 twice a week with or without cetuximab. Patients were stratified by N-status (N1 vs N2), T-status (T1-3 vs T4), and obstruction or perforation status (no obstruction and no perforation vs obstruction or perforation or both). A protocol amendment (applied in June, 2008, after 2096 patients had been randomly assigned to treatment-restricted enrolment to patients with tumours wild-type at codons 12 and 13 in exon 2 of the KRAS gene (KRAS exon 2 wild-type). The primary endpoint was DFS. Analysis was intention to treat in all patients with KRAS exon 2 wild-type tumours. The study is registered at EudraCT, number 2005-003463-23.

FINDINGS:

Between Dec 22, 2005, and Nov 5, 2009, 2559 patients from 340 sites in Europe were randomly assigned. Of these patients, 1602 had KRAS exon 2 wild-type tumours (intention-to-treat population), 791 in the FOLFOX4 plus cetuximab group and 811 in the FOLFOX4 group. Median follow-up was 3·3 years (IQR 3·2-3·4). In the experimental and control groups, DFS was similar in the intention-to-treat population (hazard ratio [HR] 1·05; 95% CI 0·85-1·29; p=0·66), and in patients with KRAS exon 2/BRAF wild-type (n=984, HR 0·99; 95% CI 0·76-1·28) or KRAS exon 2-mutated tumours (n=742, HR 1·06; 95% CI 0·82-1·37). We noted heterogeneous responses to the addition of cetuximab in preplanned subgroup analyses. Grade 3 or 4 acne-like rash (in 209 of 785 patients [27%] vs four of 805 [<1%]), diarrhoea (113 [14%] vs 70 [9%]), mucositis (63 [8%] vs 10 [1%]), and infusion-related reactions (55 [7%] vs 30 [4%]) were more frequent in patients treated with FOLFOX4 plus cetuximab than in those patients who received FOLFOX4 alone.

INTERPRETATION:

The addition of cetuximab to FOLFOX4 did not improve DFS compared with FOLFOX4 alone in patients with KRAS exon 2 wild-type resected stage III colon cancer. This trial cannot conclude on the benefit of cetuximab in the studied population, but the heterogeneity of response suggests that further investigation of the role of FOLFOX4 plus cetuximab in specific patient subgroups is warranted.

FUNDING:

Fédération Francophone de Cancérologie Digestive (FFCD), Merck KGaA, and Sanofi-Aventis.

PMID:
24928083
DOI:
10.1016/S1470-2045(14)70227-X
[Indexed for MEDLINE]
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