Lung Cancer: Still Number One

Lung Cancer: Still Number One

Although lung cancer remains the leading cause of cancer death in both men and women, gradual progress is being made in understanding and treating this all-too-common cancer.

In 1987 lung cancer surpassed breast cancer as the leading cause of cancer deaths in U.S. women.[1], [2]yet receives less than half as much research funding as breast cancer from the National Cancer Institute.[3]Nevertheless, there is reason for hope: new, targeted therapies may improve duration of survival among patients with advanced non­–small cell lung cancer (NSCLC—the most common type of lung cancer); the phenomenon of lung cancer in never-smokers is receiving increasing attention; and there remain steps we can take to reduce our risk of developing lung cancer in the first place.

Recent Advances in The Management of Lung Cancer

The last 12 months continue to show advances in the treatment of non-small cell lung cancer (NSCLC), once again most notably in the sector of precision treatment. Importantly advances in the treatment of small cell lung cancer using newer precision medicines and immunotherapy also appear promising. Recent studies show that many individuals that might benefit from these treatments are not receiving them.

Precision medicine continues to impact the lives of lung cancer patients with research into genomics and genetics leading to unprecedented progress in improving outcomes. Tailored treatments have emerged to match a person’s genetic make¬up or a tumor’s genetic profile. As a result, patients with lung cancer now typically re¬ceive molecular testing that guides their physicians in determining which therapies are more likely to boost the chances of survival while limiting the potential for adverse effects. Results from studies evaluating ALK-inhibitors continue to show efficacy and initial studies exploring immunomodulatory approaches using anti-PD-1 and anti-PD-L1 antibodies have demonstrated promising results in lung cancer. The cancer research community is moving forward in its efforts find more effective treatment for patients with lung cancer. Current clinical trials are taking innovative approaches to how therapies for both advanced and early-stage lung cancers are studied.

Targeted Therapies for Lung Cancer

Targeted therapies are anticancer drugs that interfere with specific pathways involved in cancer cell growth or survival. Some targeted therapies block growth signals from reaching cancer cells; others reduce the blood supply to cancer cells; and still others stimulate the immune system to recognize and attack the cancer cell. Depending on the specific “target,” targeted therapies may slow cancer cell growth or increase cancer cell death. Targeted therapies may be used in combination with other cancer treatments such as conventional chemotherapy.

Two targeted therapies that are currently approved for use in NSCLC are Avastin® (bevacizumab) and Tarceva® (erlotinib). Avastin blocks a protein known as vascular endothelial growth factor (VEGF), which plays a key role in the development of new blood vessels. By blocking VEGF, Avastin may deprive the cancer of nutrients and oxygen. Avastin’s effects on blood vessels may also improve the delivery of chemotherapy to the tumor. When used in combination with chemotherapy for the initial treatment of advanced, nonsquamous NSCLC, a Phase III clinical trial reported that Avastin improved overall survival by two months (from 10.3 months with chemotherapy alone to 12.3 months with chemotherapy plus Avastin); the addition of Avastin also increased the risk of serious side effects such as bleeding, however.[4]

Tarceva targets the epidermal growth factor receptor (EGFR) pathway. In a study of patients who had experienced lung cancer progression after chemotherapy, treatment with Tarceva resulted in better overall survival than treatment with placebo (6.7 months with Tarceva versus 4.7 months with placebo).[5] Although this is once again a modest improvement, certain groups of patients—such as women and those who had never smoked—appeared to derive greater benefit. To better understand who is likely to benefit from Tarceva, researchers have begun to search for tumor cell characteristics that predict responsiveness to this type of therapy. For example, some studies have suggested that lung cancers that contain an EGFR gene mutation or that contain multiple copies of the EGFR gene may be more likely to respond to drugs such as Tarceva[6]; if this is confirmed, testing tumor tissue for these characteristics could help guide treatment decisions and allow for more-individualized cancer treatment.

Research is also under way to identify new types of targeted therapies and to explore the effects of combining different targeted therapies.

Lung Cancer in Never-smokers

An estimated 15 percent of lung cancer diagnoses among U.S. women occur among women who have never smoked.[7] Factors such as secondhand smoke, residential radon exposure, and familial susceptibility are known to contribute to some cases of lung cancer in never-smokers, but the cause of many cases remains unknown.

