title: Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review.
abstract: BACKGROUND
  Although surgery offers the best chance of cure for patients with non-small cell lung cancer (NSCLC), the overall 5-year survival rate is modest, and improvements are urgently needed. In the 1990s, much interest was generated from two small trials that reported striking results with neo-adjuvant chemotherapy, and therefore our intergroup randomised trial was designed to investigate whether, in patients with operable non-small cell lung cancer of any stage, outcomes could be improved by giving platinum-based chemotherapy before surgery.
  
  
  METHODS
  Patients were randomised to receive either surgery alone (S), or three cycles of platinum-based chemotherapy followed by surgery (CT-S). Before randomisation, clinicians chose the chemotherapy that would be given from a list of six standard regimens. The primary outcome measure was overall survival, which was analysed on an intention-to-treat basis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN25582437.
  
  
  RESULTS
  519 patients were randomised (S: 261, CT-S: 258) from 70 centres in the UK, Netherlands, Germany, and Belgium. Most (61%) were clinical stage I, with 31% stage II, and 7% stage III. Neo-adjuvant chemotherapy was feasible (75% of patients received all three cycles of chemotherapy), resulted in a good response rate (49% [95% CI 43%-55%]) and down-staging in 31% (25%-37%) of patients, and did not alter the type or completeness of the surgery (lobectomy: S: 56%, CT-S: 60%, complete resection: S: 80%, CT-S: 82%). Post-operative complications were not increased in the CT-S group, and no impairment of quality of life was observed. However, there was no evidence of a benefit in terms of overall survival (hazard ratio [HR] 1.02, 95% CI 0.80-1.31, p=0.86). Updating the systematic review by addition of the present result suggests a 12% relative survival benefit with the addition of neoadjuvant chemotherapy (1507 patients, HR 0.88, 95% CI 0.76-1.01, p=0.07), equivalent to an absolute improvement in survival of 5% at 5 years
  
  
  CONCLUSIONS
  Although there was no evidence of a difference in overall survival with neo-adjuvant chemotherapy, the result is statistically consistent with previous trials, and therefore adds considerable weight to the current evidence.
authors.affiliation: Addenbrooke's Hospital, Cambridge, UK.
authors.forename: David
authors.initials: D
authors.lastname: Gilligan
authors.forename: Marianne
authors.initials: M
authors.lastname: Nicolson
authors.forename: Ian
authors.initials: I
authors.lastname: Smith
authors.forename: Harry
authors.initials: H
authors.lastname: Groen
authors.forename: Otilia
authors.initials: O
authors.lastname: Dalesio
authors.forename: Peter
authors.initials: P
authors.lastname: Goldstraw
authors.forename: Matthew
authors.initials: M
authors.lastname: Hatton
authors.forename: Penelope
authors.initials: P
authors.lastname: Hopwood
authors.forename: Christian
authors.initials: C
authors.lastname: Manegold
authors.forename: Franz
authors.initials: F
authors.lastname: Schramel
authors.forename: Hans
authors.initials: H
authors.lastname: Smit
authors.forename: Jan
authors.initials: J
authors.lastname: van Meerbeeck
authors.forename: Matthew
authors.initials: M
authors.lastname: Nankivell
authors.forename: Mahesh
authors.initials: M
authors.lastname: Parmar
authors.forename: Cheryl
authors.initials: C
authors.lastname: Pugh
authors.forename: Richard
authors.initials: R
authors.lastname: Stephens
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D008297:Male; D008875:Middle Aged; D011300:Preoperative Care / Q000379:methods*; D011788:Quality of Life; D011795:Surveys and Questionnaires; D016019:Survival Analysis