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When you breathe in, air passes from your nose or mouth through the windpipe (trachea) which divides into two tubes (airways), one going to each lung. These are known as the right and left bronchus and they divide to form smaller tubes called bronchioles, which carry air through the lungs. At the end of the bronchioles are millions of tiny air sacs or alveoli. It is here that oxygen is absorbed from the air and passes into the bloodstream to be circulated around the body.

Carbon dioxide is the waste gas that must be removed from the body. It passes from the bloodstream into the alveoli and is expelled by the lungs when you breathe out.

Lung cancers are sometimes referred to as bronchogenic carcinomas because they arise from the bronchial airways. There are four pathological types of lung cancer, including adenocarcinoma (about 35% of cases, now the most common type), squamous carcinoma (about 30% of cases), small cell carcinoma (about 20% of cases), and large cell and other carcinomas (about 15% of cases). There will be approximately 171,500 new cases in the United States in 1998 representing 14% of all new cases of cancer in the U.S. The five-year survival rate is only 14%, and it is estimated that there will be 160,100 deaths from lung cancer in 1998. This represents 28% of all cancer deaths, making lung cancer the leading cause of cancer death in both men and women in the U.S. Lung cancer is highly symptomatic, rapidly disabling, and has an average short survival measured in months. Lung cancer rates are dramatically increasing in U.S. women, while rates in men are now declining. Persons cured of one lung cancer are at great risk of developing a second lung cancer or other aerodigestive tract malignancy. The great majority of lung cancer cases are caused by tobacco use and thus the ultimate key to dealing with this malignancy is smoking cessation or never beginning to smoke cigarettes. The outlook for lung cancer is improving because new drugs prolong survival, alleviate symptoms, and improve quality of life at reasonable cost for all stages, but there is a long way to go.

The most extraordinary feature of lung cancer is that we already know its causes. Smoking is associated with 85-87% of all cases (146,000 cases/year) and radon exposure causes about 3% of cases (5,000/year). However, 40-50% of new cancers are now arising in former smokers, due to the very slow reduction in lung cancer risk after stopping smoking. Many people are surprised to discover that more deaths due to lung cancer are projected in non-smokers passively exposed to environmental tobacco smoke (3,000 per year) than due to asbestos exposure (2,000 per year). Also, the addictive potential of cigarette smoking is not generally appreciated, although the Surgeon General's report in 1988 established that nicotine was at least as addictive as cocaine.

The overwhelming majority of smokers start this habit before reaching age twenty-one. Close to 90% of smokers would like to stop smoking but can't. About 34% attempt to quit in a given year but only 2.5% succeed in quitting and remaining abstinent. All socioeconomic and racial groups are affected by smoking. As noted, there has been progress in the decline of smoking in adult males.

However, in 1993, smoking rates failed to decline for the first time since the Surgeon General's Report in 1964 and smoking in young women has actually increased. Thus, the mortality rate from lung cancer continues to rise especially in women. Because cigarette smoking rates are no longer declining, lung cancer deaths will remain the most common cause of cancer death for many years to come.

Anti-smoking activists have charged tobacco manufacturers with unethical practices for specifically targeting vulnerable populations such as young people and women with aggressive marketing efforts.

Clearly, the challenge of primary smoking prevention has never been more evident if a meaningful reduction in lung cancer rates is ever to be achieved.

Relationship to other Cancers

Lung cancer is one of many epithelial cancers (called carcinomas) which arise from cells lining glands (also included are breast, colon, stomach, prostate, pancreatic and many other cancers).

These many cancers share many similarities, including mutations causing the loss of function of tumor suppressor genes, overactivity of products of dominant oncogenes, and expression of autocrine and paracrine growth factors.

The combination of these changes leads to cells capable of metastatic spread which ultimately kills most patients.

Despite the multiple clinical differences between these common epitheleal cancers, the similarities of their underlying molecular alterations means that advances in understanding the cause, prevention, or treatment of any of these cancers will very likely rapidly translate into advances in the other cancers.

