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Lancet Oncol. 2013 Jan;14(1):29-37. doi: 10.1016/S1470-2045(12)70477-1. Epub 2012 Nov 16.

Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial.

Collaborators (230)

Andel J, Balcke P, Benedicic B, Eisterer W, Fridrik M, Jagdt B, Keil F, Kretschmer A, Krippl P, Oexle H, Pecherstorfer M, Samonigg H, Schmid M, Thaler J, Tinchon C, Weiss H, Arts J, De Man M, Demolin G, Janssens J, Polus M, Benczikova B, Melichar B, Prausova J, Vitek P, Andersen FZ, Jensen BB, Keldsen N, Østerlind K, Vistisen K, Elme A, Magi A, Ojamaa K, Ristamäki R, Salminen T, Ben Abdelghani M, Bouhier-Leporrier K, Breysacher G, Chone L, Clavero Fabri MC, Deplanque G, Desseigne F, Dourthe LM, Ezenfis J, Faroux R, François E, Garnier C, Gaspard MH, Hebbar M, Illory JF, Kaminsky MC, Lecomte T, Legoux JL, Levache B, Lobry C, Lotz JP, Mabro M, Manet-Lacombe S, Manfredi S, Matysiak Budnik T, Miglianico L, Mineur L, Moullet I, Naman H, Nouyrigat P, Oziel-Taieb S, Perrier H, Pezet D, Philip J, Pottier V, Porneuf M, Ramdani M, Re D, Rinaldi Y, Spaeth D, Taieb J, Terrebonne E, Texereau P, Thirot BA, Tournigand C, Tubiana-Mathieu N, Vantelon JM, Viret F, Ychou M, Bangerter M, Bertram ME, Bohnsteen B, Brinkmann L, Caca K, Constantin C, Cordes H, Dietrich G, Eggert J, Engel E, Fahlke J, Fensterer H, Florschütz A, Folprecht G, Forstbauer H, Freier W, Freund M, Frickhofen N, Gäbele E, Geißler M, Gieseler F, Göhler T, Graeven U, Groschek M, Grundeis M, Hacker U, Hagen V, Hebart HF, Hegewisch-Becker S, Heike M, Herrmann T, Hildebrandt B, Höffkes HG, Hübner G, Hübner J, Kettner E, Kneba M, Kohnke JW, Kojouharoff G, König C, Kretzschmar A, Kröning H, Kürner K, Lammert F, Lerchenmüller C, Lück A, Meiler J, Mergenthaler HG, Müller L, Müller-Naendrup C, Nusch A, Papke J, Porschen R, Rädle J, Reddemann C, Ridwelski K, Riera-Knorrenschild J, Rudi J, Schmalenberger A, Schimanski CC, Schlegel F, Schmidt P, Schmiegel W, Schmitz S, Schulze-Bergkamen H, Schwaner I, Schwarzer A, Schwerdtfeger M, Selbach J, Sieber M, Siebler J, Staib P, Stauch M, Stübs P, Tischendorf J, Trarbach T, Tummes D, Valdix AR, Vogel A, Von Wichert GP, Walther M, Welslau W, Wilhelm G, Wobster H, Wolf T, Zeigenhagen N, Zomorodbaksch B, Batman E, Bloemendal HJ, Kehrer DF, Guren T, Indrebø G, Kersten C, Sorbye H, Fragoso M, Fragoso R, Mellidez JC, Sa A, Aljobran A, Darwish T, Aparicio J, Aranda E, Bosch C, Galan-Brotons A, Busquier Hernandez I, Camara JC, Campos Cervera JM, Carlos Garcia Giron C, Del Prado PM, Donnay O, Escudero P, Falco E, Gallego Plazas J, Garcia Alfonso P, Gonzalez Flores E, Gravalos C, Guardeno R, Juárez A, Lopez Ladron A, Losa Gaspa F, Ma Vicent Vergé J, Marcuello Gaspar E, Massuti Sureda B, Molina J, Montero IC, Muñoa AL, Naranjo MB, Oruezabal Moreno MJ, Pachón Olmos V, Pericay C, Reina Zoilo JJ, Rivera F, Ruiz Casado A, Safont MJ, Salud Salvia A, Tobena M, Toral JC, Valenti V, Valladares Ayerbes M, Vera R, Berglund A, Fernebro E, Hess-Umbricht V, Pless M, Popescu R, Winterhalder R.

Author information

1
Institut de Cancérologie de l'Ouest, Nantes, France.

Abstract

BACKGROUND:

Bevacizumab plus fluoropyrimidine-based chemotherapy is standard treatment for first-line and bevacizumab-naive second-line metastatic colorectal cancer. We assessed continued use of bevacizumab plus standard second-line chemotherapy in patients with metastatic colorectal cancer progressing after standard first-line bevacizumab-based treatment.

METHODS:

In an open-label, phase 3 study in 220 centres in Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, the Netherlands, Norway, Portugal, Saudi Arabia, Spain, Sweden, and Switzerland, patients (aged ≥18 years) with unresectable, histologically confirmed metastatic colorectal cancer progressing up to 3 months after discontinuing first-line bevacizumab plus chemotherapy were randomly assigned in a 1:1 ratio to second-line chemotherapy with or without bevacizumab 2·5 mg/kg per week equivalent (either 5 mg/kg every 2 weeks or 7·5 mg/kg every 3 weeks, intravenously). The choice between oxaliplatin-based or irinotecan-based second-line chemotherapy depended on the first-line regimen (switch of chemotherapy). A combination of a permuted block design and the Pocock and Simon minimisation algorithm was used for the randomisation. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00700102.

FINDINGS:

Between Feb 1, 2006, and June 9, 2010, 409 (50%) patients were assigned to bevacizumab plus chemotherapy and 411 (50%) to chemotherapy alone. Median follow-up was 11·1 months (IQR 6·4-15·6) in the bevacizumab plus chemotherapy group and 9·6 months (5·4-13·9) in the chemotherapy alone group. Median overall survival was 11·2 months (95% CI 10·4-12·2) for bevacizumab plus chemotherapy and 9·8 months (8·9-10·7) for chemotherapy alone (hazard ratio 0·81, 95% CI 0·69-0·94; unstratified log-rank test p=0·0062). Grade 3-5 bleeding or haemorrhage (eight [2%] vs one [<1%]), gastrointestinal perforation (seven [2%] vs three [<1%]), and venous thromboembolisms (19 [5%] vs 12 [3%]) were more common in the bevacizumab plus chemotherapy group than in the chemotherapy alone group. The most frequently reported grade 3-5 adverse events were neutropenia (65 [16%] in the bevacizumab and chemotherapy group vs 52 [13%] in the chemotherapy alone group), diarrhoea (40 [10%] vs 34 [8%], respectively), and asthenia (23 [6%] vs 17 [4%], respectively). Treatment-related deaths were reported for four patients in the bevacizumab plus chemotherapy group and three in the chemotherapy alone group.

INTERPRETATION:

Maintenance of VEGF inhibition with bevacizumab plus standard second-line chemotherapy beyond disease progression has clinical benefits in patients with metastatic colorectal cancer. This approach is also being investigated in other tumour types, including metastatic breast and non-small cell lung cancers.

FUNDING:

F Hoffmann-La Roche.

Comment in

PMID:
23168366
DOI:
10.1016/S1470-2045(12)70477-1
[Indexed for MEDLINE]
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