Lung cancer: who is at risk and can they be screened?

By Tiffanie L. Hammond and Amrita Ford, MA

Risk Factors for Lung Cancer
The Face of Lung Cancer
Symptoms of Lung Cancer
Screening for Lung Cancer
Biomarker Tests for Diagnosis
What We Still Need to Know and Change

Lung cancer is the second most commonly diagnosed cancer in both men and women in the U.S., but it is the #1 cancer killer. In 2012, it was estimated that approximately 226,160 men and women would be diagnosed with lung cancer and about 160,340 men and women would die from it.¹ That is more deaths than from breast, prostate, colon, and cervical cancers combined. One of the reasons for the disproportionate death rate is that while these other cancers have screening guidelines issued by U.S. public health agencies aimed at increasing early diagnosis, no such formal guidelines exist for the early diagnosis of lung cancer. The most common causes of lung cancer are well known, and changes in behavior can reduce the risk, but many men and women without risk factors are diagnosed with lung cancer every year.

Risk Factors for Lung Cancer

Smokers

Smoking is the leading cause of lung cancer. It is responsible for 90% of lung cancer deaths in men and 80% in women. Today, there are over 90 million current and former smokers living in the U.S. Most are men, but while the number of new cases of men diagnosed with lung cancer is declining every year, the number of new diagnoses among women was increasing annually until very recently.² The percentage of women who smoke began to increase in the 1940s during World War II and peaked in the 1960s.³ Decades later, lung cancer cases began rising in women, and stayed high, due to the long delay between starting to smoke and being diagnosed with lung cancer. Over the last few decades, smoking declined in popularity among women and men, resulting in a gradual decline in new cases of lung cancer.

Non-smokers

About 15% of lung cancer cases occur among nonsmokers, and each year about 20,000 people who never smoked die of lung cancer.⁴ Non-smoking women are at higher risk for lung cancer than non-smoking men: one in five women who develop lung cancer are non-smokers whereas only one in twelve men with lung cancer are non-smokers.⁵  Other causes of lung cancer in non-smokers include exposure to second-hand smoke, radon, asbestos, benzene or other cancer-causing agents, air pollution, and genetic vulnerability.

It is unclear why non-smokers develop lung cancer. One study found that about 30% of non-smokers who developed lung cancer had the same rare variation in a tumor-suppressor gene. This variation limits the gene’s ability to protect certain cells from cancer.⁶  Several molecular and genetic markers are thought to predispose some people to lung cancer but more research is needed to understand precisely how these markers influence the development of the disease.

The Face of Lung Cancer

Lung cancer patients are typically former or current smokers over the age of 65.  Most are men. African-American men are 37% more likely than Caucasian men to be diagnosed with lung cancer and 22% more likely to die from lung cancer, despite similar smoking rates.⁷ Research studies have examined smoking behavior, workplace and environmental exposures, biological and genetic differences, and cultural influences as potential causes for increased susceptibility and mortality of African Americans to lung cancer without a definitive answer.

Women accounted for 46% of new lung cancer cases in 2009, the most recent statistics available.⁸  Studies indicate that biological and genetic differences between men and women may play a role in differences in susceptibility to lung cancer and risk of dying from lung cancer.  Some research shows that estrogen, a hormone found in men and women that is much higher in women, may cause certain lung cancer cells to grow and spread throughout the lungs.  For example, a 2009 study based on the Women’s Health Initiative showed that post-menopausal women who took combined estrogen and progesterone replacement therapy (HRT) had an increased risk of dying from lung cancer, although they were not more likely to be diagnosed with lung cancer.⁹  In contrast, a 2010 study indicated that HRT may also increase the risk of developing lung cancer.¹⁰ In 2011, a study showed that women who take tamoxifen or other estrogen-blocking hormones to prevent breast cancer are at reduced risk for lung cancer death.¹¹ For more on women’s risk of lung cancer, see Lung Cancer is a Women’s Health Issue.