Recent Progress

When the Surgeon General's Report first showed the direct relationship between cigarette smoking and lung cancer in 1964, the cure rate was only about 5%. In 1993, the cure rate was 13%. The current 14% cure rate is still a dismal figure, but the 1% improvement saved 17,789 additional lives in 1998.

Present and Future Opportunities

Lung cancer is similar to other solid tumors in that recent molecular and cellular advances have outpaced clinical application of these advances.

know that the mutational inactivation of both copies of one or more of several important tumor suppressor genes (p53 on chromosome 17p, Rb on chromosome 13, p16/CDKN2 on chromosome 9p, and several genes on chromosome 3p), and activating mutations of dominant oncogenes such as c-myc, ras, and bcl-2 are initiating events in the carcinogenesis/pathogenesis of the disease.

In addition, we know lung cancers exhibit generalized genetic instability ("microsatellite alterations") and express the enzyme telomerase associated with immortal cell growth.

We have also learned that lung cancer growth can be regulated by autocrine and paracrine growth factors and their receptors and that there are several antigens on dysplastic precursor cells and lung cancer cells that distinguish them from normal lung cells.

Some of these genetic changes (such as mutations in the ras gene) are associated with a bad clinical prognosis.

However, most importantly, we can now detect these genetic, growth factor, and gene expression changes in preneoplastic cells found in the lung before a clinically evident lung cancer develops.

This offers the hope for early molecular detection of cancer and the use of these markers to monitor prevention studies and to identify patients for treatment of very early lesions.

Genetic correction of any one of these defects (e.g. replacement of a damaged tumor suppressor gene, or inhibition of a mutated dominant oncogene function) can reverse malignancy.

In addition, these mutant gene products represent absolute differences between tumor and normal cells and are candidate targets for the development of new drug or vaccine therapy.

Thus, there is good reason to believe that the advances can be translated directly into clinical benefit in the next decade, especially if there is sufficient funding for this "translational" research.

In fact, several clinical trials for early detection, prevention, gene therapy, and oncopeptide vaccination are now getting started.

This type of research is often more costly and takes longer than most basic research studies.

The National Cancer Institute (NCI)'s SPORE grant mechanism (Specialized Programs of Research Excellence) is an excellent example of new programs that the NCI has initiated to speed such translational research.

New Prevention Horizons

We must never lose sight of the role of tobacco smoking as the primary cause of lung cancer and must continue to strive for cessation of smoking and prevention of smoking initiation. There are many research and demonstration programs (such as the COMMIT and ASSIST programs) to increase public awareness, educate children, and develop more effective smoking cessation programs. Unfortunately, experience has shown that these efforts are not enough.

U.S. tobacco companies spend more than $4.5 billion a year advertising smoking. This massive propaganda campaign works (explaining why tobacco companies spend so much money on it). In the U.S. more than 26% of the population continues to smoke. This percentage is in sharp contrast to the 14% of the population that smokes in California, where the state mounted a comprehensive anti-smoking campaign supported by revenues generated from tobacco taxes. The California anti-smoking program combined the deterrent of higher tobacco costs for young people (whose choice when buying cigarettes has been demonstrated to be very cost-sensitive) with the impact of a hard-hitting anti-smoking media advertising program. We must ban advertising, raise taxes, conduct more "counter-advertising" campaigns and provide alternative types of employment for farmers and other tobacco workers to decrease cigarette consumption. Since nicotine is the addictive component of cigarettes, we must control its dissemination the way we control other addictive substances.

There are recent major discoveries in lung cancer prevention. Several studies showed that lung cancer patients have low levels of vitamin A. Patients with one aerodigestive cancer such as lung cancer are at very high risk to get another aerodigestive cancer. An Italian study using retinol (vitamin A derivative) showed that retinol was able to reduce the development of second lung cancers. A similar study from the U.S. in resected head and neck cancer patients showed that 13-cis retinoic acid (vitamin A derivative) prevented second lung cancers. This drug is now being studied for its ability to prevent second lung cancers in patients with surgical removal of localized lung cancer. Of equal importance, on a basic research level, we are now understanding how lung cancer and other cells respond to these retinoids through interaction with a series of retinoid receptors. Recent information gives insight into how to design better and more specific ligands for these receptors.

