Abstract PL04-02: Oral iloprost for the chemoprevention of lung cancer: A multicenter, SPORE-initiated trial
Authors: Keith Robert L. , Wilson David O. , Bunn Paul A. , Miller York E. ,   - for the SPORE/LCBCC Iloprost Trial Investigators, Blatchford Patrick J. , Jackson Mary K. , Kittelson John K. , Franklin Wilbur A. , Hirsch Fred R. , Minna John , Mao Jenny , Massion Pierre 
Published: June 2012

Abstract
Background: Tissue microarray studies have shown that the majority of NSCLC have decreased expression of prostacyclin synthase (PGIS) and prostacyclin supplementation (genetic overexpression and the oral prostacyclin analogue iloprost) chemoprevent lung cancer in a variety of murine models, including cigarette smoke exposure. Based on these promising results, a multi-center, double-blind, placebo controlled, phase II trial of iloprost in subjects at increased risk for lung cancer conducted at SPORE in lung cancer sites.
Methods: Subjects were selected for the trial if they meet the following criteria: current or former smoker (&gt; 20 pack years); at least mild cytologic atypia on sputum cytology; no previous history of cancer. Fluorescent bronchoscopy was performed with 6 standard endobronchial sites biopsied, along with all other abnormally appearing areas. Subjects were then randomized to oral iloprost (in escalating doses) or placebo for 6 months and then a repeat bronchoscopy with biopsy of all the central airway areas sampled on the first bronchoscopy. The primary endpoints for the study are bronchial histology and Ki-67 labeling index.
Results: For the iloprost study, 152 subjects were randomized and 125 completed both bronchoscopies (60/75 iloprost, 65/77 placebo). Treatment groups were well matched for age, tobacco exposure and baseline histology. Endobronchial histology was summarized within patients using three separate measures: worst biopsy score (Max), dysplasia index (DI - defined as the percentage of biopsies with a score of at least 4 (mild dysplasia) or worse), and average of all biopsy scores (Avg). 74% of subjects had at least one biopsy displaying mild dysplasia (score 4.0) or worse on the initial bronchoscopy. A reproducibility study with two independent pathologists demonstrated that 85% of readings were within one histologic grade. Baseline histology was significantly worse for current smokers (Avg 3.0) than former smokers (Avg 2.1). Former smokers receiving oral iloprost exhibited a significant improvement in Avg (0.41 better, p=0.010), Max (1.10 units, p=0.002), and an improvement in DI (12.45%, p=0.006). No histologic improvement occurred in current smokers. Proliferation by Ki-67 index was a secondary endpoint and demonstrated no change with iloprost administration. There were no differences in dropout rates or SAEs between treatment groups. Analyses for other biomarkers in iloprost samples (including urinary prostaglandin metabolites, miRNAs, and EMT markers) are in progress.
Conclusions: Oral iloprost significantly improves endobronchial dysplasia in former smokers and deserves further study to determine if it can prevent the development of lung cancer.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):PL04-02.