title: Time trend in treatment-related deaths of patients with advanced non-small-cell lung cancer enrolled into phase III trials of systemic treatment.
abstract: OBJECTIVE
  Despite recent improvements in supportive care, treatment-related death (TRD) remains a serious problem for lung cancer patients undergoing systemic chemotherapy. However, few studies have formally assessed possible changes in the TRD rate over the past two decades.
  
  
  METHODS
  We searched phase III trials to address the role of systemic treatment of advanced non-small-cell lung cancer (NSCLC). Time trend was assessed using linear regression analysis.
  
  
  RESULTS
  The overall incidence of TRD was calculated from 119 trials including 263 chemotherapy arms (46 477 patients), with information about the causes of deaths available for 197 arms (75%, 30 147 patients). Cisplatin-based regimens were the most frequently investigated. The crude TRD rate in the overall cohort of 119 trials was 1.26% and has been notably consistent over the investigated time (P = 0.762). The most common cause of death was febrile neutropenia, with no significant change in its incidence over the years (P = 0.139). In contrast, deaths due to renal toxicity decreased significantly (P = 0.042), whereas deaths due to pulmonary disorder increased significantly (P = 0.007). Among the pharmacological agents investigated, docetaxel (Taxotere) and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) were associated with relatively high rates of deaths from pulmonary disorders, but EGFR-TKIs were not associated with death from any other cause.
  
  
  CONCLUSIONS
  Despite of potential confounders in our results, the overall TRD rate has remained low, but not negligible, in phase III trials for advanced NSCLC, over the past two decades. Notably, the incidence and pattern of TRD stratified by cause have changed considerably.
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: K
authors.initials: K
authors.lastname: Hotta
authors.forename: M
authors.initials: M
authors.lastname: Di Maio
authors.forename: K
authors.initials: K
authors.lastname: Kiura
authors.forename: N
authors.initials: N
authors.lastname: Takigawa
authors.forename: M
authors.initials: M
authors.lastname: Tabata
authors.forename: M
authors.initials: M
authors.lastname: Tanimoto
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*