title: The efficacy of pemetrexed as a third- or fourth-line therapy and the significance of thymidylate synthase expression in patients with advanced non-small cell lung cancer.
abstract: BACKGROUND
  Pemetrexed is one of the standard second-line therapies in advanced non-small cell lung cancer (NSCLC). Currently, there are no standard cytotoxic treatments beyond second-line therapy. We evaluated the efficacy and safety of pemetrexed as a salvage regimen in heavily pretreated NSCLC patients. We also analyzed thymidylate synthase (TS) expression in tumor tissues to determine whether TS expression is correlated with the clinical efficacy of pemetrexed.
  
  
  METHODS
  One hundred and ten NSCLC patients who received pemetrexed as third- or fourth-line therapy at the Samsung Medical Center between June 2006 and June 2008 were retrospectively reviewed. TS expression was analyzed by immunohistochemical staining in 55 NSCLC tissue specimens. The relationships between TS expression and clinicopathological factors were evaluated. Univariate and multivariate analyses were performed to define the predictive factors and prognostic significances.
  
  
  RESULTS
  The median age of patients in this study was 59 years (range: 24-84), 50.9% were men, and 27 (24.6%) were smokers or previous smokers. Sixty-five patients (59.1%) received pemetrexed as third-line treatment, and 95 (86.4%) had non-squamous cell carcinoma. Platinum-based chemotherapy (84.6%) was the most common first-line therapy, and EGFR TKIs [erlotinib (17.3%) or gefitinib (43.6%)] were a common second-line therapy. The median time from date of diagnosis to the date of the first pemetrexed treatment was 12.8 months (range: 1.8-62.2 months) and the median number of pemetrexed treatments was 4 (range 1-22). Eighteen patients achieved PR (16.3%), 41 patients SD (37.3%), and 43 patients PD (39.1%), with a disease control rate of 53.6%. The median follow-up duration was 16.1 months, the median progression-free survival (PFS) was 3.2 months (95% CI: 1.9-4.5 months), and the median overall survival (OS) was 11.6 months (95% CI: 9.0-14.1 months). Male gender was the only independent variable for poor PFS (HR=1.673, 95% CI: 1.103-2.535), with poor performance status (HR=2.454, 95% CI: 1.405-4.287) and history of smoking (HR=1.856, 95% CI: 1.087-3.168) being independent adverse factors for OS. Thirteen of 55 tumor tissues (23.6%) showed TS expression; however, there were no significant correlations between TS expression and the clinicopathological factors.
  
  
  CONCLUSIONS
  Pemetrexed was suggested as a third- or fourth-line therapy due to its favorable efficacy and tolerable toxicity. Further studies are warranted to define the adequate sequence of salvage treatments, especially in patients with adenocarcinoma lung cancer.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Seoul 135-710, Republic of Korea.
authors.forename: Myung Hee
authors.initials: MH
authors.lastname: Chang
authors.forename: Jin Seok
authors.initials: JS
authors.lastname: Ahn
authors.forename: Jeeyun
authors.initials: J
authors.lastname: Lee
authors.forename: Kyoung Ha
authors.initials: KH
authors.lastname: Kim
authors.forename: Yeon Hee
authors.initials: YH
authors.lastname: Park
authors.forename: Joungho
authors.initials: J
authors.lastname: Han
authors.forename: Myung-Ju
authors.initials: MJ
authors.lastname: Ahn
authors.forename: Keunchil
authors.initials: K
authors.lastname: Park
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D005971:Glutamates / Q000008:administration & dosage / Q000627:therapeutic use*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D000068437:Pemetrexed; D011379:Prognosis; D012189:Retrospective Studies; D016879:Salvage Therapy; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D054316:Biomarkers, Pharmacological; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D013940:Thymidylate Synthase