Peter Mazzone, MD, MPH, FCCP

In 1984, a worker at a Pennsylvania nuclear power plant triggered the radiation detector as he was getting ready to go home. This would not be unusual for such a facility, but there was no nuclear fuel on site at the time. The alarm went off every time he left work.

One day, he triggered the alarm as he crossed the detector on arriving at the plant, leading him to suspect that he was bringing radiation from home. He eventually convinced the plant’s health physicists to check his home, although at first they were opposed to the idea. The results revealed high concentrations of radon everywhere, especially in his basement.

Radon was already known to be associated with health risks in underground miners at that time. This event revealed that a naturally occurring radioactive gas could be found in households at potentially hazardous concentrations.

The incident captured the public’s attention, and the Environmental Protection Agency (EPA) and the US Centers for Disease Control and Prevention (CDC) recommended that nearly all homes be tested.^1,2 In 1988, the International Agency for Research on Cancer classified radon as a human carcinogen, and Congress passed the Indoor Radon Abatement Act in response to growing concern over health risks.³ This law funded state and federal measures to survey schools and federal buildings for radon levels, to educate citizens, and to develop programs for technical assistance. The long-term goal was to reduce indoor levels nationwide to no more than outdoor levels.

Radon is still considered an important public health hazard. From 15,000 to 21,000 people are estimated to die of lung cancer as a result of radon exposure each year in the United States, making it the second most common cause of lung cancer, behind smoking.⁴

Considering the relevance of this issue, this article will review the unique characteristics of radon as a risk factor for lung cancer.

WHAT IS RADON?

Radon is a noble gas that occurs naturally as a decay product of uranium 238 and thorium 232. It is colorless, tasteless, and imperceptible to our senses. Its most common isotope is radon 222 (²²²Rn), which has a half-life of 3.8 days and decays by emitting an alpha particle to become polonium 218. The decay chain continues through several intermediate steps until the stable isotope lead 206 is formed (Figure 1). Two of the isotopes in this chain, polonium 218 and polonium 214, also emit alpha particles.^5–7

Radon is primarily formed in soil. Its most important precursor, uranium 238, is ubiquitous, found in most soils and rocks in various concentrations. Radon can also be found in surface water, metal mines (uranium, phosphorus, silver, gold), residue of coal combustion, and natural gas.

Outdoor levels are usually much lower than indoor levels, as radon dissipates very quickly. Indoor radon mostly comes from the soil under the house or building, but it can also originate from coal combustion, gas appliances, and water (especially from private wells). In municipal water systems or surface reservoirs, most of the radon dissipates into the air or decays before the water reaches homes.^8,9

Radon’s only commercial application in the United States is in calibrating measuring instruments. In the past, it was used in radiography and to treat cancer but was later replaced by other radiation sources that cost less and pose less hazard of alpha radiation.¹⁰

HOW RADON CAN HARM

Alpha particles, emitted by radon 222 and its progenies polonium 218 and polonium 214, are highly effective in damaging tissues. Although they do not travel far or fast, with their two protons and two neutrons, alpha particles are heavy and therefore can cause considerable damage at short range. Although alpha particles can be stopped by a thin barrier such as a piece of paper or the skin, if the source is inhaled or ingested and lodges against mucosal linings, the alpha particles emitted can destroy cells.¹¹

The main route of radon exposure is by inhalation. Since radon is biologically inert, it is readily exhaled after it reaches the lungs. However, radon’s progenies can also be inhaled, either as free particles or attached to airborne particles such as dust, which they tend to attract as a result of their charged state. This attached fraction is believed to be more carcinogenic because it tends to deposit on the respiratory epithelium, notably in the carinae of bronchi. The smaller the dust particle, the deeper it can travel into the lung. The radiation emissions damage the genetic material of cells lining the airways, with the potential to result in lung cancer if the repair process is incomplete.^5,8,9

Other routes of exposure include ingestion and dermal exposure. Radon and its progenies can be swallowed in drinking water, passing through the stomach walls and bowels and entering the blood.¹² Dermal exposure is not considered a significant route unless the dermis is exposed, since in usual circumstances the skin protects the body from alpha radiation.¹³

Possible biologic mechanisms by which radon exposure might increase the risk of cancer include gene mutations, chromosome aberrations, generation of reactive oxygen species, up- or down-regulation of cytokines, and production of proteins associated with cell-cycle regulation.^14–16

HOW IS RADON MEASURED?

Several devices are commercially available to measure radon levels at home. The most common ones are activated charcoal detectors, electret ion chambers, alpha-track detectors, electronic integrating devices, and continuous monitors. There is no evidence that one device is better than another, but devices that measure radon gas are usually preferred over those that measure decay products because they are simpler to use and more cost-effective. These devices are divided into those used for short-term testing (2–90 days) and long-term testing (Table 1).¹⁷

Radon levels can be expressed as follows:

Working levels. One working level (WL) is any combination of radon progeny in 1 L of air that ultimately releases 1.3 × 10⁵ MeV of alpha energy during decay. In studies of miners, the radon progeny concentrations are generally expressed in WL. The cumulative exposure of an individual to this concentration over a “working month” of 170 hours is defined as a working level month (WLM).

Picocuries per liter. In the United States, the rate of decay is commonly reported in picocuries per liter (pCi/L): 1 pCi/L translates to 0.005 WL under usual conditions. The outdoor radon level is normally around 0.4 pCi/L.

Becquerel per cubic meter (Bq/m³) is an International System unit of measure: 1 WL corresponds to 3.7 × 10³ Bq/m³, and 1 pCi/L is equivalent to 37 Bq/m³.

Different areas have different radon levels

The Indoor Radon Abatement Act of 1988 helped identify areas in the United States that have the potential for elevated indoor radon levels. An estimated 6 million homes have concentrations greater than 4 pCi/L.

To assist in implementing radon-reducing strategies and allocation of resources, the EPA has created a map (Figure 2) that classifies counties according to the predicted indoor level.¹⁸

WHAT IS THE RELATIONSHIP BETWEEN RADON AND LUNG CANCER?

Determining the degree to which radon exposure contributes to lung cancer is a complex task. Radon can be found nearly everywhere, and there are diurnal, seasonal, and random year-to-year variations in the concentration of radon in indoor air.

A minority view

Not everyone agrees that radon is completely bad. For centuries, people have flocked to spas to “take the waters,” and the water at many of these spas has been found to contain radon. In the early 20th century, radiation was touted as having medicinal benefits, and people in many places in the world still go to “radon spas” (some of them in abandoned uranium mines) to help treat conditions such as arthritis and to feel invigorated and energized.

In 2006, a report by Zdrojewicz and Strzelczyk¹⁹ urged the medical community to keep an open mind about the possibility that radon exposure may be beneficial in very low doses, perhaps by stimulating repair mechanisms. This concept, called hormesis, differs from the mainstream view that cancer risk rises linearly with radiation dose, with no minimum threshold level (see below).

 

 

Risk in miners

As early as in the 16th century, metal miners in central Europe were noted to have a high rate of death from respiratory disease. Radon was discovered in 1900, and in the 20th century lung cancer was linked to high levels of radon detected in uranium mines.

Several small studies of underground miners exposed to high concentrations of radon consistently demonstrated an increased risk of lung cancer.

The Committee on the Biological Effects of Ionizing Radiation (BEIR VI 1999) reviewed 11 major cohort studies of miners. The studies included more than 60,000 miners in Europe, North America, Asia, and Australia, of whom 2,600 died of lung cancer. Lung cancer rates increased linearly with cumulative radon exposure, and the estimated average increase in the lung cancer death rate per WLM in the combined studies was 0.44% (95% confidence interval [CI] 0.20–1.00%). The percentage increase in the lung cancer death rate per WLM varied with time since exposure, with the highest increase in risk during the 5 to 14 years after exposure.^4,17 Furthermore, the increase in risk was higher in younger miners, who were exposed to a relatively low radon concentration.

Risk in the general population

The magnitude of the risk in miners led to concern about radon exposure as a cause of lung cancer in the general population. Statistical models were generated that suggested a causal link between radon exposure and lung cancer. Although extrapolation of the results from miners caused controversy, the BEIR VI estimation of risk was validated by studies in the general population.^7,20–23

Since the 1980s, several small case-control studies with limited power examined the relationship between indoor radon and lung cancer in the general population. In these studies, individuals who had developed lung cancer were compared with controls who had not developed the disease but who otherwise represented the population from which the cases of lung cancer came.

To improve the statistical power, the investigators of the major studies in Europe, North America, and China pooled the results in separate analyses (Table 2).^7,20–23 The average radon concentration to which each individual had been exposed over the previous decades was estimated by measuring the radon concentration at their present and previous homes. On the basis of information from the uranium miners, these studies assumed that the period of exposure was the 30 years ending 5 years before the diagnosis or at death from lung cancer.

The results provided convincing evidence that radon exposure is a cause of lung cancer in the general population and substantiated the extrapolation from the studies of miners. Further, the results of all three pooled analyses were consistent with a linear dose-response relationship with no threshold, suggesting an increased risk of lung cancer even with a radon level below 4 pCi/L (200 Bq/m³), which is the concentration at which mitigation actions are recommended in many countries.¹⁷

The North American pooled analysis included 3,662 cases and 4,966 controls from seven studies in the United States and Canada. When data from all studies were combined, the risk of lung cancer was found to increase by 11% per 100-Bq/m³ (about 2.7-pCi/L) increase in measured radon concentration (95% CI 0%–28%). The estimated increase in lung cancer was independent of age, sex, or smoking history.^7,20

The Chinese pooled data²² demonstrated a 13% (95% CI 1%–36%) increased risk per 100 Bq/m³.