Lung cancer that develops in never-smokers appears to have different biologic characteristics than lung cancer that develops in smokers. For example, lung cancer in never-smokers tends to be more responsive to drugs such as Tarceva. To further explore the optimal approach to the treatment of lung cancer in never-smokers, a handful of clinical trials are now focusing specifically on never-smokers. Continued research into the ways in which lung cancer in never-smokers differs from lung cancer in smokers will help further individualize lung cancer treatment and may offer new insights into prevention.

An issue that remains uncertain is whether female never-smokers are more likely than male never-smokers to develop lung cancer. A higher rate of lung cancer among female never-smokers has been reported,[8], [9]but a recent combined analysis of several previous studies raised some doubts about these findings.[10] In the combined analysis, the overall frequency of lung cancer was similar among male and female never-smokers. In certain age groups, however, there did appear to be differences in lung cancer incidence rates between men and women: among younger never-smokers, women had higher rates of lung cancer than men, whereas the reverse was true among older never-smokers. This variability by age did not meet the criteria for statistical significance, however, suggesting that it could have occurred by chance alone. A point on which there is more agreement is that female never-smokers have a lower rate of death from lung cancer than male never-smokers.

Lung Cancer Prevention

Smoking Cessation and Avoidance of Secondhand Smoke

Smoking accounts for a large majority of lung cancer deaths in both men and women,[11] meaning that the best way to reduce our risk of lung cancer is never to smoke. But for women who do smoke, it’s important to realize that quitting smoking provides important lung cancer benefits.

Compared with nonsmokers, women who smoke more than 20 cigarettes per day are roughly 20 times more likely to die of lung cancer.[12] For a woman who was a heavy smoker, the risk of dying of lung cancer drops to roughly ninefold higher than a nonsmoker within six to 10 years of quitting and to less than threefold higher by 16 years after quitting. So although it’s true that never-smokers have the lowest lung cancer death rates, women who are smokers can greatly reduce their risk of lung cancer by quitting smoking.

Avoidance of secondhand smoke is also important. Secondhand smoke is the third-leading cause of lung cancer in the United States. It is thought to account for roughly 3,000 lung cancer deaths each year.[13]Fortunately, policies to eliminate smoking in indoor public places have had a dramatic effect on exposure to environmental tobacco smoke in the United States. Between 1988 and 2002, the percentage of U.S. nonsmokers who had evidence of cotinine in their blood fell from 88 to 43 percent.[14] Cotinine is a byproduct of nicotine metabolism and indicates recent exposure to tobacco smoke. Because smoking rates did not change greatly during this time period, these improvements are likely due to a reduction in smoking in public places.

The Risk of Radon

Radon is a radioactive gas produced by the decay of naturally occurring uranium in soil and water. It has no color, odor, or taste.[15] In the United States, radon is the leading cause of lung cancer in nonsmokers and the second-leading cause of lung cancer overall. It is thought to account for 21,000 lung cancer deaths in the United States each year, with 2,900 of those deaths occurring in nonsmokers.[13] Worldwide, the World Health Organization estimates that up to 15 percent of lung cancers are caused by radon.[16]

For most individuals homes are the greatest source of radon exposure. An estimated one in 15 U.S. homes has high levels of radon.[13]Within a home radon levels tend to be highest in basements and cellars and other parts of the house that are in contact with the ground. Within a neighborhood radon concentrations can vary greatly from house to house.

One radon-related concern that made the news in 2008 involved granite countertops. An article published in the New York Times described a home with high radon levels linked to a granite countertop that contained high levels of uranium.[17] Although the countertop described in the article was a cause for concern, information from the U.S. Environmental Protection Agency (EPA), states, “Some granite used for countertops may contribute variably to indoor radon levels. At this time, however, EPA does not believe sufficient data exist to conclude that the types of granite commonly used in countertops are significantly increasing indoor radon levels.”[18] The EPA notes that the principal source of radon in homes is likely to be soil gas that is drawn indoors.

To identify high levels of radon, homeowners should test for radon every two years, or whenever they move, make structural changes to their homes, or occupy a previously unused level of their home.[15] Do-it-yourself radon test kits are available at many hardware stores, and testing can also be performed by a professional. If the test identifies high radon levels (greater than 4 picocuries per liter, steps to reduce radon include increasing ventilation under floors and sealing gaps and cracks in floors. During the construction of new homes, radon-reduction measures can be built into the house from the start.

What About Lung Cancer Screening?

