Hypertension drug may improve endobronchial dysplasia in former smokers

AACR 102nd Annual Meeting

ORLANDO, Fla. — An oral formulation of the hypertension drug iloprost resulted in significant improvement in a series of biopsy scores among former smokers, according to findings presented at the American Association for Cancer Research 102nd Annual Meeting.

Paul A. Bunn, MD, professor and James Dudley Chair in Cancer Research at the University of Colorado School of Medicine, said about half of lung cancer cases are among former smokers.

“Stopping smoking is still not preventing these former smokers from getting cancers, so the question became one of increasing prevention in this population,” Bunn said. “We know that the arachidonic acid pathway leads to many cancers, and that this pathway has been inhibited by many drugs, most of which are COX 1 or 2 inhibitors.”

Bunn said there is little evidence that these drugs — and particularly iloprost (Ventavis, Actelion Pharms) — can prevent lung cancers.

“Iloprost is approved for primary pulmonary hypertension because it is a vasodilator,” he said. “This study was predicated on the fact that if we could stimulate the prostacyclin analogue, we could conceivably prevent cancer.”

Results

Eligible participants in the multicenter, double blind, placebo-controlled phase 2 trial were current or former smokers with more than 20 pack-years; had at least mild cytologic atypia on sputum cytology; and had no previous history of cancer. “These individuals were at very high risk for lung cancer,” Bunn said.

At least one biopsy displaying mild dysplasia or worse was observed in 74% of patients at the initial bronchoscopy. Results of a reproducibility study conducted by two independent pathologists indicated that 85% of the readings were within one histologic grade.

Current smokers had average baseline histology of 3, compared with 2.1 in former smokers.

Former smokers in the study drug group experienced improvements in the worst biopsy score (1.10 units, P=.002) and the average of all biopsy scores (0.41 or better, P=.010), and improvement in dysplasia index (12.45%, P=.006).

Current smokers did not experience histologic improvement.

“Histologic improvement was larger in iloprost-treated former smokers and was larger in magnitude than the difference between current and former smokers,” Bunn said.

The secondary endpoint was proliferation by Ki-67 index. Iloprost was not linked to any change in this index.

Dropout rates and serious adverse event profiles were similar between the two groups. “Oral iloprost was well tolerated,” he said.

Protocols

The researchers performed autofluorescence and white light bronchoscopy and biopsied six standard endobronchial sites along with all other abnormally appearing areas.

The treatment regimens were an escalating dose of oral iloprost or placebo. After 6 months of this regimen, a second bronchoscopy with repeat biopsy of all the central areas sampled during the first bronchoscopy was performed. Any new areas suspicious for dysplasia at this time point also were biopsied.

The primary outcome measure was the average bronchial histologic score as defined by WHO classification of premalignant lesions in all patients. This outcome measure was also broken down by current vs. former smoking status.

“Former smokers have a lower risk, so not surprisingly, they have less atypia in the bronchial epithelium,” Bunn said.

Of 152 patients who met eligibility criteria, 60 of 75 patients in the treatment group and 65 of 77 patients in the placebo group completed both bronchoscopies. Groups were comparable with regard to age, tobacco exposure and baseline histology.

Three separate measures of endobronchial histology were used: worst biopsy score, dysplasia index (defined as the percentage of biopsies with a score of at least 4 — mild dysplasia — or worse) and average of all biopsy scores.

Dr. Bunn reports that his discussion included off label use of oral iloprost for the chemoprevention of lung cancer.

For more information:

• Bunn PA. #LB-90. Presented at: AACR 102nd Annual Meeting; April 2-6, 2011; Orlando, Fla.

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