In the European study, the risk of lung cancer increased by 8% per 100 Bq/m³ (95% CI 3%–16%). The European investigators repeated the analysis, taking into account the random year-to-year variability in measured radon concentration, finding the final estimated risk was an increase of 16% per 100 Bq/m³ using long-term average concentration.²¹

The combined estimate^21,24 from the three pooling studies based on measured radon concentration is an increased risk of lung cancer of 10% per 100 Bq/m³.

Synergistic risk with smoking

Radon exposure was independently associated with lung cancer, and the relationship with cigarette smoking is believed to be synergistic. The radon progeny particles attach themselves to smoke and dust and are then deposited in the bronchial epithelium.²⁵

In the pool of European case-control studies, the cancer risk for current smokers of 15 to 24 cigarettes per day relative to that in never-smokers was 25.8 (95% CI 21–31). Assuming that in the same analysis the lung cancer risk increased by 16% per 100 Bq/m³ of usual radon concentration regardless of smoking status, the cumulative absolute risk by age 75 would be 0.67% in those who never smoked and 16% in smokers at usual radon levels of 400 Bq/m³ (11 pCi/L).²¹

Rates of all lung cancer subtypes increased

Radon exposure is not associated with a specific histologic subtype of lung cancer. It has been speculated that the incidence of the small-cell subtype might be slightly increased because radon tends to deposit in the more central bronchial carinae.^20,21 However, all subtypes have been described in association with radon, the most common being adenocarcinoma and squamous cell carcinoma.^26–28

EFFECT OF MITIGATION MEASURES

The US Surgeon General and the EPA recommend that all homes be tested.¹⁸ Short-term tests should be used first, keeping in mind that diurnal and seasonal variations may occur.

The World Health Organization has proposed a reference level of 100 Bq/m³ (2.7 pCi/L) to minimize health hazards from indoor radon exposure.¹⁷ If this level cannot be reached under the country-specific conditions, the chosen reference level should not exceed 300 Bq/m³ (8 pCi/L).

In the United States, if the result of home testing is higher than 4 pCi/L, a follow-up measurement should be done using a different short-term test or a long-term test. If the follow-up result confirms a level of more than 4 pCi/L, mitigating actions are recommended. The goal is to reduce the indoor radon level as much as possible—down to zero or at least comparable to outdoor levels (national average 0.4 pCi/L).¹⁸

A variety of radon mitigation strategies have been used, with different rates of efficacy (Table 3). The optimal strategy depends on the likely source or cause, construction characteristics, soil, and climate.²⁹ Table 4 lists resources for the general public about testing and mitigation measures.

How beneficial is radon mitigation?

Although it is logical to try to reduce the indoor radon concentration, there is no strong evidence yet that this intervention decreases the incidence of lung cancer in the general population.

Using the BEIR VI risk model, Méndez et al³⁰ estimated a 21% reduction in the annual radon-related lung cancer mortality rate by 2100 if all households were compliant with government recommendations (mitigation actions at levels of 4 pCi/L) and assuming that the percentage of cigarette smokers remained constant.

On the other hand, if the number of smokers continues to decline, the benefits from radon mitigation may be less. The expected benefit from mitigation in this scenario is a reduction of 12% in annual radon-related deaths by the year 2100.³⁰ However, it will be challenging to determine whether the expected decline in the incidence of lung cancer and lung cancer deaths is truly attributable to mitigation measures.

 

MANAGING PATIENTS EXPOSED TO RADON

Screen for lung cancer in smokers only

The National Lung Screening Study (NLST) was a large multicenter trial of annual low-dose computed tomography (CT) to screen for lung cancer in a cohort at high risk: age 55 to 74, at least a 30 pack-year history of smoking in a current smoker, or a former smoker who quit within the past 15 years. The trial demonstrated a 20% reduction in lung cancer deaths in the CT screening group.³¹

Since the publication of the NLST results, many societies have endorsed screening for lung cancer with low-dose CT using the study criteria. The National Comprehensive Cancer Network (NCCN) expanded these criteria and has recommended screening in patients over age 50 who have a history of smoking and one additional risk factor, such as radon exposure.

However, radon exposure has not been incorporated into a lung cancer risk-prediction model, and there is no empirical evidence suggesting that people who have such a history would benefit from screening.^32,33 The joint guidelines of the American College of Chest Physicians and American Society of Clinical Oncology recommend annual low-dose CT screening only for patients who meet the NLST criteria.³⁴

What to do about indeterminate lung nodules

The widely used guidelines from the Fleischner Society³⁵ on how to manage small lung nodules stratify patients into groups at low and high risk of developing lung cancer on the basis of risk factors. The guidelines apply to adults age 35 and older in whom an indeterminate solid nodule was recently detected.

If a patient is at high risk, the recommended approach includes follow-up in shorter intervals depending on the nodule size. History of smoking is recognized as a major risk factor, and the statement also lists family history and exposure to asbestos, uranium, and radon.³⁵

Although the association of radon with lung cancer has been shown in epidemiologic studies, radon exposure has not been included in validated statistical models that assess the probability that an indeterminate lung nodule is malignant. We would expect the risk to be higher in miners, who suffer a more intense exposure to higher levels of radon, than in the general population, which has a low and constantly variable residential exposure. Furthermore, there are no data to support a more aggressive follow-up approach in patients with indeterminate lung nodules and a history of radon exposure.

RADON AND OTHER CANCERS

When a person is exposed to radon, the bronchial epithelium receives the highest dose of ionizing radiation, but other organs such as the kidneys, stomach, and bone marrow may receive doses as well, although lower. Several studies have looked into possible associations, but there is no strong evidence to suggest an increased mortality rate related to radon from cancers other than lung.^24,36 However, there seems to be a positive association between radon and the incidence of lymphoproliferative disorders in uranium miners.^37,38

Radon can be measured in drinking water, and a few studies have looked at a possible association with gastrointestinal malignancies. The results did not reveal a consistent positive correlation.^39,40 The risk of cancer from exposure to radon in the public water supply is likely small and mostly from the transfer of radon particles into the air and not from drinking the water. On the other hand, the risk could be higher with private wells, where radon levels are variable and are possibly higher than from public sources.⁴¹

DATA ARE INSUFFICIENT TO GUIDE MANAGEMENT

Radon is a naturally occurring and ubiquitous radioactive gas that can cause tissue damage. Cohort and case-control studies have demonstrated that radon exposure is associated with increased risk of lung cancer. It is recommended that radon levels be measured in every home in the United States and mitigation measures instituted if levels exceed 4 pCi/L.

There are insufficient data to help guide the management of patients with a history of radon exposure, and prospective studies are needed to better understand the individual risk of developing lung cancer and the appropriate management of such patients.

Smoking cessation is an integral part of lung cancer risk reduction from radon exposure.

In 1984, a worker at a Pennsylvania nuclear power plant triggered the radiation detector as he was getting ready to go home. This would not be unusual for such a facility, but there was no nuclear fuel on site at the time. The alarm went off every time he left work.

One day, he triggered the alarm as he crossed the detector on arriving at the plant, leading him to suspect that he was bringing radiation from home. He eventually convinced the plant’s health physicists to check his home, although at first they were opposed to the idea. The results revealed high concentrations of radon everywhere, especially in his basement.

Radon was already known to be associated with health risks in underground miners at that time. This event revealed that a naturally occurring radioactive gas could be found in households at potentially hazardous concentrations.

The incident captured the public’s attention, and the Environmental Protection Agency (EPA) and the US Centers for Disease Control and Prevention (CDC) recommended that nearly all homes be tested.^1,2 In 1988, the International Agency for Research on Cancer classified radon as a human carcinogen, and Congress passed the Indoor Radon Abatement Act in response to growing concern over health risks.³ This law funded state and federal measures to survey schools and federal buildings for radon levels, to educate citizens, and to develop programs for technical assistance. The long-term goal was to reduce indoor levels nationwide to no more than outdoor levels.

Radon is still considered an important public health hazard. From 15,000 to 21,000 people are estimated to die of lung cancer as a result of radon exposure each year in the United States, making it the second most common cause of lung cancer, behind smoking.⁴

Considering the relevance of this issue, this article will review the unique characteristics of radon as a risk factor for lung cancer.

WHAT IS RADON?

Radon is a noble gas that occurs naturally as a decay product of uranium 238 and thorium 232. It is colorless, tasteless, and imperceptible to our senses. Its most common isotope is radon 222 (²²²Rn), which has a half-life of 3.8 days and decays by emitting an alpha particle to become polonium 218. The decay chain continues through several intermediate steps until the stable isotope lead 206 is formed (Figure 1). Two of the isotopes in this chain, polonium 218 and polonium 214, also emit alpha particles.^5–7

Radon is primarily formed in soil. Its most important precursor, uranium 238, is ubiquitous, found in most soils and rocks in various concentrations. Radon can also be found in surface water, metal mines (uranium, phosphorus, silver, gold), residue of coal combustion, and natural gas.

