Lung cancer is the leading cause of cancer-related death in the United States. In 1996, 177,000 new cases are anticipated, resulting in 158,700 deaths. Lung cancer mortality relative to incidence has not changed substantially in the past 50 years - largely due to the failure of effective systemic chemotherapy to manage metastatic disease.

Increasingly, both basic science and clinical researchers have turned their attention to chemoprevention of lung cancer as a means of reducing these pessimistic survival statistics. Lung carcinogenesis is still poorly understood, which makes chemopreventive strategies difficult to develop. Laboratories such as those at the Allegheny Center for Lung and Thoracic Disease are actively studying the regulation of programmed cell death (apoptosis) and cellular differentiation (maturation) in both lung cancer and normal lung tissue to understand how nature regulates cell growth and what goes wrong with these orderly events when lung cancer occurs. A number of years will likely pass, however, before clinical approaches directed toward regulation of these processes are realized. In the interim, most of the chemopreventive strategies in lung cancer have centered around supplemented administration of vitamin A derivatives or N-acetyl cysteine, which are agents with presumed salutary effects on orderly tissue differentiation. These trials have fallen into two categories: 1) those that attempt to intervene when premalignant changes are detected in high-risk patients (cigarette smokers) who have not had a previous lung cancer; and 2) in patients who have had a resected stage I non-small cell lung cancer (NSCLC) at high risk for the development of a second primary lung cancer.

To date one large randomized trial in Europe has demonstrated benefit with the use of adjunctive vitamin A derivatives in reducing the occurrence of second primary tumors in patients with previously resected stage I non-small cell lung cancer. Subjects in those trials were randomized to receive either retinyl palmitate (a vitamin A derivative) or placebo by mouth. There was a statistically significant reduction in the formation of second primary tumors in this trial among patients receiving vitamin A. Additional promising data using N-acetyl cysteine among smokers at high risk for developing cancer also has surfaced from Europe. A larger, randomized trial is under way (EUROSCAN) studying this agent.

On the other hand, three trials employing prophylactic administration of beta carotene in patients at risk for lung cancer (cigarette smokers) suggested that this naturally occurring carotenoid (a vegetable derivative of vitamin A) may actually promote the development of lung cancer in these individuals. Based on these data from Finland (the ATBC Trial) and the United States (the CARET and PHS trials), the National Cancer Institute has advised that it may be dangerous for cigarette smokers to take high-dose beta carotene. Some of the confusion regarding these seemingly contradictory study findings can be explained in that it is clear from laboratory studies that various vitamin A derivatives may have very different biological effects on cancers.

At the Allegheny Cancer Center and the Allegheny Center for Lung and Thoracic Disease, we are participating in a large National Cancer Institute-sponsored, multi-institutional randomized trial testing the efficacy of 13-cis-retinoic acid (a different vitamin A derivative) compared to placebo in preventing second primary tumors in a group of patients who have undergone resection of stage I non-small cell lung cancer. Patients in this trial must have had their cancer resected within the last three years. While participating in the study, these patients are to receive either a low dose of 13-cis-retinoic acid or placebo, either of which is taken for three years. These patients are followed closely for the development of second primary tumors, particularly second lung cancers. This agent has effectively prevented the development of second primary tumors - including those in the lung - in patients who received this agent following resection of squamous cell cancer of the head and neck. The National Cancer Institute has determined that there is no risk in continuing this trial as, unlike beta carotene, no potential cancer-promoting effects of 13-cis-retinoic acid have ever been detected. We are actively recruiting patients for this trial. The drug is supplied free by the National Cancer Institute.

Additionally, Allegheny University Hospitals has recently been awarded a Master Agreement from the National Cancer Institute to conduct other novel chemoprevention trials. This will result in additional protocols under the leadership of the center's physicians in the near future.

In summary, although chemoprevention of lung cancer still is in its infancy, this approach holds great promise - particularly in our changing health-care environment - to reduce the mortality rate from lung cancer in the United States.

References

1. Lippman SM, Benner SE, Hong WK. Cancer Chemoprevention. J Clin Oncol. 1994;12:851-873.
2. Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330:1029-1035.
3. Pastorino U, Infante M, Maioli M, et al. Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J Clin Oncol. 1993;11:1216-1222.
4. Law C, Ra'ad D. Beta carotene's fall from grace draws mixed reactions. J Natl Cancer Inst. 1996;88:235.
5. Law C, Ra'ad D. CARET, PHS findings have inconsistent impact on other beta carotene trials. J Natl Cancer Inst. 1996;88:236.
6. Smigel K. Beta carotene fails to prevent cancer in two major studies; CARET intervention stopped. J Natl Cancer Inst. 1996;88:145.

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