title: Skin rash and bronchoalveolar histology correlates with clinical benefit in patients treated with gefitinib as a therapy for previously treated advanced or metastatic non-small cell lung cancer.
abstract: BACKGROUND
  Only 15% of patients with non-small cell lung cancer (NSCLC) treated with oral epidermal growth factor tyrosine kinase inhibitor gefitinib, as a second-line therapy have objective responses. Fifty percent will have improvement of lung cancer related symptoms. It will be critical to identify patients who will benefit clinically from this therapy even when there is no objective response seen on imaging studies. We have performed a retrospective analysis of 76 patients who received gefitinib as a therapy for previously treated metastatic NSCLC at the University of Minnesota Comprehensive Cancer Center in order to describe characteristics of patients who will likely derive benefits from gefitinib therapy.
  
  
  METHODS
  All patients treated with gefitinib therapy at the University of Minnesota from September 2001 to January 2004 were entered into the study. The Log-rank Test and Cox proportional hazards regression were used to assess the effect of the number of previous therapy lines, histology subtype, performance status, gender, stage of disease at initial diagnosis, and presence of skin rash on time to disease progression and overall survival (OS). Fisher's Exact Test and multiple logistic regressions were used to assess the effect of these covariates on disease response.
  
  
  RESULTS
  Seventy-six patients entered the study, with a median age of 60 years (range 37-82). There were 37 female and 39 male patients; 47 patients had adenocarcinoma, 22 had squamous and 7 had other NSCLC histologies. Six patients had no prior therapy, 23 had one, 32 had two, 8 had three, and 7 had four prior therapies for lung cancer. Fifty-six were current smokers. Median time to disease progression was 3 months (95% CI: 3.0, 6.0). There was no difference in time to disease progression whether patients had one or more prior therapies. Patients with brain metastases (26 patients) benefited from gefitinib therapy at least equally well as those without brain metastatic disease. Patients with adenocarcinoma histology with bronchoalveolar features had superior median time to progression versus other lung cancer histology (14 months versus 3 months, p=0.076), which translated into survival advantage in this group >24 months (95% CI: 0.76, 24+) versus 6.6 months (p=0.0096). Patients with EGFR positive tumors had median survival of 10.2 months (95% CI: 1.45, 16.94) versus 3.7 months (95% CI: 2.66, 4.74) with EGFR negative tumors. Patients who developed any degree of skin rash had prolonged time to disease progression with median of 6 months (95% CI: 2.56, 15.5) versus patients without skin rash median 3 months (95% CI: 1.43, 2.83) (p=0.023). This last factor was the best predictor of improved time to disease progression in multiple regression analysis (p=0.0405).
  
  
  CONCLUSIONS
  A subgroup of patients with NSCLC will benefit from gefitinib therapy. Objective responses will likely be seen in half the patients with mutation of internal domain of EGFR; however, a larger group of patients will also enjoy prolonged disease stabilization and clinical benefit. We suggest that adenocarcinoma with bronchoalveolar features and the presence of skin rash may be used as predictors of gefitinib benefit.
authors.affiliation: Division of Hematology, Oncology and Transplantation, University of Minnesota, MMC 480, 420 Delaware Street S.E., Minneapolis, MN 55455, USA. dudek002@umn.edu
authors.forename: Arkadiusz Z
authors.initials: AZ
authors.lastname: Dudek
authors.forename: Krzysztof Lesniewski-
authors.initials: KL
authors.lastname: Kmak
authors.forename: Joseph
authors.initials: J
authors.lastname: Koopmeiners
authors.forename: Mani
authors.initials: M
authors.lastname: Keshtgarpour
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000556:secondary*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000401:mortality / Q000556:secondary*; D018450:Disease Progression; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005076:Exanthema / Q000139:chemically induced* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib