Oral Iloprost Shows Preventive Potential in Lung Cancer
By Caroline Helwick
Medscape Medical News
May 20, 2010 (New Orleans, Louisiana) — Oral iloprost, an analogue of prostacyclin, shows promise in the prevention of lung cancer in former smokers by improving endobronchial dysplasia, according to the results of a randomized phase?2 trial reported here at the American Thoracic Society 2010 International Conference.
"Iloprost improved the histology of former smokers, indicating that it may reduce the risk of developing lung cancer," said principal investigator Robert Keith, MD, from the Denver Veterans Affairs Medical Center and the University of Colorado, Denver. "Interestingly, current smokers did not show benefit."
The inhaled formulation of iloprost is currently used for the treatment of pulmonary hypertension. The oral form is no longer used in the United States, but the inhaled version was not available when this study was initiated, he noted.
Subjects were selected for the trial if they were current or former smokers (>20 pack years) and had at least mild cytologic atypia on sputum cytology and no history of cancer.
Autofluorescence and white light bronchoscopy were performed, and 6 standard endobronchial sites were biopsied, along with all other abnormally appearing areas. The histologic parameters of interest were bronchial histology, Ki-67 level, eicosanoid pathway, MCM2 protein expression, tyrosine kinase receptor protein expression, apoptotic index, and microvessel density.
The 152 subjects were randomized to 6 months of oral iloprost (in doses escalating from 50 to 150?μg twice daily) or placebo, after which they underwent a second fluorescent bronchoscopy with repeat biopsy of all the central airway areas sampled during the first bronchoscopy. The predetermined primary end point of the study was bronchial histology in all subjects, and in current and former smokers separately.
Each bronchial biopsy specimen was scored according to the World Health Organization classification for preneoplasia (scale of 1 to 8). Within-patient endobronchial histology was summarized using 3 separate measures: worst biopsy score, dysplasia index (percent of biopsies with a score of ?4, indicating mild dysplasia or worse), and average of all biopsy scores.
The average biopsy score was significantly better for former smokers than for current smokers, but there were no differences at baseline between the treatment and placebo groups in this category. Baseline demographics were also similar for the treatment groups in current smokers.
Follow-up was completed by 60 subjects in the iloprost group and 65 in the placebo group.
Favorable Histologic Changes Seen in Former Smokers
Histologic evaluation from baseline to 6 months showed that treatment with iloprost was associated with significant improvements in former smokers but not current smokers, Dr. Keith reported at the late-breaking clinical trials session.
Response to treatment was defined as a reduction of 1 point or more in maximum histology. Responses were observed in 14 of 29 (48%) former smokers receiving iloprost, compared with 4 of 28 (14%) receiving placebo. In current smokers, responses were similar between the groups (32% vs 24%, respectively).
For former smokers receiving iloprost, the average biopsy score decreased from 2.12 at baseline to 1.73 after 6 months of treatment. Scores in the placebo group were 2.07 and 2.11, respectively.
The worst biopsy score improved by 1.4 in former smokers, he added.
A significant treatment effect was seen for all measures — average biopsy score, worst biopsy score, and dysplasia index — among the former smokers receiving the drug. The most common adverse effect of the drug was headache.
"If you take this medicine and you are a former smoker, your lung damage diminishes," Dr. Keith reiterated.
He predicted that, if further trials confirm a benefit, the likely candidates for this drug are patients diagnosed with stage?1A lung cancer whose 5-year survival is 75% and those deemed at very high risk.
He noted that the incidence of lung cancer was not used as the primary end point because this requires long-term follow-up. Lung cancer could be chosen as an end point, however, if the proposed phase?3 study is conducted. "We have now got the necessary steps to push on [to a phase?3 trial]," he told the media.
Charles Powell, MD, associate professor of medicine in the Division of Pulmonary and Critical Care at Columbia University in New York City, told Medscape Pulmonary Medicine that this is an "interesting and potentially important study because it is one of the first randomized clinical trials to show a difference in the histology of the lung" after an intervention.
He also praised the study for its "rational approach," because the investigators identified a specific target, tested the approach in an animal model, and then brought it into clinical trials.
Although the results are encouraging, he cautioned that an effect on a clinical end point — reduction in lung cancer occurrence — needs to be shown before "enthusiastically grasping onto" iloprost for chemoprevention. He also noted that the population was largely male, and that the effect was observed only in former smokers; therefore, the results cannot be extrapolated to the broader population of smokers without further study.
Dr. Keith reports having personal financial relationships with Pfizer and Boehringer-Ingelheim, and a patent application for the use of oral prostacyclin analogues in the chemoprevention of cancer.
American Thoracic Society (ATS) 2010 International Conference: Abstract?9997. Presented May?18, 2010.