Outdoor levels are usually much lower than indoor levels, as radon dissipates very quickly. Indoor radon mostly comes from the soil under the house or building, but it can also originate from coal combustion, gas appliances, and water (especially from private wells). In municipal water systems or surface reservoirs, most of the radon dissipates into the air or decays before the water reaches homes.^8,9

Radon’s only commercial application in the United States is in calibrating measuring instruments. In the past, it was used in radiography and to treat cancer but was later replaced by other radiation sources that cost less and pose less hazard of alpha radiation.¹⁰

HOW RADON CAN HARM

Alpha particles, emitted by radon 222 and its progenies polonium 218 and polonium 214, are highly effective in damaging tissues. Although they do not travel far or fast, with their two protons and two neutrons, alpha particles are heavy and therefore can cause considerable damage at short range. Although alpha particles can be stopped by a thin barrier such as a piece of paper or the skin, if the source is inhaled or ingested and lodges against mucosal linings, the alpha particles emitted can destroy cells.¹¹

The main route of radon exposure is by inhalation. Since radon is biologically inert, it is readily exhaled after it reaches the lungs. However, radon’s progenies can also be inhaled, either as free particles or attached to airborne particles such as dust, which they tend to attract as a result of their charged state. This attached fraction is believed to be more carcinogenic because it tends to deposit on the respiratory epithelium, notably in the carinae of bronchi. The smaller the dust particle, the deeper it can travel into the lung. The radiation emissions damage the genetic material of cells lining the airways, with the potential to result in lung cancer if the repair process is incomplete.^5,8,9

Other routes of exposure include ingestion and dermal exposure. Radon and its progenies can be swallowed in drinking water, passing through the stomach walls and bowels and entering the blood.¹² Dermal exposure is not considered a significant route unless the dermis is exposed, since in usual circumstances the skin protects the body from alpha radiation.¹³

Possible biologic mechanisms by which radon exposure might increase the risk of cancer include gene mutations, chromosome aberrations, generation of reactive oxygen species, up- or down-regulation of cytokines, and production of proteins associated with cell-cycle regulation.^14–16

HOW IS RADON MEASURED?

Several devices are commercially available to measure radon levels at home. The most common ones are activated charcoal detectors, electret ion chambers, alpha-track detectors, electronic integrating devices, and continuous monitors. There is no evidence that one device is better than another, but devices that measure radon gas are usually preferred over those that measure decay products because they are simpler to use and more cost-effective. These devices are divided into those used for short-term testing (2–90 days) and long-term testing (Table 1).¹⁷

Radon levels can be expressed as follows:

Working levels. One working level (WL) is any combination of radon progeny in 1 L of air that ultimately releases 1.3 × 10⁵ MeV of alpha energy during decay. In studies of miners, the radon progeny concentrations are generally expressed in WL. The cumulative exposure of an individual to this concentration over a “working month” of 170 hours is defined as a working level month (WLM).

Picocuries per liter. In the United States, the rate of decay is commonly reported in picocuries per liter (pCi/L): 1 pCi/L translates to 0.005 WL under usual conditions. The outdoor radon level is normally around 0.4 pCi/L.

Becquerel per cubic meter (Bq/m³) is an International System unit of measure: 1 WL corresponds to 3.7 × 10³ Bq/m³, and 1 pCi/L is equivalent to 37 Bq/m³.

Different areas have different radon levels

The Indoor Radon Abatement Act of 1988 helped identify areas in the United States that have the potential for elevated indoor radon levels. An estimated 6 million homes have concentrations greater than 4 pCi/L.

To assist in implementing radon-reducing strategies and allocation of resources, the EPA has created a map (Figure 2) that classifies counties according to the predicted indoor level.¹⁸

WHAT IS THE RELATIONSHIP BETWEEN RADON AND LUNG CANCER?

Determining the degree to which radon exposure contributes to lung cancer is a complex task. Radon can be found nearly everywhere, and there are diurnal, seasonal, and random year-to-year variations in the concentration of radon in indoor air.

A minority view

Not everyone agrees that radon is completely bad. For centuries, people have flocked to spas to “take the waters,” and the water at many of these spas has been found to contain radon. In the early 20th century, radiation was touted as having medicinal benefits, and people in many places in the world still go to “radon spas” (some of them in abandoned uranium mines) to help treat conditions such as arthritis and to feel invigorated and energized.

In 2006, a report by Zdrojewicz and Strzelczyk¹⁹ urged the medical community to keep an open mind about the possibility that radon exposure may be beneficial in very low doses, perhaps by stimulating repair mechanisms. This concept, called hormesis, differs from the mainstream view that cancer risk rises linearly with radiation dose, with no minimum threshold level (see below).

 

 

Risk in miners

As early as in the 16th century, metal miners in central Europe were noted to have a high rate of death from respiratory disease. Radon was discovered in 1900, and in the 20th century lung cancer was linked to high levels of radon detected in uranium mines.

Several small studies of underground miners exposed to high concentrations of radon consistently demonstrated an increased risk of lung cancer.

The Committee on the Biological Effects of Ionizing Radiation (BEIR VI 1999) reviewed 11 major cohort studies of miners. The studies included more than 60,000 miners in Europe, North America, Asia, and Australia, of whom 2,600 died of lung cancer. Lung cancer rates increased linearly with cumulative radon exposure, and the estimated average increase in the lung cancer death rate per WLM in the combined studies was 0.44% (95% confidence interval [CI] 0.20–1.00%). The percentage increase in the lung cancer death rate per WLM varied with time since exposure, with the highest increase in risk during the 5 to 14 years after exposure.^4,17 Furthermore, the increase in risk was higher in younger miners, who were exposed to a relatively low radon concentration.

Risk in the general population

The magnitude of the risk in miners led to concern about radon exposure as a cause of lung cancer in the general population. Statistical models were generated that suggested a causal link between radon exposure and lung cancer. Although extrapolation of the results from miners caused controversy, the BEIR VI estimation of risk was validated by studies in the general population.^7,20–23

Since the 1980s, several small case-control studies with limited power examined the relationship between indoor radon and lung cancer in the general population. In these studies, individuals who had developed lung cancer were compared with controls who had not developed the disease but who otherwise represented the population from which the cases of lung cancer came.

To improve the statistical power, the investigators of the major studies in Europe, North America, and China pooled the results in separate analyses (Table 2).^7,20–23 The average radon concentration to which each individual had been exposed over the previous decades was estimated by measuring the radon concentration at their present and previous homes. On the basis of information from the uranium miners, these studies assumed that the period of exposure was the 30 years ending 5 years before the diagnosis or at death from lung cancer.

The results provided convincing evidence that radon exposure is a cause of lung cancer in the general population and substantiated the extrapolation from the studies of miners. Further, the results of all three pooled analyses were consistent with a linear dose-response relationship with no threshold, suggesting an increased risk of lung cancer even with a radon level below 4 pCi/L (200 Bq/m³), which is the concentration at which mitigation actions are recommended in many countries.¹⁷

The North American pooled analysis included 3,662 cases and 4,966 controls from seven studies in the United States and Canada. When data from all studies were combined, the risk of lung cancer was found to increase by 11% per 100-Bq/m³ (about 2.7-pCi/L) increase in measured radon concentration (95% CI 0%–28%). The estimated increase in lung cancer was independent of age, sex, or smoking history.^7,20

The Chinese pooled data²² demonstrated a 13% (95% CI 1%–36%) increased risk per 100 Bq/m³.

In the European study, the risk of lung cancer increased by 8% per 100 Bq/m³ (95% CI 3%–16%). The European investigators repeated the analysis, taking into account the random year-to-year variability in measured radon concentration, finding the final estimated risk was an increase of 16% per 100 Bq/m³ using long-term average concentration.²¹

The combined estimate^21,24 from the three pooling studies based on measured radon concentration is an increased risk of lung cancer of 10% per 100 Bq/m³.

Synergistic risk with smoking

Radon exposure was independently associated with lung cancer, and the relationship with cigarette smoking is believed to be synergistic. The radon progeny particles attach themselves to smoke and dust and are then deposited in the bronchial epithelium.²⁵

In the pool of European case-control studies, the cancer risk for current smokers of 15 to 24 cigarettes per day relative to that in never-smokers was 25.8 (95% CI 21–31). Assuming that in the same analysis the lung cancer risk increased by 16% per 100 Bq/m³ of usual radon concentration regardless of smoking status, the cumulative absolute risk by age 75 would be 0.67% in those who never smoked and 16% in smokers at usual radon levels of 400 Bq/m³ (11 pCi/L).²¹

Rates of all lung cancer subtypes increased

Radon exposure is not associated with a specific histologic subtype of lung cancer. It has been speculated that the incidence of the small-cell subtype might be slightly increased because radon tends to deposit in the more central bronchial carinae.^20,21 However, all subtypes have been described in association with radon, the most common being adenocarcinoma and squamous cell carcinoma.^26–28

EFFECT OF MITIGATION MEASURES

The US Surgeon General and the EPA recommend that all homes be tested.¹⁸ Short-term tests should be used first, keeping in mind that diurnal and seasonal variations may occur.

The World Health Organization has proposed a reference level of 100 Bq/m³ (2.7 pCi/L) to minimize health hazards from indoor radon exposure.¹⁷ If this level cannot be reached under the country-specific conditions, the chosen reference level should not exceed 300 Bq/m³ (8 pCi/L).

In the United States, if the result of home testing is higher than 4 pCi/L, a follow-up measurement should be done using a different short-term test or a long-term test. If the follow-up result confirms a level of more than 4 pCi/L, mitigating actions are recommended. The goal is to reduce the indoor radon level as much as possible—down to zero or at least comparable to outdoor levels (national average 0.4 pCi/L).¹⁸

A variety of radon mitigation strategies have been used, with different rates of efficacy (Table 3). The optimal strategy depends on the likely source or cause, construction characteristics, soil, and climate.²⁹ Table 4 lists resources for the general public about testing and mitigation measures.

How beneficial is radon mitigation?

Although it is logical to try to reduce the indoor radon concentration, there is no strong evidence yet that this intervention decreases the incidence of lung cancer in the general population.

Using the BEIR VI risk model, Méndez et al³⁰ estimated a 21% reduction in the annual radon-related lung cancer mortality rate by 2100 if all households were compliant with government recommendations (mitigation actions at levels of 4 pCi/L) and assuming that the percentage of cigarette smokers remained constant.

On the other hand, if the number of smokers continues to decline, the benefits from radon mitigation may be less. The expected benefit from mitigation in this scenario is a reduction of 12% in annual radon-related deaths by the year 2100.³⁰ However, it will be challenging to determine whether the expected decline in the incidence of lung cancer and lung cancer deaths is truly attributable to mitigation measures.