New Horizons in Detection

Seventy-five percent of lung cancer cases have spread beyond the primary site at the time of diagnosis. Unfortunately, screening with chest x-ray and sputum cytologies, while identifying early stage lung cancers, does not lead to prolonged survival. This is in contrast to the success of mammography in breast cancer, and occurs because of the tendency of lung cancer to metastasize relatively early in its natural history. Nevertheless, a new major early detection study, the PLCO study, sponsored by the NCI, is now re-addressing this screening issue.

However, advances in molecular and cellular biology give us new tools to detect lung cancer at an earlier point than is possible with chest x-rays and sputum cytologies. The multiple genetic and antigenic changes in lung cancer cells are often found in preneoplastic respiratory epithelial lesions such as hyperplasias, dysplasias, and carcinoma in situ. In addition, advances in genetic epidemiology have identified persons at greatly increased risk of developing lung cancer. It is of great importance to determine if the combination of genetic epidemiology and the identification of molecular preneoplastic abnormalities will provide enhanced early detection and serve as "intermediate markers" for lung cancer prevention efforts. This is of special importance for ex-smokers who have truly stopped smoking yet continue to have a greatly increased risk of developing lung cancer. Likewise, we must rapidly evaluate new and more effective chemoprevention agents. Thus, it is vital to continue and expand randomized clinical trials of early detection and prevention.

New Horizons in Therapy

Fewer than 25% of patients are first diagnosed with localized disease which is amenable to surgical resection, but less than half of the resected patients are cured. These failures are primarily because of occult spread of cancer cells to distant parts of the body. There is growing evidence that currently available chemotherapy given before or after surgery and/or in combination with radiation may increase the cure rate of Stage I, II, and III patients. Routine application of such combined modality therapy could save several thousand lives each year. In addition, there is interest in a number of recently available drugs with new mechanisms of action. These include the anti-tubulin agents Taxol and Taxotere; the topoisomerase 1 inhibitors CPT-11, topotecan and 9-aminocamptothecin; the anti-mitotic agent vinorelbine and the anti-metabolite gemcitabine. Several of these agents improved survival and quality of life and have already produced a small but definite improvement in the cure rate. Newer agents, the "designer drugs" resulting from the biologic revolution described above, are also now entering clinical trials.

Economics of Lung Cancer

Cost of Cigarette Smoking to Society

The economic costs of smoking in the U.S., including the cost of lung cancers, exceed $100 billion per year. This can be translated into about $2.20 per pack of cigarettes. About 20% of all deaths in the U.S. and about 14% of all hospitalizations are due to tobacco use. Cigarette smokers experience more than 33% excess workdays lost compared to non-smokers.

Economic Consequences of Lung Cancer Research

Prevention: The discovery of effective prevention measures would reduce the direct medical costs of care as well as the cost of lost work productivity. Effective chemoprevention agents will therefore be a great economic boon to communities through decreased health care costs and increased employment at the companies that produce such agents.

Treatment: The development of effective systemic therapy would increase the cure rate and, thus, markedly diminish the lost productivity from lung cancer relapse and progression.

Conclusions

Lung cancer is the most common cause of cancer deaths in the U.S., accounting for 28% of such deaths. There are more deaths from lung cancer each year than from breast cancer, prostate cancer, and colon cancer combined (the next 3 leading causes of cancer death). New drug therapies have been proven to prolong the survival, alleviate symptoms, and improve quality of life of lung cancer patients at all stages at acceptable medical costs. An explosion in our understanding of the biology and molecular biology of lung cancer over the last decade is being translated into early detection, prevention, and therapy trials which should lead to a decrease in mortality in the next decade. If we can reduce cigarette consumption, lung cancer mortality would be expected to drop from first to a much lower ranking. In addition to a loss of death and suffering, we would retain the contribution of a large group of people through their peak years of productivity.

Recent Progress and Future

A Fact Sheet of the American Association for Cancer Research