The need to prevent lung cancer in a growing population of former smokers has led researchers to test inhalers as a means of delivering drugs directly to the lungs, a strategy that has proven to be safe and effective for treating chronic asthma.

By directing medication straight to the lungs, inhalers limit side effects in other parts of the body. The method also allows for lower doses than are needed when pills are used.

"Inhalation is the preferred route for doing chemoprevention in lung cancer at this time," says Dr. Stephen Lam, a senior scientist in the Department of Cancer Imaging at the BC Cancer Research Centre in Vancouver, British Columbia.

"Inhaled medication is easy to use, and there are fewer side effects when drugs are delivered directly into an organ rather than administered systemically," Dr. Lam adds.

Several years ago, Dr. Lam led a phase II lung cancer prevention clinical trial involving smokers who took inhaled budesonide for 6 months. The drug had no effect on the growth of bronchial lesions or the prevention of new lesions, the trial found.

Through the use of imaging tools known as spiral CT scans, however, the researchers observed that the drug may have affected small nodules in the peripheral lungs, some of which might have been precancerous growths.

Based on this observation, a new lung cancer prevention trial testing inhaled budesonide will begin soon in Italy. The phase II trial, led by the European Institute of Oncology, will be enrolling individuals who are already receiving annual spiral CTs as part of a larger lung cancer screening trial.

The researchers will focus on individuals who, after the second annual CT scan, have persistent lung nodules that appear not to be malignant but may be precursors to lung adenocarcinomas, according to Dr. Eva Szabo of NCI's Division of Cancer Prevention (DCP), which is sponsoring the trial.

These individuals will be treated for 1 year with either budesonide or a placebo. The study will assess the efficacy of inhaled budesonide, and a larger trial will be planned if the results are positive. In addition, the researchers will focus on safety.

Safety is critical because the drug would be used by individuals who are at risk for cancer but who are also in apparent good health. "The challenge in making cancer prevention part of routine health care is to ensure long-term safety," says Dr. Szabo.

When people start taking a drug to prevent cancer, in all likelihood they will need to take it for an extended period of time. If the side effects diminish quality of life, or if there is an increase in other diseases due to the drug, the drug will not be taken.

An advantage of targeted delivery, then, is that healthy tissues are largely spared and the overall toxicity is reduced, much in the way that targeted cancer therapies attack mutant cells, sparing the others.

"Low toxicity is critical to getting chemoprevention to the public because, after all, real people have to take the drugs," says Dr. Szabo. "If a treatment to prevent cancer leads to another life-threatening condition, like heart disease, then you haven't made much progress."

Once a person stops smoking, the risk of lung cancer does not continue to increase, but neither does it go away. Cancer prevention for lung cancer attempts to intervene in the early and potentially treatable stages of a lengthy disease process.

The preclinical evidence that inhaled budesonide might be effective during the early stages of the process has come largely from research in mice, led by Dr. Vernon Steele of NCI's DCP.

Dr. Steele and his colleagues have shown that glucocorticoids, which include budesonide, were nearly 90 percent effective in preventing lung adenomas in mice. These results were the basis for the clinical trial led by Dr. Lam.

"There are different forms of lung cancer, and we think a combination of drugs that has multiple targets is likely to be the best strategy for chemoprevention," says Dr. Steele, adding, "It is difficult to predict what kind of lung cancer a person is going to get."

In humans, aerosols can be delivered either as a liquid or a very fine powder. "Engineers have come up with devices for both kinds of delivery, and we're trying to identify and develop the drugs to put in them," says Dr. Steele.

By Edward R. Winstead