title: Phase II study of first-line bortezomib and cisplatin in malignant pleural mesothelioma and prospective validation of progression free survival rate as a primary end-point for mesothelioma clinical trials (European Organisation for Research and Treatment of Cancer 08052).
abstract: BACKGROUND
  This was a prospective phase II study of cisplatin and bortezomib (CB) in the first line treatment of malignant pleural mesothelioma (MPM) with validation of progression free survival rate at 18 weeks (PFSR-18)(1) as primary end-point.
  
  
  METHODS
  Chemotherapy-naïve patients with histologically proven MPM and performance status (PS) 0/1, were treated with cisplatin 75 mg/m(2) on day 1 and bortezomib 1.3mg/m(2) on days 1, 4, 8, 11 every 3 weeks. The primary end-point validation utilised the landmark method.
  
  
  RESULTS
  Between 2007 and 2010 82 patients were entered. PFSR-18 was 53% (80% confidence intervals, CIs, 42-64%). The overall survival (OS) was 13.5 months (95% CI 10.5-15) with 56% (95% CI 44-66%) alive at 1 year. The median PFS was 5.1months (95% CI 3.3-6.5) and the response rate was 28.4% (95% CI 18.9-39.5%). The most frequent grade 3-4 toxicities were hyponatremia (46%), hypokalaemia (17%), fatigue (12.2%), thrombocytopenia (11%), neutropenia (9.7%) and neurotoxicity (motor, sensory, other: 1.2%, 8.5%, 2.4%). There were two toxic deaths (32 and 74days) due to acute pneumonitis and cardiac arrest. End-point validation showed that patients with no progression/progression at 18 weeks had median OS of 16.9/11.9 months, respectively. Hazard ratio was 0.46 (CI 0.32-0.67), logrank test and C-index were 0.007 and 0.60.
  
  
  CONCLUSIONS
  The 50% PFSR-18 for CB was contained within the 80% CI for (42-64%). Therefore the null hypothesis could not be rejected. Accordingly this combination does not warrant further investigation. PFSR-18 was confirmed as a strong predictor of survival.
authors.affiliation: The Royal Marsden NHS Foundation, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom. mary.obrien@rmh.nhs.uk
authors.forename: Mary E R
authors.initials: ME
authors.lastname: O'Brien
authors.forename: Rabab M
authors.initials: RM
authors.lastname: Gaafar
authors.forename: Sanjay
authors.initials: S
authors.lastname: Popat
authors.forename: Francesco
authors.initials: F
authors.lastname: Grossi
authors.forename: Allan
authors.initials: A
authors.lastname: Price
authors.forename: Denis C
authors.initials: DC
authors.lastname: Talbot
authors.forename: Tanja
authors.initials: T
authors.lastname: Cufer
authors.forename: Christian
authors.initials: C
authors.lastname: Ottensmeier
authors.forename: Sarah
authors.initials: S
authors.lastname: Danson
authors.forename: Athanasios
authors.initials: A
authors.lastname: Pallis
authors.forename: Baktiar
authors.initials: B
authors.lastname: Hasan
authors.forename: Jan P
authors.initials: JP
authors.lastname: Van Meerbeeck
authors.forename: Paul
authors.initials: P
authors.lastname: Baas
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005060:Europe; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000401:mortality; D011446:Prospective Studies; D011719:Pyrazines / Q000008:administration & dosage; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D002945:Cisplatin
keywords: Bortezomib; Cisplatin; Mesothelioma; PFSR-18