Abstract LB-90: Oral iloprost improves endobronchial dysplasia in former smokers

Abstract

Abstract Introduction: Prostacyclin supplementation by either genetic overexpression or the oral prostacyclin analogue iloprost prevents development of lung cancer in a variety of murine models, including cigarette smoke exposure. We conducted a multi-center, double-blind, placebo controlled, phase II trial of iloprost in subjects at increased risk for lung cancer. Methods: Entry criteria included: current or former smoker (> 20 pack years); at least mild cytologic atypia on sputum cytology; no previous history of cancer. Autofluorescence and white light 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 second bronchoscopy with repeat biopsy of all the central airway areas sampled during the first bronchoscopy, as well as any new areas suspicious for dysplasia. The predetermined primary endpoint for the study was average bronchial histologic score (based on the WHO classification of premalignant lesions) in all subjects, as well as in current and ex-smokers separately. Results: The accrual goal of 152 subjects was reached 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. 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 Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-90. doi:10.1158/1538-7445.AM2011-LB-90