Symptoms of Lung Cancer

One of the reasons why lung cancer is so deadly is that symptoms usually appear during the later stages, when treatment is least effective. General symptoms include:

• a persistent cough that may worsen over time, including coughing up blood
• breathing trouble, such as shortness of breath
• chest pain
• raspy or hoarse voice
• frequent lung infections, such as pneumonia
• extreme and constant fatigue
• unintentional weight loss

Most lung cancers are detected by accident when testing for other health problems, or when the lung cancer is so advanced that symptoms are relatively obvious. The majority of lung cancer patients are diagnosed with late-stage lung cancer, when the cancer has usually already spread to other parts of the body, and at this point the 5-year survival rate is only 3.7%.¹²

Screening for Lung Cancer

The purpose of screening for cancer is to diagnose it early before symptoms appear. Cancer screening is only recommended when there is a method that is low-risk and accurate, and when the cancer can be detected early on.

There is currently no approved screening test for lung cancer.

Because of this, only 16% of lung cancer patients are diagnosed before their cancer has metastasized (spread to other parts of the body) compared to over 60% of breast cancer patients and over 90% of prostate cancer patients whose cancers are detected early-on through screening.¹³

Three major clinical trials in the 1970s evaluated two potential screening methods: chest x-ray and sputum cytology, an examination of cells found in the mucus of the lungs. The Johns Hopkins Lung Project, the Memorial Sloan-Kettering Lung Study, and the Mayo Lung Project evaluated men screened annually with only a chest x-ray (control group) against men screened with an annual chest x-ray plus sputum cytology (an analysis of their spit) every four months (intervention group). The studies found that screening men more often and with both screening tests resulted in more lung cancer diagnoses in one of the projects (the Mayo Lung Project), but there was no difference in the rate of lung cancer deaths.^14  15
In 1992 the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial evaluated nearly 155,000 men and women, comparing those who got an annual chest x-ray screening for 4 years to those who did not undergo any screening. More lung cancer cases were detected in the screening group, but after 13 years of follow-up the study found that annual chest x-ray screening did not reduce lung cancer deaths.¹⁶

In 1999, the Early Lung Cancer Action Project found that low-dose computerized tomography scans (low-dose CT) were four times more likely than chest x-rays to detect a cancerous tumor. Most of the cancers detected (85%) were very early lung cancers (Stage I).¹⁷

In 1999, Stephen J. Swensen and his colleagues at the Mayo Clinic found that having a low-dose CT scan every year for 5 years increased survival times, but it did not reduce mortality rates. Survival is a measure of how long a person lives once cancer is diagnosed. If mortality does not change, it means a person might be aware of his or her diagnosis for a longer period of time than someone who did not undergo screening, but he or she does not live any longer.¹⁸

The National Lung Screening Trial (NLST), which started in 2002, evaluated the use of chest x-rays and low-dose CT scans in men and women who were heavy smokers. Each randomized group was screened annually for three years. Researchers found that using low-dose CT scans could reduce lung cancer deaths by 20%. Based on a 2011 report of the trial,¹⁹ low-dose CT screening could potentially increase the 5-year lung cancer survival rate to 70% if it allowed lung cancer to be detected in its earliest stage (stage 1A), when the tumor is still relatively small, still in the lung, and can be removed easily through surgery.^{17 18
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Low-Dose CT Scans

Prior to these most recent low-dose CT scan findings, the U.S. Preventive Services Task Force, which is the government agency that reviews scientific evidence and makes recommendations on health care services, had concluded that there was insufficient evidence to recommend for or against screening people who do not have symptoms with low-dose CT, chest x-ray, sputum cytology, or any combination of these tests. ²¹ It is expected that the Task Force will re-visit their conclusions.

Who is recommending them?

Although no U.S. public health agency has recommended screening for lung cancer, in January 2013 the American Cancer Society (ACS) did so for the first time, saying that annual screening with low dose CT scans “could save many lives.”²²  ACS has recommended that people at highest risk for lung cancer, as defined by the National Lung Screening Trial, have a discussion with their doctor about the benefits and risks of annual screening. They advised doctors to have this conversation only with patients who match the profile of the people who were enrolled in the National Lung Cancer Screening Trial: current and former smokers who are 55 to 74 years old and have a 30-pack-year history of smoking (20 cigarettes a day for 30 years, 40 cigarettes a day for 15 years, and so on. To calculate your pack years, visit http://smokingpackyears.com/). If the patients are former smokers, they should have quit within the last 15 years.  Doctors should discuss screening with patients only if low dose CT scans and high quality treatment are available in their area, and only if the patient seems healthy and able to undergo treatment in the event that cancer is found.  For all other patients, “there is too much uncertainty regarding the balance of benefits and harms …”

