title: A Phase II study of pulse dose imatinib mesylate and weekly paclitaxel in patients aged 70 and over with advanced non-small cell lung cancer.
abstract: BACKGROUND
  In non-small cell lung cancer (NSCLC), interstitial hypertension is a barrier to chemotherapy delivery, and is mediated by platelet derived growth factor receptor (PDGFR). Antagonizing PDGFR with imatinib may improve intra-tumoral delivery of paclitaxel, increasing response rate (RR).
  
  
  METHODS
  This single-stage, open-label phase II study evaluated pulse dose imatinib and weekly paclitaxel in elderly patients with advanced NSCLC. Eligible patients were aged ≥ 70 with untreated, stage IIIB-IV NSCLC and ECOG performance status 0-2. Primary endpoint was RR. Secondary endpoints included median progression free and overall survival (PFS, OS) and correlatives of PDGFR pathway activation. Baseline Charlson Comorbidity Index (CCI) and Vulnerable Elder Survey-13 (VES-13) were correlated with outcomes.
  
  
  RESULTS
  Thirty-four patients with median age 75 enrolled. Eleven of 29 (38%) were frail by VES-13 score. Overall RR was 11/34 (32%; 95% CI 17%-51%), meeting the primary endpoint. Median PFS and OS were 3.6 and 7.3 months, respectively. High tumoral PDGF-B expression predicted inferior PFS. Frail patients by VES-13 had significantly worse median PFS (3.2 vs. 4.5 months; p=0.02) and OS (4.8 vs. 12 months; p=0.02) than non-frail.
  
  
  CONCLUSIONS
  The combination of imatinib and paclitaxel had encouraging activity as measured by the primary endpoint of RR. However, PFS and OS were typical for elderly patients treated with single agent chemotherapy and the regimen is not recommended for further study. Adjunct imatinib did not overcome the established association of tumoral PDGF-B expression with inferior PFS. VES-13 was a powerful predictor of poor survival outcomes. Frailty should be further studied as a predictor of non-benefit from chemotherapy.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01011075.
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology and Biostatistics, University of New Mexico Cancer Center, Albuquerque, New Mexico, USA. baumanje@upmc.edu
authors.forename: Julie E
authors.initials: JE
authors.lastname: Bauman
authors.forename: Keith D
authors.initials: KD
authors.lastname: Eaton
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Wallace
authors.forename: Laurie L
authors.initials: LL
authors.lastname: Carr
authors.forename: Sang-Joon
authors.initials: SJ
authors.lastname: Lee
authors.forename: Dennie V
authors.initials: DV
authors.lastname: Jones
authors.forename: Hugo
authors.initials: H
authors.lastname: Arias-Pulido
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cerilli
authors.forename: Renato G
authors.initials: RG
authors.lastname: Martins
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D016330:Frail Elderly; D006801:Humans; D000068877:Imatinib Mesylate; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D009367:Neoplasm Staging; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D012074:Remission Induction; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D010879:Piperazines; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor; D017239:Paclitaxel