 

MANAGING PATIENTS EXPOSED TO RADON

Screen for lung cancer in smokers only

The National Lung Screening Study (NLST) was a large multicenter trial of annual low-dose computed tomography (CT) to screen for lung cancer in a cohort at high risk: age 55 to 74, at least a 30 pack-year history of smoking in a current smoker, or a former smoker who quit within the past 15 years. The trial demonstrated a 20% reduction in lung cancer deaths in the CT screening group.³¹

Since the publication of the NLST results, many societies have endorsed screening for lung cancer with low-dose CT using the study criteria. The National Comprehensive Cancer Network (NCCN) expanded these criteria and has recommended screening in patients over age 50 who have a history of smoking and one additional risk factor, such as radon exposure.

However, radon exposure has not been incorporated into a lung cancer risk-prediction model, and there is no empirical evidence suggesting that people who have such a history would benefit from screening.^32,33 The joint guidelines of the American College of Chest Physicians and American Society of Clinical Oncology recommend annual low-dose CT screening only for patients who meet the NLST criteria.³⁴

What to do about indeterminate lung nodules

The widely used guidelines from the Fleischner Society³⁵ on how to manage small lung nodules stratify patients into groups at low and high risk of developing lung cancer on the basis of risk factors. The guidelines apply to adults age 35 and older in whom an indeterminate solid nodule was recently detected.

If a patient is at high risk, the recommended approach includes follow-up in shorter intervals depending on the nodule size. History of smoking is recognized as a major risk factor, and the statement also lists family history and exposure to asbestos, uranium, and radon.³⁵

Although the association of radon with lung cancer has been shown in epidemiologic studies, radon exposure has not been included in validated statistical models that assess the probability that an indeterminate lung nodule is malignant. We would expect the risk to be higher in miners, who suffer a more intense exposure to higher levels of radon, than in the general population, which has a low and constantly variable residential exposure. Furthermore, there are no data to support a more aggressive follow-up approach in patients with indeterminate lung nodules and a history of radon exposure.

RADON AND OTHER CANCERS

When a person is exposed to radon, the bronchial epithelium receives the highest dose of ionizing radiation, but other organs such as the kidneys, stomach, and bone marrow may receive doses as well, although lower. Several studies have looked into possible associations, but there is no strong evidence to suggest an increased mortality rate related to radon from cancers other than lung.^24,36 However, there seems to be a positive association between radon and the incidence of lymphoproliferative disorders in uranium miners.^37,38

Radon can be measured in drinking water, and a few studies have looked at a possible association with gastrointestinal malignancies. The results did not reveal a consistent positive correlation.^39,40 The risk of cancer from exposure to radon in the public water supply is likely small and mostly from the transfer of radon particles into the air and not from drinking the water. On the other hand, the risk could be higher with private wells, where radon levels are variable and are possibly higher than from public sources.⁴¹

DATA ARE INSUFFICIENT TO GUIDE MANAGEMENT

Radon is a naturally occurring and ubiquitous radioactive gas that can cause tissue damage. Cohort and case-control studies have demonstrated that radon exposure is associated with increased risk of lung cancer. It is recommended that radon levels be measured in every home in the United States and mitigation measures instituted if levels exceed 4 pCi/L.

There are insufficient data to help guide the management of patients with a history of radon exposure, and prospective studies are needed to better understand the individual risk of developing lung cancer and the appropriate management of such patients.

Smoking cessation is an integral part of lung cancer risk reduction from radon exposure.

In 1984, a worker at a Pennsylvania nuclear power plant triggered the radiation detector as he was getting ready to go home. This would not be unusual for such a facility, but there was no nuclear fuel on site at the time. The alarm went off every time he left work.

One day, he triggered the alarm as he crossed the detector on arriving at the plant, leading him to suspect that he was bringing radiation from home. He eventually convinced the plant’s health physicists to check his home, although at first they were opposed to the idea. The results revealed high concentrations of radon everywhere, especially in his basement.

Radon was already known to be associated with health risks in underground miners at that time. This event revealed that a naturally occurring radioactive gas could be found in households at potentially hazardous concentrations.

The incident captured the public’s attention, and the Environmental Protection Agency (EPA) and the US Centers for Disease Control and Prevention (CDC) recommended that nearly all homes be tested.^1,2 In 1988, the International Agency for Research on Cancer classified radon as a human carcinogen, and Congress passed the Indoor Radon Abatement Act in response to growing concern over health risks.³ This law funded state and federal measures to survey schools and federal buildings for radon levels, to educate citizens, and to develop programs for technical assistance. The long-term goal was to reduce indoor levels nationwide to no more than outdoor levels.

Radon is still considered an important public health hazard. From 15,000 to 21,000 people are estimated to die of lung cancer as a result of radon exposure each year in the United States, making it the second most common cause of lung cancer, behind smoking.⁴

Considering the relevance of this issue, this article will review the unique characteristics of radon as a risk factor for lung cancer.

WHAT IS RADON?

Radon is a noble gas that occurs naturally as a decay product of uranium 238 and thorium 232. It is colorless, tasteless, and imperceptible to our senses. Its most common isotope is radon 222 (²²²Rn), which has a half-life of 3.8 days and decays by emitting an alpha particle to become polonium 218. The decay chain continues through several intermediate steps until the stable isotope lead 206 is formed (Figure 1). Two of the isotopes in this chain, polonium 218 and polonium 214, also emit alpha particles.^5–7

Radon is primarily formed in soil. Its most important precursor, uranium 238, is ubiquitous, found in most soils and rocks in various concentrations. Radon can also be found in surface water, metal mines (uranium, phosphorus, silver, gold), residue of coal combustion, and natural gas.

Outdoor levels are usually much lower than indoor levels, as radon dissipates very quickly. Indoor radon mostly comes from the soil under the house or building, but it can also originate from coal combustion, gas appliances, and water (especially from private wells). In municipal water systems or surface reservoirs, most of the radon dissipates into the air or decays before the water reaches homes.^8,9

Radon’s only commercial application in the United States is in calibrating measuring instruments. In the past, it was used in radiography and to treat cancer but was later replaced by other radiation sources that cost less and pose less hazard of alpha radiation.¹⁰

HOW RADON CAN HARM

Alpha particles, emitted by radon 222 and its progenies polonium 218 and polonium 214, are highly effective in damaging tissues. Although they do not travel far or fast, with their two protons and two neutrons, alpha particles are heavy and therefore can cause considerable damage at short range. Although alpha particles can be stopped by a thin barrier such as a piece of paper or the skin, if the source is inhaled or ingested and lodges against mucosal linings, the alpha particles emitted can destroy cells.¹¹

The main route of radon exposure is by inhalation. Since radon is biologically inert, it is readily exhaled after it reaches the lungs. However, radon’s progenies can also be inhaled, either as free particles or attached to airborne particles such as dust, which they tend to attract as a result of their charged state. This attached fraction is believed to be more carcinogenic because it tends to deposit on the respiratory epithelium, notably in the carinae of bronchi. The smaller the dust particle, the deeper it can travel into the lung. The radiation emissions damage the genetic material of cells lining the airways, with the potential to result in lung cancer if the repair process is incomplete.^5,8,9

Other routes of exposure include ingestion and dermal exposure. Radon and its progenies can be swallowed in drinking water, passing through the stomach walls and bowels and entering the blood.¹² Dermal exposure is not considered a significant route unless the dermis is exposed, since in usual circumstances the skin protects the body from alpha radiation.¹³

Possible biologic mechanisms by which radon exposure might increase the risk of cancer include gene mutations, chromosome aberrations, generation of reactive oxygen species, up- or down-regulation of cytokines, and production of proteins associated with cell-cycle regulation.^14–16

HOW IS RADON MEASURED?

Several devices are commercially available to measure radon levels at home. The most common ones are activated charcoal detectors, electret ion chambers, alpha-track detectors, electronic integrating devices, and continuous monitors. There is no evidence that one device is better than another, but devices that measure radon gas are usually preferred over those that measure decay products because they are simpler to use and more cost-effective. These devices are divided into those used for short-term testing (2–90 days) and long-term testing (Table 1).¹⁷

Radon levels can be expressed as follows:

Working levels. One working level (WL) is any combination of radon progeny in 1 L of air that ultimately releases 1.3 × 10⁵ MeV of alpha energy during decay. In studies of miners, the radon progeny concentrations are generally expressed in WL. The cumulative exposure of an individual to this concentration over a “working month” of 170 hours is defined as a working level month (WLM).

Picocuries per liter. In the United States, the rate of decay is commonly reported in picocuries per liter (pCi/L): 1 pCi/L translates to 0.005 WL under usual conditions. The outdoor radon level is normally around 0.4 pCi/L.

Becquerel per cubic meter (Bq/m³) is an International System unit of measure: 1 WL corresponds to 3.7 × 10³ Bq/m³, and 1 pCi/L is equivalent to 37 Bq/m³.

Different areas have different radon levels

The Indoor Radon Abatement Act of 1988 helped identify areas in the United States that have the potential for elevated indoor radon levels. An estimated 6 million homes have concentrations greater than 4 pCi/L.

To assist in implementing radon-reducing strategies and allocation of resources, the EPA has created a map (Figure 2) that classifies counties according to the predicted indoor level.¹⁸

WHAT IS THE RELATIONSHIP BETWEEN RADON AND LUNG CANCER?

Determining the degree to which radon exposure contributes to lung cancer is a complex task. Radon can be found nearly everywhere, and there are diurnal, seasonal, and random year-to-year variations in the concentration of radon in indoor air.

A minority view

Not everyone agrees that radon is completely bad. For centuries, people have flocked to spas to “take the waters,” and the water at many of these spas has been found to contain radon. In the early 20th century, radiation was touted as having medicinal benefits, and people in many places in the world still go to “radon spas” (some of them in abandoned uranium mines) to help treat conditions such as arthritis and to feel invigorated and energized.

In 2006, a report by Zdrojewicz and Strzelczyk¹⁹ urged the medical community to keep an open mind about the possibility that radon exposure may be beneficial in very low doses, perhaps by stimulating repair mechanisms. This concept, called hormesis, differs from the mainstream view that cancer risk rises linearly with radiation dose, with no minimum threshold level (see below).

 

 

Risk in miners

As early as in the 16th century, metal miners in central Europe were noted to have a high rate of death from respiratory disease. Radon was discovered in 1900, and in the 20th century lung cancer was linked to high levels of radon detected in uranium mines.

Several small studies of underground miners exposed to high concentrations of radon consistently demonstrated an increased risk of lung cancer.

The Committee on the Biological Effects of Ionizing Radiation (BEIR VI 1999) reviewed 11 major cohort studies of miners. The studies included more than 60,000 miners in Europe, North America, Asia, and Australia, of whom 2,600 died of lung cancer. Lung cancer rates increased linearly with cumulative radon exposure, and the estimated average increase in the lung cancer death rate per WLM in the combined studies was 0.44% (95% confidence interval [CI] 0.20–1.00%). The percentage increase in the lung cancer death rate per WLM varied with time since exposure, with the highest increase in risk during the 5 to 14 years after exposure.^4,17 Furthermore, the increase in risk was higher in younger miners, who were exposed to a relatively low radon concentration.

Risk in the general population

The magnitude of the risk in miners led to concern about radon exposure as a cause of lung cancer in the general population. Statistical models were generated that suggested a causal link between radon exposure and lung cancer. Although extrapolation of the results from miners caused controversy, the BEIR VI estimation of risk was validated by studies in the general population.^7,20–23

Since the 1980s, several small case-control studies with limited power examined the relationship between indoor radon and lung cancer in the general population. In these studies, individuals who had developed lung cancer were compared with controls who had not developed the disease but who otherwise represented the population from which the cases of lung cancer came.

To improve the statistical power, the investigators of the major studies in Europe, North America, and China pooled the results in separate analyses (Table 2).^7,20–23 The average radon concentration to which each individual had been exposed over the previous decades was estimated by measuring the radon concentration at their present and previous homes. On the basis of information from the uranium miners, these studies assumed that the period of exposure was the 30 years ending 5 years before the diagnosis or at death from lung cancer.

The results provided convincing evidence that radon exposure is a cause of lung cancer in the general population and substantiated the extrapolation from the studies of miners. Further, the results of all three pooled analyses were consistent with a linear dose-response relationship with no threshold, suggesting an increased risk of lung cancer even with a radon level below 4 pCi/L (200 Bq/m³), which is the concentration at which mitigation actions are recommended in many countries.¹⁷

The North American pooled analysis included 3,662 cases and 4,966 controls from seven studies in the United States and Canada. When data from all studies were combined, the risk of lung cancer was found to increase by 11% per 100-Bq/m³ (about 2.7-pCi/L) increase in measured radon concentration (95% CI 0%–28%). The estimated increase in lung cancer was independent of age, sex, or smoking history.^7,20

The Chinese pooled data²² demonstrated a 13% (95% CI 1%–36%) increased risk per 100 Bq/m³.

In the European study, the risk of lung cancer increased by 8% per 100 Bq/m³ (95% CI 3%–16%). The European investigators repeated the analysis, taking into account the random year-to-year variability in measured radon concentration, finding the final estimated risk was an increase of 16% per 100 Bq/m³ using long-term average concentration.²¹

The combined estimate^21,24 from the three pooling studies based on measured radon concentration is an increased risk of lung cancer of 10% per 100 Bq/m³.

Synergistic risk with smoking

Radon exposure was independently associated with lung cancer, and the relationship with cigarette smoking is believed to be synergistic. The radon progeny particles attach themselves to smoke and dust and are then deposited in the bronchial epithelium.²⁵

In the pool of European case-control studies, the cancer risk for current smokers of 15 to 24 cigarettes per day relative to that in never-smokers was 25.8 (95% CI 21–31). Assuming that in the same analysis the lung cancer risk increased by 16% per 100 Bq/m³ of usual radon concentration regardless of smoking status, the cumulative absolute risk by age 75 would be 0.67% in those who never smoked and 16% in smokers at usual radon levels of 400 Bq/m³ (11 pCi/L).²¹

Rates of all lung cancer subtypes increased

Radon exposure is not associated with a specific histologic subtype of lung cancer. It has been speculated that the incidence of the small-cell subtype might be slightly increased because radon tends to deposit in the more central bronchial carinae.^20,21 However, all subtypes have been described in association with radon, the most common being adenocarcinoma and squamous cell carcinoma.^26–28

EFFECT OF MITIGATION MEASURES

The US Surgeon General and the EPA recommend that all homes be tested.¹⁸ Short-term tests should be used first, keeping in mind that diurnal and seasonal variations may occur.

The World Health Organization has proposed a reference level of 100 Bq/m³ (2.7 pCi/L) to minimize health hazards from indoor radon exposure.¹⁷ If this level cannot be reached under the country-specific conditions, the chosen reference level should not exceed 300 Bq/m³ (8 pCi/L).

In the United States, if the result of home testing is higher than 4 pCi/L, a follow-up measurement should be done using a different short-term test or a long-term test. If the follow-up result confirms a level of more than 4 pCi/L, mitigating actions are recommended. The goal is to reduce the indoor radon level as much as possible—down to zero or at least comparable to outdoor levels (national average 0.4 pCi/L).¹⁸

A variety of radon mitigation strategies have been used, with different rates of efficacy (Table 3). The optimal strategy depends on the likely source or cause, construction characteristics, soil, and climate.²⁹ Table 4 lists resources for the general public about testing and mitigation measures.

How beneficial is radon mitigation?

Although it is logical to try to reduce the indoor radon concentration, there is no strong evidence yet that this intervention decreases the incidence of lung cancer in the general population.

Using the BEIR VI risk model, Méndez et al³⁰ estimated a 21% reduction in the annual radon-related lung cancer mortality rate by 2100 if all households were compliant with government recommendations (mitigation actions at levels of 4 pCi/L) and assuming that the percentage of cigarette smokers remained constant.

On the other hand, if the number of smokers continues to decline, the benefits from radon mitigation may be less. The expected benefit from mitigation in this scenario is a reduction of 12% in annual radon-related deaths by the year 2100.³⁰ However, it will be challenging to determine whether the expected decline in the incidence of lung cancer and lung cancer deaths is truly attributable to mitigation measures.

 

MANAGING PATIENTS EXPOSED TO RADON

Screen for lung cancer in smokers only

The National Lung Screening Study (NLST) was a large multicenter trial of annual low-dose computed tomography (CT) to screen for lung cancer in a cohort at high risk: age 55 to 74, at least a 30 pack-year history of smoking in a current smoker, or a former smoker who quit within the past 15 years. The trial demonstrated a 20% reduction in lung cancer deaths in the CT screening group.³¹

Since the publication of the NLST results, many societies have endorsed screening for lung cancer with low-dose CT using the study criteria. The National Comprehensive Cancer Network (NCCN) expanded these criteria and has recommended screening in patients over age 50 who have a history of smoking and one additional risk factor, such as radon exposure.

However, radon exposure has not been incorporated into a lung cancer risk-prediction model, and there is no empirical evidence suggesting that people who have such a history would benefit from screening.^32,33 The joint guidelines of the American College of Chest Physicians and American Society of Clinical Oncology recommend annual low-dose CT screening only for patients who meet the NLST criteria.³⁴

What to do about indeterminate lung nodules

The widely used guidelines from the Fleischner Society³⁵ on how to manage small lung nodules stratify patients into groups at low and high risk of developing lung cancer on the basis of risk factors. The guidelines apply to adults age 35 and older in whom an indeterminate solid nodule was recently detected.

If a patient is at high risk, the recommended approach includes follow-up in shorter intervals depending on the nodule size. History of smoking is recognized as a major risk factor, and the statement also lists family history and exposure to asbestos, uranium, and radon.³⁵

Although the association of radon with lung cancer has been shown in epidemiologic studies, radon exposure has not been included in validated statistical models that assess the probability that an indeterminate lung nodule is malignant. We would expect the risk to be higher in miners, who suffer a more intense exposure to higher levels of radon, than in the general population, which has a low and constantly variable residential exposure. Furthermore, there are no data to support a more aggressive follow-up approach in patients with indeterminate lung nodules and a history of radon exposure.

RADON AND OTHER CANCERS

When a person is exposed to radon, the bronchial epithelium receives the highest dose of ionizing radiation, but other organs such as the kidneys, stomach, and bone marrow may receive doses as well, although lower. Several studies have looked into possible associations, but there is no strong evidence to suggest an increased mortality rate related to radon from cancers other than lung.^24,36 However, there seems to be a positive association between radon and the incidence of lymphoproliferative disorders in uranium miners.^37,38

Radon can be measured in drinking water, and a few studies have looked at a possible association with gastrointestinal malignancies. The results did not reveal a consistent positive correlation.^39,40 The risk of cancer from exposure to radon in the public water supply is likely small and mostly from the transfer of radon particles into the air and not from drinking the water. On the other hand, the risk could be higher with private wells, where radon levels are variable and are possibly higher than from public sources.⁴¹

DATA ARE INSUFFICIENT TO GUIDE MANAGEMENT

Radon is a naturally occurring and ubiquitous radioactive gas that can cause tissue damage. Cohort and case-control studies have demonstrated that radon exposure is associated with increased risk of lung cancer. It is recommended that radon levels be measured in every home in the United States and mitigation measures instituted if levels exceed 4 pCi/L.

There are insufficient data to help guide the management of patients with a history of radon exposure, and prospective studies are needed to better understand the individual risk of developing lung cancer and the appropriate management of such patients.

Smoking cessation is an integral part of lung cancer risk reduction from radon exposure.

In 2011, two papers were published that will shape the way we think about lung cancer screening for years to come.

See related patient information sheet

In one, the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized controlled trial of chest radiography for lung cancer screening,¹ researchers found that chest radiography was not an effective lung cancer screening tool. However, the National Lung Screening Trial (NLST)² has transformed medicine by finding that screening with low-dose computed tomography (CT) reduced the lung cancer mortality rate (Table 1).

While the ability to screen for lung cancer is a major positive change, it also raises many thorny questions, such as who should be screened, how often should they be screened, and how should we respond when a nodule is detected.

To answer some of these questions, we will outline how Cleveland Clinic has structured its lung cancer screening program, and the rationale we used for making pragmatic patient-care decisions within this program. We will conclude with our thoughts about the potential evolution of lung cancer screening programs.

THE 40-YEAR QUEST FOR EFFECTIVE LUNG CANCER SCREENING

Lung cancer kills more people in the United States than the next four most lethal types of cancer combined.³ It is curable if found early in its course. Unfortunately, most people who develop lung cancer feel no symptoms when it is early in its course, and therefore it is too often diagnosed at a late stage. Treatment for late-stage lung cancer is effective, but it is rarely curative.

Screening refers to testing people at risk of developing a disease before its symptoms or signs have appeared. The goal of screening is to reduce the disease-specific mortality rate. For this to happen, the disease must be detectable in a preclinical form, and treatment must be more successful when applied early. Ideally, the screening test should pose little risk to the patient, be sensitive for detecting the disease early in its course, give few false-positive results, be acceptable to the patient, and be relatively inexpensive to the health system.

Over the past 4 decades, a large volume of research has been done in the hope of proving that conventional radiography or CT could be an effective screening test for lung cancer.^4,5

Cohort studies (ie, in which all the patients were screened) of radiography or CT have shown a longer survival from the time of lung cancer diagnosis than would be expected without screening. These studies were not designed to prove a reduction in the lung cancer-specific mortality rate.

Controlled trials (in which half the patients received the screening and the other half did not) of chest radiography have been interpreted as not showing a reduction in lung cancer mortality rates, though debate about the interpretation of these trials persisted until this past year. Biases inherent in using duration of survival rather than the mortality rate as an end point have been suggested as the reason for the apparent benefit in survival without a reduction in the mortality rate.

Controlled trials of CT screening were started nearly a decade ago. Until 2011, the results of these trials were not mature enough to comment on.

THE PROSTATE, LUNG, COLORECTAL, AND OVARIAN TRIAL

The lung cancer screening portion of the PLCO trial aimed to determine the effect of screening chest radiography on lung cancer-specific mortality rates.¹

In this trial, 154,901 people were randomized to undergo either posteroanterior chest radiography every year for 4 years or usual care, ie, no lung cancer screening. Participants were men and women age 55 to 74 with no history of prostate, lung, colorectal, or ovarian cancer. They did not need to be a smoker to participate. Those who had never smoked and who were randomized to the screening group received only 3 years of testing. All were followed for 13 years or until the conclusion of the study (8 years after the final participant was enrolled). About half were women, and nearly two-thirds were age 55 through 64. Only 10% were current smokers, while a full 45% had never smoked.

Results. Adherence to screening in the screening group ranged from 79% to 86.6% over the years of screening, and 11% of the usual-care group was estimated to have undergone screening chest radiography.

Cumulative lung cancer incidence rates were 201 per 100,000 person-years in the screening group and 192 in the usual-care group.

In the screening group, there were a total of 1,696 lung cancers during the entire study. Of these, 307 (18%) were detected by screening, 198 (12%) were interval cancers (diagnosed during the screening period but not by the screening test), and the remainder were diagnosed after the screening period during the years of follow-up. In the screening group, the cancers detected by screening were more likely to be adenocarcinomas and less likely to be small-cell carcinomas than those not detected by screening. Also in the screening group, the cancers detected by screening were more likely to be stage I (50%) than those not detected by screening.

The cumulative number of deaths from lung cancer was slightly but not significantly lower in the screening group from years 4 through 11. However, by the end of follow-up, the number of lung cancer deaths was equal between the groups (1,213 in the screening group vs 1,230 in the usual-care group). The cumulative overall mortality rate was also similar between the groups. For the subgroup who would have qualified for the NLST (see below), the lung cancer mortality rate was statistically similar between the two groups.

Comments. The results of the PLCO screening trial will be interpreted as the final word in lung cancer screening with standard chest radiography. The conclusion is that annual screening with chest radiography does not reduce lung cancer mortality rates and thus should not be performed in this context.

 

THE NATIONAL LUNG SCREENING TRIAL

The NLST aimed to determine if screening with low-dose chest CT could reduce lung cancer mortality rates.²

This controlled trial enrolled 53,454 people, who were randomized to undergo either low-dose chest CT or posteroanterior chest radiography at baseline and then yearly for 2 years.

Participants were men and women age 55 to 74 with at least 30 pack-years of cigarette smoking. If they had quit smoking, they had to have quit within the past 15 years. All were followed until study conclusion (median 6.5 years, maximum 7.4). About 41% were women, and nearly three-quarters were age 55 through 64. More than 48% were current smokers, with the rest being former smokers.

Results. Adherence to screening was 95% in the CT group and 93% in the radiography group, with a 4.3% annual rate of CT outside the study during the screening phase.

Cumulative lung cancer incidence rates were 645 per 100,000 person-years in the CT group and 572 in the radiography group.

In the CT group there were a total of 1,060 lung cancers during the entire study. Of these, 649 (61%) were detected by screening, 44 (4%) were interval cancers, and the rest were diagnosed after the screening period during follow-up.

In the chest radiography group, there were a total of 941 lung cancers during the entire study. Of these, 279 (30%) were detected by screening, 137 (15%) were interval cancers, and the rest were diagnosed after the screening period. Within the CT group, the cancers detected by screening were more likely to be adenocarcinomas and less likely to be small-cell carcinomas than those not detected by screening. Also within the CT group, the cancers detected by screening were more likely to be stage I (63%) than those not detected by screening.

The cumulative number of deaths from lung cancer was 443 in the radiography group, but only 356 in the CT group—20.0% lower (P =.004). The cumulative overall mortality rate was 6.7% lower in the CT group (P = .02).

Comments. The results of the NLST provide the first evidence that lung cancer mortality rates can be reduced by screening. Though many questions remain, the conclusions of this study are that screening a well-defined high-risk group with low-dose CT reduces the rate of death from lung cancer.

REMAINING CHALLENGES

The NLST showed that lung cancer screening with low-dose CT can meet the most important criterion for a successful screening program, ie, a reduction in the disease-specific mortality rate. Many challenges remain in meeting the other criteria for a successful or ideal screening program (low risk, few false-positive results, acceptability to the patient, and affordability). The issues with low-dose CT-based screening that challenge these ideals are outlined in this section.

Lung nodules: Benign or malignant?

Imaging-based lung cancer screening is designed to find lung nodules. CT has been more successful than radiography largely because it is more sensitive at finding lung nodules. Unfortunately, most lung nodules found by modern CT are not cancerous, but rather are benign. Distinguishing between a nodule that is an early malignancy and one that is benign remains challenging (Figure 1).

A meta-analysis of CT screening studies found that for every 1,000 people screened at baseline, 9 were found to have stage I non-small-cell lung cancer, 235 had false-positive nodules, and 4 underwent thoracotomy for benign lesions.⁶

The NLST results were similar. In this trial, only nodules that were 4 mm or greater in diameter were reported. Using these criteria, over 27% of all study participants were found to have a lung nodule on CT at baseline and at year 1. The rate fell to nearly 17% at year 2, as nodules present from baseline were not reported. Of all the lung nodules detected, only 3.6% were ultimately proven to represent lung cancer.²

Many issues with small lung nodules need to be considered. The nodules are difficult to find, with highly variable reporting even by expert radiologists.⁷ They are difficult to measure accurately and thus are difficult to assess for growth.⁸ Adjunctive imaging and nonsurgical biopsy have a low yield for small nodules.^9–11 Follow-up of these lung nodules includes additional imaging and nonsurgical and surgical biopsy procedures, adding expense to the program and risk to the patient. Finally, knowing that they have a lung nodule makes patients feel anxious and thus negatively affects their quality of life.^12,13

Radiation exposure: How great is the risk?

There is a great deal of concern about radiation exposure from medical imaging, as many people receive a substantial amount of radiation each year from medical testing.¹⁴ A single low-dose scan with chest CT delivers a whole-body effective dose of about 1.5 mSv—less than one-fifth of the radiation dose of a typical diagnostic CT scan.

Many have tried to estimate the consequences of radiation exposure from low-dose CT screening. All estimates are extrapolations from unrelated radiation exposures. The increase in risk of death ranged from 0.01% to a few percent,¹⁵ and the increase in cancers was as high as 1.8% over a 25-year screening period.¹⁶ In general, the risks are felt to be very low but not negligible.

Cost-effectiveness is unknown

The cost-effectiveness of lung cancer screening is also unknown. Many highly variable estimates have been published.^17–20 The studies have differed in the perspective taken, the costs of testing assumed, and the rounds of screening included. The most cost-effective estimates are in populations with the highest risk of cancer, in programs that achieve the greatest reduction in mortality rate, and in programs that lead to high rates of smoking cessation.

Screening in the real world as opposed to a clinical trial may involve different risks, benefits, and costs. Compliance with screening and with nodule management algorithms may be lower outside of a study. One study suggested that those at highest risk of developing lung cancer would be the least likely to enroll in a screening program and the least likely to accept curative-intent surgery for screening-detected cancer.²¹

We expect that the NLST data will be analyzed for cost-effectiveness. This should provide the most accurate estimates for the group that was studied.