In 2012, the American Lung Association became the first national lung organization—devoted to lung health as opposed to lung cancer—to endorse low dose CT scans for lung cancer screening. Three other organizations have issued guidelines for lung cancer screening on the basis of the National Lung Screening Trial results. Most of the guidelines are fairly similar but there are some key differences. The National Comprehensive Cancer Network (NCCN), a group of the nation’s major cancer centers, for instance, has a broader definition of high risk. Unlike the American Cancer Society, the NCCN allows people to skip annual screenings for an unspecified period of time if they have had 3 years in a row of normal results. The NCCN uses the same definition of high risk as the American Cancer Society but they also have a second definition that includes people as young as 50 and as old as 79 with only a 20-pack-year history—provided they have one other risk factor for lung cancer such as a family history, Chronic Obstructive Pulmonary Disease (COPD), or exposure to radon.  Given the close link between COPD and lung cancer, the Network’s screening criteria could potentially find more cases of lung cancer than the 30-pack criteria. (For more on COPD, read: Chronic Obstructive Lung Disease and Lung Cancer). The American College of Chest Physicians and the American Society of Clinical Oncology also have guidelines.  Only time will tell which guidelines work best, but any of these guidelines make it more likely that insurance companies will pay for screening. As a result of the National Lung Cancer Screening Trial, the U.S. Department of Veterans Affairs is starting to implement a screening program using CT scans for veterans at high risk.  However, most government health programs, such as Medicare and Medicaid, do not usually reimburse for lung cancer screening and might not do so until a public health agency has issued guidelines.

In the past, the lung cancer screening debate focused on the lack of evidence that screening reduced lung cancer deaths. Since the NLST trial, the debate is focusing on the benefits, risks, and cost of low-dose CT scans. Some of the risks include radiation exposure, a high rate of false-positive test results, and over-diagnosis (diagnosis of tumors that are not cancerous or not threatening to the patient).

False Positives

Chest x-rays report fewer false positives than low-dose CT scans, but they usually find large, aggressive tumors that are typical of later stages of lung cancer when treatment is usually not effective. When the men and women who had abnormal findings on either low-dose CT scans or x-rays underwent biopsies, approximately 96% did not have lung cancer. Biopsies can cause serious complications for patients. Since the low-dose CT scans found three times as many abnormal findings compared to x-rays, it resulted in many more false positives, biopsies, and complications. The approximately 1% of smokers screened with the CT scan who were found to have lung cancer would have an improved chance of survival. In contrast, the approximately one in four people screened who had false positive results would be at risk for complications, and those numbers would increase the more often people were screened.¹⁸
Computer-aided detection (CAD) methods may enhance the accuracy of CT screening and are being investigated. A European study which incorporated CAD into CT screening found a sensitivity of 95% in accurately detecting lung cancer. This means that out of 100 people at high risk for lung cancer with detected abnormalities, 95 really have lung cancer and 5 people have false-positive results. This same screening method was found to have a specificity of 99% in accurately ruling out disease in patients at high risk for lung cancer, which means that out of 100 people determined not to have lung cancer, only 1 person really does (a “false negative”).²³

Over-Diagnosis

Over-diagnosis is the identification of a disease in a person who would never have any symptoms or be harmed by the disease. Over-diagnosis can result in the treatment of pre-cancerous lesions with radiation therapy, hormone therapy, or surgery even though the lesions will never develop into lung cancer.

There are numerous reasons to be concerned about over-diagnosis of lung cancer. Those most likely to be screened are elderly, current or former smokers who may have co-existing medical conditions such as heart disease or emphysema. Scarring in the lungs from years of smoking and related respiratory illnesses can lead to a misdiagnosis of lung cancer, which will require further evaluation.

