Oral Iloprost Shows Promise for Lung Cancer Chemoprevention

Roxanne Nelson

April 07, 2011

April 7, 2011 (Orlando, Florida) — Oral iloprost (Ventavis), an analogue of prostacyclin, shows promise as a chemopreventive agent for lung cancer. Data presented here at the American Association for Cancer Research 102nd Annual Meeting showed that it significantly improved endobronchial dysplasia in former smokers.

No histologic improvement was seen in current smokers, but in former smokers who received oral iloprost, there was a significant improvement in average bronchial histologic score (based on the World Health Organization classification of premalignant lesions) and in the dysplasia index score.

Iloprost is commercially available and currently approved for use in primary pulmonary hypertension

"This is an exciting study in chemoprevention," said Daniel Von Hoff, MD, who was approached by Medscape Medical News for independent comment. "But regulatory-wise, it's a long road."

This particular drug is going off patent, and the majority of drugs involved will go off patent before the final chemoprevention study results are known, said Dr. Von Hoff, who is physician-in-chief and distinguished professor at the Translational Genomics Research Institute in Phoenix, Arizona.

"Right now, the National Cancer Institute will probably have to sponsor these studies," he said. "We may need some legislation, similar to that for orphan drugs, so that companies will maintain exclusivity for a longer period of time."

Targeting Former Smokers

Dr. Paul Bunn

Cigarette smoking remains the number 1 cause of lung cancer. "About half of all smokers have stopped smoking in the United States, and about half of all cases of lung cancer in the United States are in former smokers," said study author Paul Bunn, MD, executive director of the International Association for the Study of Lung Cancer and the James Dudley endowed professor of lung cancer research at the University of Colorado Cancer Center, Denver.

What can we do for former smokers?

"There's no way that stopping smoking is going to reduce their chance of getting lung cancer," he said. "So the question is: What can we do for former smokers?"

The study by Dr. Bunn and colleagues was predicated on the notion that if prostacyclin could be stimulated, or if patients were given a prostacyclin analogue, lung cancer might be prevented. Preliminary experimental data have already shown that prostacyclin supplementation, with either genetic overexpression or the oral prostacyclin analogue iloprost, prevents the development of lung cancer in a variety of models, including cigarette smoke exposure.

The phase 2 trialinvolved 152 participants who were either smokers or former smokers, who had been exposed to at least 20 pack-years of cigarettes, and who 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, along with all other abnormally appearing areas, were biopsied.

Participants were then randomly assigned to receive oral iloprost (in escalating doses) or placebo for 6 months. A second bronchoscopy was conducted, as were repeat biopsies of all the central airway areas sampled during the first bronchoscopy and biopsies of any new areas suspicious for dysplasia.

The predetermined primary end point was average bronchial histologic score in all members of the cohort; separate analyses were performed on current and former smokers.

Within this cohort, both bronchoscopies were available for 125 individuals (60 of 75 in the iloprost group, 65 of 77 in the placebo group). The authors evaluated endobronchial histology using 3 separate measures: worst biopsy score, dysplasia index score (defined as the percentage of biopsies with a score of at least 4), and average of all biopsy scores.

The lesions were scored from 1 to 7, with 1 being normal and 7 being carcinoma in situ, explained Dr. Bunn. "At baseline, smokers had worse bronchial histology than former smokers, but we know, of course, that formers smokers have a lower risk. Not surprisingly, they have less atypia in their bronchial epithelium."

Comparison of Smokers and Former Smokers at Baseline

Score Current Former Difference P value
Average of All Biopsies 3.1 2.6 –0.5 0.015
Worst Biopsy 4.7 4.4 –0.4 0.10
Dysplasia Index 46% 31% –15% 0.008


Within the cohort, 74% of individuals had at least 1 biopsy that showed mild dysplasia (dysplasia index score of 4.0) or worse on the initial bronchoscopy. The authors note that a reproducibility study with 2 independent pathologists demonstrated that 85% of readings were within 1 histologic grade.

Former smokers in the oral iloprost group achieved a significant improvement in the average of all biopsy scores (0.41 better; p = .010), worst biopsy score (1.10 units; P = .002), and dysplasia index score (12.45%; P = .006).

Former Smokers Before Therapy and 6 Months After Therapy

Score Baseline Biopsy 6 Months After Biopsy Difference
Average of All Biopsies 3.3 2.1 –1.2
Worst Biopsy 4.6 3.1 –1.5
Dysplasia Index 43% 19.6% –23.6%


A secondary end point was the Ki-67 index, a measure of cell proliferation; there was no change in this index after iloprost administration.

"Histologic improvements in iloprost-treated former smokers were larger in magnitude than the difference between current and former smokers," concluded Dr. Bunn.

American Association for Cancer Research (AACR) 102nd Annual Meeting: Abstract LB-90. April 4, 2011.

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