 

WE SET OUT TO DESIGN A SCREENING PROGRAM

With the evidence supporting a reduction in the rate of lung cancer mortality, and knowing the remaining challenges, we set out to provide a lung cancer screening program within Cleveland Clinic. In the design of our program, we considered several questions, outlined below.

Who should be offered low-dose CT screening?

The results of the NLST led to a great deal of excitement about lung cancer screening in both the medical community and the general public. The positive side of this publicity is that lung cancer is receiving attention that may lead to support for further advances. The negative side is that many patients who may seek out lung cancer screening are not at high enough risk of lung cancer to clearly benefit from it.

In the NLST, a very high-risk cohort was studied, as defined by clinical variables (age 55 to 74, at least 30 pack-years of smoking, and if a former smoker, had quit within the past 15 years). In this high-risk group, 320 patients needed to be screened (with three yearly chest CT scans) for one life to be saved from lung cancer, and only 3.6% of all lung nodules found (4 mm or larger) were actually lung cancer. In a group at lower risk, the number that needed to be screened to save one life would be higher, and the percentage of lung nodules that truly were lung cancer would be lower. This would lead to higher risks and costs related to screening, without a proven benefit to members of the lower-risk group.

The risk of the NLST cohort developing lung cancer was approximately 0.6% per year. Lung cancer risk-prediction models have been developed and published. Up to 2011, the three most commonly used models had only moderate accuracy at predicting risk.^22–25 In 2011 a risk model based on the PLCO cohort was developed and published.²⁶ This model seemed to be more accurate but perhaps a bit harder to apply in practice.

We discussed whether using a validated risk predictor with a target of 0.6% per year (ie, the risk in the NLST trial) would be an adequate means of deciding on candidacy for lung cancer screening or if we should strictly adhere to the inclusion criteria of the NLST cohort. We feel that the NLST cohort is the only group with true evidence of benefit (a reduction in the lung cancer-specific mortality rate). Thus, for our program’s entry criteria, we decided to use the same clinical predictors used for entry in the NLST.

How will the right patients get scheduled for low-dose screening CT?

Patients who enter the lung cancer screening program from our health system will require a physician’s order.

We are fortunate to have an electronic medical record in place. We have created an order set within the electronic record for low-dose chest CT. The order will eventually be able to be entered as “CT lung screening w/o” (ie, without contrast).

For patients from outside of our health system who would like to enter the lung cancer screening program, the entry criteria will be the same (see above). We will ask for the name of the patient’s primary care practitioner. If the patient does not have one, a member of our Respiratory Institute will see and enroll the patient.

How often should patients be screened, and for how many years?

Unfortunately, questions about the frequency of screening and how many years it should continue remain unanswered.

In the NLST, a similar number of early-stage lung cancers were detected during each of the three screening rounds. In both the NLST and PLCO trials, differences in the mortality rate curves began to narrow during the observation period, when active screening was no longer occurring. Thus, it is possible that a longer duration of screening could lead to a further reduction in mortality rates. Others have questioned whether a similar benefit, with less cost and risk, could be obtained by screening every 2 years.

The large amount of data obtained from the NLST and other CT-based studies is being reviewed so that models can be developed to help answer these questions. For now, we suggest at least three yearly CT screenings, with the hope that we will have clearer answers to these questions over time.

How will low-dose CT be performed and interpreted?

The parameters for low-dose CT were very tightly controlled and monitored during the NLST. This quality-control effort, designed to improve consistency across sites and to minimize risk to patients, should be carried into lung cancer screening programs.

Our program will closely mimic the CT performance criteria used in the NLST (tube current-time product 40 mAs for all patients, field of view lungs only, lung kernel images 3 mm at 1.5-mm intervals, and soft-tissue kernel images 5 mm at 2.5-mm intervals).²⁷ In the initial phase of the program, all screening scans will be performed at Cleveland Clinic’s main imaging facility.

Small lung nodules remain quite challenging to detect and measure. To minimize variability in scan interpretation, the NLST readers were all expertly trained radiologists. Despite this, much variability was noted in the number of nodules detected, their measured size, and the follow-up recommendations. All of the screening CT images for our program will be interpreted by board-certified radiologists with expertise in chest imaging.

Other screening studies have included novel imaging assessment in their testing algorithms, particularly volumetric analysis of lung nodules.²⁸ These tools may prove to assist in nodule detection, measurement, and management over time. At this point, we do not think they have been studied and standardized enough to include them in a standard-of-care screening program. We hope that they will evolve to the point of clinical utility in the near future.

Lung cancer screening is not currently covered by most insurers, including Medicare, although one major insurer has recently started to cover it. We expect decisions on coverage from other insurers in the next 12 months. In the meantime, we offer a low-dose screening chest CT to our patients for $125, which includes the radiologist’s fee for interpreting the scan.

Smoking cessation

The NLST showed that low-dose CT screening can reduce lung cancer mortality rates by 20% in a high-risk group. A 50-year-old active smoker who quits smoking reduces his or her risk of dying of lung cancer by more than 50%.²⁹ Entry into a lung cancer screening program provides an opportunity for education and assistance with tobacco dependency.

At Cleveland Clinic, we have an active Tobacco Treatment Center within our Wellness Institute. All lung cancer screening participants who are identified as active smokers will be given a program brochure and will be offered a consult in the program.

 

 

What do we identify as a lung nodule, and how should they be managed?

Studies of CT-based screening have highlighted the tremendous number of lung nodules that are identified and the low likelihood of malignancy in those that are less than 1 cm in diameter. Many screening studies define a positive result as a lung nodule above a particular size. The NLST used 4 mm or greater as the cutoff. The lower the cutoff, the greater the number of nodules found, and the lower the overall likelihood of malignancy in the nodules.

Studies in which annual CT screening was the intervention are able to use size criteria in part because the study design ensures another CT will be performed 12 months later. Current nodule management guidelines suggest 12-month CT follow-up of incidentally discovered lung nodules, 4 mm or smaller, in at-risk patients.³⁰ In a screening program, particularly one for which the patient must pay, the 12-month screening CT cannot be guaranteed. This makes it more difficult to ignore the smallest nodules identified on CT screening. Given this, we will be reporting all lung nodules identified, regardless of size on the initial screening.

Most studies of CT screening have reported any new nodule identified in subsequent screening rounds regardless of size. Though it is intuitive that a new nodule would have a high likelihood of malignancy in a high-risk cohort, malignancy rates have been reported to be as low as 1% for new nodules. As with the initial round of screening, we will report all new lung nodules identified in subsequent screening rounds.

All screening CT scans will be read and reported by board-certified radiologists with expertise in chest imaging. The report generated will be in a standard format and sent to the ordering physician (Table 2). The ordering physician will choose to manage the evaluation of any nodule that is detected or refer the patient to a specialty lung nodule clinic within the Respiratory Institute. A reminder of the availability of the lung nodule clinic will be present within the templated report. A consult to the lung nodule clinic is an order available within the electronic medical record.

The recommendations for the evaluation of lung nodules, both within the report and at the lung nodule clinic, are in keeping with currently available guidelines, such as those from the Fleischner Society³⁰ and the American College of Chest Physicians.³¹ For incidentally discovered lung nodules in patients at high risk, the Fleischner Society recommendations are as follows³⁰:

• For nodules 4 mm or smaller, follow-up in 12 months; if no growth, then no further follow-up
• For nodules 4 to 6 mm, follow-up at 6 to 12 months, then 18 to 24 months if no growth
• For nodules 6 to 8 mm, follow-up at 3 to 6 months, then 9 to 12 months, then 24 months if no growth
• For nodules 8 mm or larger, follow-up at 3, 9, and 24 months, or positron emission tomography, or biopsy, or both.

If the nodule is large enough or is deemed to be of high enough risk, adjuvant testing with diagnostic imaging, guided bronchoscopy, transthoracic needle aspiration, or minimally invasive resection will be offered. All patients with nodules believed to require biopsy will be discussed at our multidisciplinary lung cancer tumor board before biopsy.

How do we make practitioners and patients aware of the program and its indications, risks, and benefits?

Education will be the key to having lung cancer screening adopted as the standard of care, to lung cancer screening being provided within a well-designed and capable system, and to ensuring that patients have realistic expectations about screening. Articles such as this and grand rounds presentations within our health system will help provide education to our colleagues. Broader marketing campaigns will be considered in the future once demand and system capabilities are clearly identified. A patient information brochure will be provided at the time of the screening test (see the patient information sheet that accompanies this article).

How do we help to advance best practice?

As excited as we are that low-dose CT-based lung cancer screening has been proven to reduce lung cancer mortality rates, it is clear that there is a lot of room to improve the programs that are developed based on current data.

Advances in our ability to accurately predict an individual’s risk of developing lung cancer will allow us to offer screening to those it is most likely to benefit.

Advances in smoking cessation and chemoprevention will help to minimize the number of lung cancers that develop.

Advances in our ability to determine the nature of lung nodules will allow us to accelerate treatment of very early lung cancer while minimizing additional testing on benign nodules; advances in our ability to treat localized and advanced disease will improve the outcome for those identified as having lung cancer.

To help move the science of screening forward, we will develop a screening program registry that can be populated from the order set and the templated report. The registry can be used to ensure appropriate patient care, while studying relevant epidemiologic, quality, and cost-related questions.

We hope to assess novel imaging software capable of assisting with the detection and characterization of lung nodules.

We have an active biomarker development program to assess the ability of breath and blood-based biomarkers to identify those at risk of developing lung cancer; to assist with the management of screening-detected lung nodules; to assist with the diagnosis of early stage lung cancer; and to characterize the nature of the cancers identified. Accurate biomarkers could lead to further decreases in mortality rates while reducing the risks and costs of a screening program.