For cancers such as breast cancer, colorectal cancer, and cervical cancer, the early detection of disease through the screening of asymptomatic individuals has contributed to decreased rates of death from these cancers. Understandably, there has also been a great deal of interest in whether lung cancer screening with tests such as chest X-rays or computerized axial tomography (CT) scans could reduce lung cancer mortality. Unfortunately, there is still no conclusive evidence that screening for lung cancer reduces the risk of death from lung cancer. Furthermore, as is the case when screening for any disease, screening for lung cancer carries potential risks. If the screening test produces a false-positive result (suggesting that there is cancer when in fact there is not), it will expose the individual to unnecessary and often invasive follow-up tests. Screening may also detect some cancers that do not actually need to be detected (very slow-growing cancers that will not affect the individual’s health during his or her lifetime). Before implementing routine screening programs, it’s therefore important to establish that screening provides benefits (most importantly, a reduced risk of death from the disease) that outweigh the potential risks.

Two large randomized trials that will help address many of the uncertainties surrounding lung cancer screening are the NELSON trial and the National Lung Cancer Screening Trial (NLST).19 The NELSON trial, conducted in the Netherlands, Belgium, and Denmark, is comparing CT screening with no screening among current and former smokers. In the United States, the NSLT will compare CT screening with chest X-ray screening among current and former smokers. It will be several years before the final results of these studies are available.

Promoting Lung Cancer as a Women’s Health Issue

In the area of women’s health, many topics compete for our attention. We often read headlines about breast cancer, heart disease, and bone health but hear less often about the important needs of women with lung cancer. If you’d like to help change this, consider getting involved with a lung cancer advocacy organization (see sidebar). And, if you’ve been diagnosed with lung cancer, talk with your doctor about the risks and the benefits of participating in a clinical trial evaluating novel approaches to treatment. Progress is being made in the treatment of lung cancer, but together we must ensure that this progress continues.

[1]. Fu JB, Kau TY, Severson RK, Kalemkerian GP. Lung cancer in women: Analysis of the national Surveillance, Epidemiology, and End Results database. Chest. 2005;127(3):768-77.

[2]. Cancer Facts and Figures 2008. American Cancer Society Web site. Available at: Accessed December 27, 2008.

[3]. 2007 Fact Book. National Cancer Institute Web site. Available at: Accessed December 27, 2008.

[4]. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. New England Journal of Medicine. 2006;355(24):2542-50.

[5]. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. New England Journal of Medicine. 2005;353(2):123-32.

[6]. Zhu CQ, da Cunha Santos G, Ding K, et al. Role of as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. Journal of Clinical Oncology.2008;26(26):4268-75.

[7]. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers—a different disease. Nature Reviews. Cancer. 2007;7(10):778-90.

[8]. Wakelee HA, Chang ET, Gomez SL, et al. Lung cancer incidence in never smokers. Journal of Clinical Oncology. 2007;25(5):472-78.

[9]. Freedman ND, Leitzmann MF, Hollenbeck AR, Schatzkin A, Abnet CC. Cigarette smoking and subsequent risk of lung cancer in men and women: Analysis of a prospective cohort study. Lancet Oncology.2008;9(7):649-56.

[10]. Thun MJ, Hannan LM, Adams-Campbell LL, et al. Lung cancer occurrence in never-smokers: An analysis of 13 cohorts and 22 cancer registry studies. PLoS Medicine. 2008;5(9):e185.

[11]. US Department of Health and Human Services. The Health Consequences of Smoking: A Report of the Surgeon General. Atlanta: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2004. Available at: Accessed December 27, 2008.

[12]. US Department of Health and Human Services. Women and Smoking: A Report of the Surgeon General–2001. Atlanta: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2001.

[13]. US Environmental Protection Agency. Indoor Air Quality: Radon: Health Risks: Exposure to Radon Causes Lung Cancer in Non-smokers and Smokers Alike. Available at: Accessed December 27, 2008.

[14]. Pirkle JL, Bernert JT, Caudill SP, Sosnoff CS, Pechacek TF. Trends in the exposure of nonsmokers in the U.S. population to secondhand smoke: 1988-2002. Environmental Health Perspectives.2006;114(6):853-58.

[15]. Surgeon General Releases National Health Advisory on Radon [press release]. US Department of Health and Human Services. January 13, 2005. Available at: Accessed December 27, 2008.