title: Six versus fewer planned cycles of first-line platinum-based chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data.
abstract: BACKGROUND
  Platinum-based chemotherapy is the standard first-line treatment for patients with advanced non-small-cell lung cancer. However, the optimum number of treatment cycles remains controversial. Therefore, we did a systematic review and meta-analysis of individual patient data to compare the efficacy of six versus fewer planned cycles of platinum-based chemotherapy.
  
  
  METHODS
  All randomised trials comparing six versus fewer planned cycles of first-line platinum-based chemotherapy for patients with advanced non-small-cell lung cancer were eligible for inclusion in this systematic review and meta-analysis. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients with an objective response, and toxicity. Statistical analyses were by intention-to-treat, stratified by trial. Overall survival and progression-free survival were compared by log-rank test. The proportion of patients with an objective response was compared with a Mantel-Haenszel test. Prespecified analyses explored effect variations by trial and patient characteristics.
  
  
  RESULTS
  Five eligible trials were identified; individual patient data could be collected from four of these trials, which included 1139 patients-568 of whom were assigned to six cycles, and 571 to three cycles (two trials) or four cycles (two trials). Patients received cisplatin (two trials) or carboplatin (two trials). No evidence indicated a benefit of six cycles of chemotherapy on overall survival (median 9·54 months [95% CI 8·98-10·69] in patients assigned to six cycles vs 8·68 months [8·03-9·54] in those assigned to fewer cycles; hazard ratio [HR] 0·94 [95% CI 0·83-1·07], p=0·33) with slight heterogeneity between trials (p=0·076; I(2)=56%). We recorded no evidence of a treatment interaction with histology, sex, performance status, or age. Median progression-free survival was 6·09 months (95% CI 5·82-6·87) in patients assigned to six cycles and 5·33 months (4·90-5·62) in those assigned to fewer cycles (HR 0·79, 95% CI 0·68-0·90; p=0·0007), and 173 (41·3%) of 419 patients assigned to six cycles and 152 (36·5%) of 416 patients assigned to three or four cycles had an objective response (p=0·16), without heterogeneity between the four trials. Anaemia at grade 3 or higher was slightly more frequent with a longer duration of treatment: 12 (2·9%) of 416 patients assigned to three-to-four cycles and 32 (7·8%) of 411 patients assigned to six cycles had severe anaemia.
  
  
  CONCLUSIONS
  Six cycles of first-line platinum-based chemotherapy did not improve overall survival compared with three or four courses in patients with advanced non-small-cell lung cancer. Our findings suggest that fewer than six planned cycles of chemotherapy is a valid treatment option for these patients.
  
  
  BACKGROUND
  None.
authors.affiliation: Division of Medical Oncology, S.G. Moscati Hospital, Avellino, Italy. Electronic address: arossi_it@yahoo.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Medical Statistics, Second University, Napoli, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Chiodini
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Jong-Mu
authors.initials: JM
authors.lastname: Sun
authors.affiliation: Royal Marsden Hospital, Fulham Road, London, UK.
authors.forename: Mary E R
authors.initials: ME
authors.lastname: O'Brien
authors.affiliation: Department of Pulmonary and Infectious Diseases, North Zealand Hospital, Hillerød, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: von Plessen
authors.affiliation: Pneumology, Coimbra Central Hospital, Coimbra, Portugal.
authors.forename: Fernando
authors.initials: F
authors.lastname: Barata
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Keunchil
authors.initials: K
authors.lastname: Park
authors.affiliation: Royal Marsden Hospital, Fulham Road, London, UK.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Popat
authors.affiliation: Department of Respiratory Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Bergman
authors.affiliation: Pneumology, Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal.
authors.forename: Barbara
authors.initials: B
authors.lastname: Parente
authors.affiliation: Medical Statistics, Second University, Napoli, Italy.
authors.forename: Ciro
authors.initials: C
authors.lastname: Gallo
authors.affiliation: Division of Medical Oncology, S.G. Moscati Hospital, Avellino, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Gridelli
authors.affiliation: Clinical Trials Unit, Istituto Nazionale Tumori Fondazione "G Pascale", IRCCS, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Perrone
authors.affiliation: Clinical Trials Unit, Istituto Nazionale Tumori Fondazione "G Pascale", IRCCS, Naples, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Di Maio
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D016190:Carboplatin; D002945:Cisplatin