The testing can itself cause health problems. Radiologic imaging examinations, such as chest x-rays, chest CTs, and FDG-PET scans (fluorodeoxyglucose positron emission tomography), are the most common follow-up measures that are used to determine if additional invasive diagnostic procedures are needed. Radiologic imaging has little short-term risk, but it exposes patients to unnecessary radiation that can be harmful later in life. Invasive procedures, such as needle biopsies, are inserted into the lung to remove tissue samples and determine if there is cancer. This procedure can puncture the lung and cause it to collapse. Bleeding can also occur in the tumor or at the site of the needle insertion. Although very serious complications are rare (less than one in 1,000), they can occur.

Surgery may be necessary for diagnostic evaluation. It is also the preferred treatment for early-stage lung cancer. As with any invasive procedure, there are risks. Age and co-existing medical conditions increase the risk of death or complications from surgery. If a section of the lung is removed to reduce the chance of cancer spreading outside of the lung, then the patient will have reduced respiratory function. This could make breathing more difficult, especially for current and former smokers who already have respiratory issues.

Unnecessary treatment can also lead to pain, lost time at work, increased medical costs, and a reduction in the quality of life.

Radiation Exposure

Low-dose CT scans might result in earlier diagnosis of lung cancer, but radiation exposure from the screening test might actually increase a person’s risk of lung cancer, especially with repeated screenings. Although low-dose CT releases one tenth of the radiation of standard diagnostic CTs, the radiation that is released may act together with smoking to increase the risk of lung cancer. More research is needed to accurately measure the potential risk from exposure to radiation.

The frequency and dose of radiation exposure could affect risk, in addition to smoking history and age. The impact of frequency, dose, and age are still being determined, but risk modeling suggests that the risk of cancer caused by annual low-dose CT screening decreases with age.

Dr. David J. Brenner of Columbia University suggests that there is up to a 5.5% increase in the risk for lung cancer between the ages of 50 and 75 from annual low-dose CT screening of smokers or others at high risk for lung cancer during those 25 years. That risk would be reduced by half if screening was done every 2 years instead. He concludes that the screening method chosen for lung cancer must reduce lung cancer deaths by more than 5.5% to compensate for the potential risk of cancer caused by the CT radiation.²⁴

Costs, Benefits, and Insurance Coverage

On average, low-dose CT scans cost about $300 per screening, making them more expensive than mammograms for breast cancer ($80-$150) and pap smears for cervical cancer ($25-$75). No private insurance agencies (except for WellPoint) cover lung cancer screening with CT scans because it is not currently recommended by the U.S. Preventive Services Task Force. Medicare will cover low-dose CT scans for individuals who meet the following criteria:

• Age 55-77 years
• Has a tobacco smoking history of at least 30-pack years
• Is a current smoker or quit within the past 15 years
• Receives a written order for a low-dose CT scan from a qualified individual such as a doctor

A 2012 study conducted by actuaries (people trained to calculate the cost of risk and uncertainty) and published in Health Affairs, concluded that CT screening for lung cancer could save thousands of lives at a relatively low cost if it were covered by insurance companies.²⁵ The study examined the costs and benefits of providing high-risk individuals—smokers and long-term former smokers ages 50 to 64—with lung cancer screening using low-dose CT. Most private insurers do not currently cover the screening because evidence of the screening’s cost effectiveness has been scarce or conflicting until now. The researchers found that the screening would cost insurance companies about $247 per member screened annually, and when the total expense of screening was spread over the commercially insured population, the cost was under $1 per insured member per month. According to the study if the screening had been in place for the last 15 years, 130,000 more people under the age of 65 would be alive today, and the cost per life-year saved would be lower than screening for both cervical and breast cancers. The authors acknowledged that actual costs could be higher and the benefits lower if the screenings are not conducted according to best practice guidelines for pricing and follow-up of patients. The study is the first to show that low-dose CT screening is potentially cost-effective and could actually save insurance companies money since lung cancer would often be detected earlier and therefore require less expensive treatment. More importantly, detecting lung cancer early could save lives and improve the quality of life for people diagnosed with lung cancer.

Biomarker Tests for Diagnosis

Biomarker tests, which examine urine, blood, sputum (spit), tissue samples, and even exhaled air, for abnormal levels of certain proteins, antibodies or other substances, are being investigated as another type of diagnostic tool for detecting lung cancer.²⁶  Used together with low-dose CT scans, biomarker tests could potentially result in fewer misdiagnoses and less unnecessary treatment.

