title: Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial.
abstract: BACKGROUND
  Malignant pleural mesothelioma is an aggressive cancer with poor prognosis, linked to occupational asbestos exposure. Vascular endothelial growth factor is a key mitogen for malignant pleural mesothelioma cells, therefore targeting of vascular endothelial growth factor might prove effective. We aimed to assess the effect on survival of bevacizumab when added to the present standard of care, cisplatin plus pemetrexed, as first-line treatment of advanced malignant pleural mesothelioma.
  
  
  METHODS
  In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged 18-75 years with unresectable malignant pleural mesothelioma who had not received previous chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0-2, had no substantial cardiovascular comorbidity, were not amenable to curative surgery, had at least one evaluable (pleural effusion) or measurable (pleural tumour solid thickening) lesion with CT, and a life expectancy of >12 weeks from 73 hospitals in France. Exclusion criteria were presence of central nervous system metastases, use of antiaggregant treatments (aspirin ≥325 mg per day, clopidogrel, ticlopidine, or dipyridamole), anti-vitamin K drugs at a curative dose, treatment with low-molecular-weight heparin at a curative dose, and treatment with non-steroidal anti-inflammatory drugs. We randomly allocated patients (1:1; minimisation method used [random factor of 0·8]; patients stratified by histology [epithelioid vs sarcomatoid or mixed histology subtypes], performance status score [0-1 vs 2], study centre, or smoking status [never smokers vs smokers]) to receive intravenously 500 mg/m(2) pemetrexed plus 75 mg/m(2) cisplatin with (PCB) or without (PC) 15 mg/kg bevacizumab in 21 day cycles for up to six cycles, until progression or toxic effects. The primary outcome was overall survival (OS) in the intention-to treat population. Treatment was open label. This IFCT-GFPC-0701 trial is registered with ClinicalTrials.gov, number NCT00651456.
  
  
  RESULTS
  From Feb 13, 2008, to Jan 5, 2014, we randomly assigned 448 patients to treatment (223 [50%] to PCB and 225 [50%] to PC). OS was significantly longer with PCB (median 18·8 months [95% CI 15·9-22·6]) than with PC (16·1 months [14·0-17·9]; hazard ratio 0·77 [0·62-0·95]; p=0·0167). Overall, 158 (71%) of 222 patients given PCB and 139 (62%) of 224 patients given PC had grade 3-4 adverse events. We noted more grade 3 or higher hypertension (51 [23%] of 222 vs 0) and thrombotic events (13 [6%] of 222 vs 2 [1%] of 224) with PCB than with PC.
  
  
  CONCLUSIONS
  Addition of bevacizumab to pemetrexed plus cisplatin significantly improved OS in malignant pleural mesothelioma at the cost of expected manageable toxic effects, therefore it should be considered as a suitable treatment for the disease.
  
  
  BACKGROUND
  Intergroupe Francophone de Cancérologie Thoracique (IFCT).
authors.affiliation: Department of Pulmonology and Thoracic Oncology, University of Caen, Centre Hospitalier Universitaire Côte de Nacre, Caen, France; Department of Thoracic Oncology, Centre d'investigation clinique Institut national de la santé et de la recherche médicale 1425, Hospital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris-Diderot University (Paris 7), Paris, France. Electronic address: gerard.zalcman@aphp.fr.
authors.forename: Gérard
authors.initials: G
authors.lastname: Zalcman
authors.affiliation: Department of Pulmonology, Larrey Hospital, Toulouse, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Mazieres
authors.affiliation: Gustave Roussy Institute, Villejuif, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Margery
authors.affiliation: Assistance Publique Hôpitaux du Marseille, Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Greillier
authors.affiliation: Department of Pulmonology, Centre Hospitalier Intercommunal Toulon, Toulon, France.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Audigier-Valette
authors.affiliation: Pôle Thorax and Vaisseaux Centre Hospitalier Universitaire Grenoble, Grenoble, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Moro-Sibilot
authors.affiliation: Department of Pulmonology, Centre Hospitalier Le Mans, Le Mans, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Molinier
authors.affiliation: Department of Pulmonology, Ponchaillou University Hospital, Rennes, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Corre
authors.affiliation: Department of Pulmonology, Centre Hospitalier Intercommunal Créteil, Créteil, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Monnet
authors.affiliation: Hôpital Tenon, Assistance Publique Hopitaux du Paris, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Gounant
authors.affiliation: Department of Pulmonology, Hôpital d'instruction des armées Percy, Clamart, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rivière
authors.affiliation: Department of Pulmonology, Gabriel-Montpied University Hospital, Clermont-Ferrand, France.
authors.forename: Henri
authors.initials: H
authors.lastname: Janicot
authors.affiliation: Centre régional de lutte contre le cancer François Baclesse, Caen, France.
authors.forename: Radj
authors.initials: R
authors.lastname: Gervais
authors.affiliation: Department of Pulmonology, Centre Hospitalier Meaux, Meaux, France.
authors.forename: Chrystèle
authors.initials: C
authors.lastname: Locher
authors.affiliation: French Cooperative Thoracic Group, Paris, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Milleron
authors.affiliation: French Cooperative Thoracic Group, Paris, France.
authors.forename: Quan
authors.initials: Q
authors.lastname: Tran
authors.affiliation: French Cooperative Thoracic Group, Paris, France.
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Lebitasy
authors.affiliation: French Cooperative Thoracic Group, Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Morin
authors.affiliation: Department of Biostatistics and Clinical Research, Centre Hospitalier Universitaire Côte de Nacre, Caen, France; Equipe d'Accueil 4655, Caen Normandy University, Caen, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Creveuil
authors.affiliation: Department of Biostatistics and Clinical Research, Centre Hospitalier Universitaire Côte de Nacre, Caen, France; Equipe d'Accueil 4655, Caen Normandy University, Caen, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Parienti
authors.affiliation: Pulmonary and Thoracic Oncology Department, Centre Hospitalier Universitaire Lille, University of Lille, U1019 Institut national de la santé et de la recherche médicale, Centre d'Infection et d'Immunité de Lille, Lille, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Scherpereel
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000009:adverse effects; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects; D003404:Creatinine / Q000097:blood; D005260:Female; D006801:Humans; D006973:Hypertension / Q000453:epidemiology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D000068437:Pemetrexed / Q000008:administration & dosage* / Q000009:adverse effects; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011507:Proteinuria / Q000453:epidemiology; D013927:Thrombosis / Q000453:epidemiology; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D042461:Vascular Endothelial Growth Factor A; D000068437:Pemetrexed; D000068258:Bevacizumab; D003404:Creatinine; D002945:Cisplatin