What We Still Need to Know and Change

The latest research suggests that lung cancer deaths can be reduced with low-dose CT screening in people who are at increased risk for lung cancer due to heavy smoking, and that annual chest x-rays are not effective regardless of smoking history. Questions remain about who else would benefit from screening (such as non-smokers who live with smokers or have had substantial radon exposure), at what age different groups should begin screening, and how often they should get screened. For now, low-dose CT appears to be the screening method with the most favorable ratio of benefit to harm, but the number of people harmed is quite large compared to the number of people who would benefit. Researchers will continue to search for other less risky and more accurate methods for lung cancer screening.

Funding and Legislation

Lung cancer research has not been a priority at the National Cancer Institute. Research dollars for lung cancer investigations continue to lag far behind other cancers that are less fatal. In fiscal year 2010, the National Cancer Institute spent $631 million for breast cancer research and $300 million for prostate cancer research. Lung cancer, the #1 cancer killer for women and men, received only $282 million. In fact in 2009, lung cancer research funding at NCI was actually reduced from the previous year, while breast and prostate cancer research funding continued to grow. Breast and prostate cancers have benefited from vigorous federal funding, and as a result, have made great strides in the early detection and treatment of the cancers.²⁷

Increased funding is needed to understand gender and racial differences in lung cancer and to continue research at the cellular and molecular levels for targeted, individualized, and less invasive detection and treatment of lung cancer. For more on lung cancer treatments, read here (Lung Cancer is a Women’s Health Issue).

In a 2010 report, the Institute of Medicine recommended that the NCI increase reimbursement from $2000 to $6000 per patient in their studies to encourage investigators in large cooperative groups to increase their involvement in lung cancer research. This reimbursement level has remained unchanged for over 10 years and the IOM report found that investigators limit their involvement in cancer research based on reimbursement concerns. Study participants would also benefit from increased funds. Patients in under-represented groups such as racial and ethnic minorities may be more likely to participate in trials that include reimbursement costs for patient care during the duration of the trial.²⁸

As policy-makers continue to debate about federal research funding, some are proposing that the tobacco industry help underwrite the costs of screening smokers. Most of the state funding for lung cancer prevention activities comes from the 1998 tobacco industry lawsuit. States will collect $25.3 billion this year from the tobacco lawsuit and state taxes from the sale and distribution of tobacco products. However, only about 2% of that revenue will go toward smoking cessation programs. The distribution of settlement money from the lawsuit is at the discretion of states, most of which are using the funding for unrelated state projects because of economic problems that they face. Unfortunately, most states have now reduced funding for prevention and smoking cessation programs to 1999 levels. Although the lawsuit did not stipulate that the settlement money go towards lung cancer prevention, treatment, or early detection programs, progress in finding more effective screening is less likely unless funding from the law suit is used to improve lung cancer screening, diagnosis, and treatment activities.²⁹

There is some pending legislation that may help persuade the federal government to fund more lung cancer research. The Lung Cancer Mortality Reduction Act of 2011 is a bipartisan bill currently in Congress which aims to reduce lung cancer mortality by 50% by 2020.³⁰ The bill, first introduced in 2008, calls on the cooperation of the Department of Health and Human Services, the Department of Defense, and Veterans Affairs to meet that goal and develop a coordinated plan that addresses the prevention, early detection, and treatment of lung cancer. It would require the National Cancer Institute to review and prioritize research grants related to lung cancer, the Food and Drug Administration to establish quality standards and guidelines for facilities that screen for lung cancer using low-dose CT scans, and the Centers for Disease Control and Prevention to establish a Lung Cancer Early Detection Program which would provide low-income, uninsured, and underserved populations at high risk for lung cancer with access to early detection services. For more information and to support this important legislation in the fight against lung cancer, visit http://www.opencongress.org/bill/112-h1394/show.

As lung cancer continues to take lives, increased funding for lung cancer research will be critical for ensuring better screening, earlier diagnosis, more effective treatment, longer survival, and an overall lower mortality for patients diagnosed with the disease. New research will not only benefit smokers and former smokers, but nonsmokers as well who make up 15% of lung cancer cases.