We have strong surgical, medical, and radiation oncology programs, actively pursuing advances in minimally invasive resection procedures and ablative and targeted therapies.

ENTERING A NEW ERA

We are entering a new era of lung cancer screening. The NLST has shown that lung cancer morality rates can be reduced through low-dose CT screening in a high-risk population. Many challenges remain, such as managing the nodules that are discovered, determining if the program is cost-effective, and minimizing radiation exposure. These need to be considered when designing a lung cancer screening program. Advances over time will help us optimize the programs that are developed.

In 2011, two papers were published that will shape the way we think about lung cancer screening for years to come.

See related patient information sheet

In one, the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized controlled trial of chest radiography for lung cancer screening,¹ researchers found that chest radiography was not an effective lung cancer screening tool. However, the National Lung Screening Trial (NLST)² has transformed medicine by finding that screening with low-dose computed tomography (CT) reduced the lung cancer mortality rate (Table 1).

While the ability to screen for lung cancer is a major positive change, it also raises many thorny questions, such as who should be screened, how often should they be screened, and how should we respond when a nodule is detected.

To answer some of these questions, we will outline how Cleveland Clinic has structured its lung cancer screening program, and the rationale we used for making pragmatic patient-care decisions within this program. We will conclude with our thoughts about the potential evolution of lung cancer screening programs.

THE 40-YEAR QUEST FOR EFFECTIVE LUNG CANCER SCREENING

Lung cancer kills more people in the United States than the next four most lethal types of cancer combined.³ It is curable if found early in its course. Unfortunately, most people who develop lung cancer feel no symptoms when it is early in its course, and therefore it is too often diagnosed at a late stage. Treatment for late-stage lung cancer is effective, but it is rarely curative.

Screening refers to testing people at risk of developing a disease before its symptoms or signs have appeared. The goal of screening is to reduce the disease-specific mortality rate. For this to happen, the disease must be detectable in a preclinical form, and treatment must be more successful when applied early. Ideally, the screening test should pose little risk to the patient, be sensitive for detecting the disease early in its course, give few false-positive results, be acceptable to the patient, and be relatively inexpensive to the health system.

Over the past 4 decades, a large volume of research has been done in the hope of proving that conventional radiography or CT could be an effective screening test for lung cancer.^4,5

Cohort studies (ie, in which all the patients were screened) of radiography or CT have shown a longer survival from the time of lung cancer diagnosis than would be expected without screening. These studies were not designed to prove a reduction in the lung cancer-specific mortality rate.

Controlled trials (in which half the patients received the screening and the other half did not) of chest radiography have been interpreted as not showing a reduction in lung cancer mortality rates, though debate about the interpretation of these trials persisted until this past year. Biases inherent in using duration of survival rather than the mortality rate as an end point have been suggested as the reason for the apparent benefit in survival without a reduction in the mortality rate.

Controlled trials of CT screening were started nearly a decade ago. Until 2011, the results of these trials were not mature enough to comment on.

THE PROSTATE, LUNG, COLORECTAL, AND OVARIAN TRIAL

The lung cancer screening portion of the PLCO trial aimed to determine the effect of screening chest radiography on lung cancer-specific mortality rates.¹

In this trial, 154,901 people were randomized to undergo either posteroanterior chest radiography every year for 4 years or usual care, ie, no lung cancer screening. Participants were men and women age 55 to 74 with no history of prostate, lung, colorectal, or ovarian cancer. They did not need to be a smoker to participate. Those who had never smoked and who were randomized to the screening group received only 3 years of testing. All were followed for 13 years or until the conclusion of the study (8 years after the final participant was enrolled). About half were women, and nearly two-thirds were age 55 through 64. Only 10% were current smokers, while a full 45% had never smoked.

Results. Adherence to screening in the screening group ranged from 79% to 86.6% over the years of screening, and 11% of the usual-care group was estimated to have undergone screening chest radiography.

Cumulative lung cancer incidence rates were 201 per 100,000 person-years in the screening group and 192 in the usual-care group.

In the screening group, there were a total of 1,696 lung cancers during the entire study. Of these, 307 (18%) were detected by screening, 198 (12%) were interval cancers (diagnosed during the screening period but not by the screening test), and the remainder were diagnosed after the screening period during the years of follow-up. In the screening group, the cancers detected by screening were more likely to be adenocarcinomas and less likely to be small-cell carcinomas than those not detected by screening. Also in the screening group, the cancers detected by screening were more likely to be stage I (50%) than those not detected by screening.

The cumulative number of deaths from lung cancer was slightly but not significantly lower in the screening group from years 4 through 11. However, by the end of follow-up, the number of lung cancer deaths was equal between the groups (1,213 in the screening group vs 1,230 in the usual-care group). The cumulative overall mortality rate was also similar between the groups. For the subgroup who would have qualified for the NLST (see below), the lung cancer mortality rate was statistically similar between the two groups.

Comments. The results of the PLCO screening trial will be interpreted as the final word in lung cancer screening with standard chest radiography. The conclusion is that annual screening with chest radiography does not reduce lung cancer mortality rates and thus should not be performed in this context.

 

THE NATIONAL LUNG SCREENING TRIAL

The NLST aimed to determine if screening with low-dose chest CT could reduce lung cancer mortality rates.²

This controlled trial enrolled 53,454 people, who were randomized to undergo either low-dose chest CT or posteroanterior chest radiography at baseline and then yearly for 2 years.

Participants were men and women age 55 to 74 with at least 30 pack-years of cigarette smoking. If they had quit smoking, they had to have quit within the past 15 years. All were followed until study conclusion (median 6.5 years, maximum 7.4). About 41% were women, and nearly three-quarters were age 55 through 64. More than 48% were current smokers, with the rest being former smokers.

Results. Adherence to screening was 95% in the CT group and 93% in the radiography group, with a 4.3% annual rate of CT outside the study during the screening phase.

Cumulative lung cancer incidence rates were 645 per 100,000 person-years in the CT group and 572 in the radiography group.

In the CT group there were a total of 1,060 lung cancers during the entire study. Of these, 649 (61%) were detected by screening, 44 (4%) were interval cancers, and the rest were diagnosed after the screening period during follow-up.

In the chest radiography group, there were a total of 941 lung cancers during the entire study. Of these, 279 (30%) were detected by screening, 137 (15%) were interval cancers, and the rest were diagnosed after the screening period. Within the CT group, the cancers detected by screening were more likely to be adenocarcinomas and less likely to be small-cell carcinomas than those not detected by screening. Also within the CT group, the cancers detected by screening were more likely to be stage I (63%) than those not detected by screening.

The cumulative number of deaths from lung cancer was 443 in the radiography group, but only 356 in the CT group—20.0% lower (P =.004). The cumulative overall mortality rate was 6.7% lower in the CT group (P = .02).

Comments. The results of the NLST provide the first evidence that lung cancer mortality rates can be reduced by screening. Though many questions remain, the conclusions of this study are that screening a well-defined high-risk group with low-dose CT reduces the rate of death from lung cancer.

REMAINING CHALLENGES

The NLST showed that lung cancer screening with low-dose CT can meet the most important criterion for a successful screening program, ie, a reduction in the disease-specific mortality rate. Many challenges remain in meeting the other criteria for a successful or ideal screening program (low risk, few false-positive results, acceptability to the patient, and affordability). The issues with low-dose CT-based screening that challenge these ideals are outlined in this section.

Lung nodules: Benign or malignant?

Imaging-based lung cancer screening is designed to find lung nodules. CT has been more successful than radiography largely because it is more sensitive at finding lung nodules. Unfortunately, most lung nodules found by modern CT are not cancerous, but rather are benign. Distinguishing between a nodule that is an early malignancy and one that is benign remains challenging (Figure 1).

A meta-analysis of CT screening studies found that for every 1,000 people screened at baseline, 9 were found to have stage I non-small-cell lung cancer, 235 had false-positive nodules, and 4 underwent thoracotomy for benign lesions.⁶

The NLST results were similar. In this trial, only nodules that were 4 mm or greater in diameter were reported. Using these criteria, over 27% of all study participants were found to have a lung nodule on CT at baseline and at year 1. The rate fell to nearly 17% at year 2, as nodules present from baseline were not reported. Of all the lung nodules detected, only 3.6% were ultimately proven to represent lung cancer.²

Many issues with small lung nodules need to be considered. The nodules are difficult to find, with highly variable reporting even by expert radiologists.⁷ They are difficult to measure accurately and thus are difficult to assess for growth.⁸ Adjunctive imaging and nonsurgical biopsy have a low yield for small nodules.^9–11 Follow-up of these lung nodules includes additional imaging and nonsurgical and surgical biopsy procedures, adding expense to the program and risk to the patient. Finally, knowing that they have a lung nodule makes patients feel anxious and thus negatively affects their quality of life.^12,13

Radiation exposure: How great is the risk?

There is a great deal of concern about radiation exposure from medical imaging, as many people receive a substantial amount of radiation each year from medical testing.¹⁴ A single low-dose scan with chest CT delivers a whole-body effective dose of about 1.5 mSv—less than one-fifth of the radiation dose of a typical diagnostic CT scan.

Many have tried to estimate the consequences of radiation exposure from low-dose CT screening. All estimates are extrapolations from unrelated radiation exposures. The increase in risk of death ranged from 0.01% to a few percent,¹⁵ and the increase in cancers was as high as 1.8% over a 25-year screening period.¹⁶ In general, the risks are felt to be very low but not negligible.

Cost-effectiveness is unknown

The cost-effectiveness of lung cancer screening is also unknown. Many highly variable estimates have been published.^17–20 The studies have differed in the perspective taken, the costs of testing assumed, and the rounds of screening included. The most cost-effective estimates are in populations with the highest risk of cancer, in programs that achieve the greatest reduction in mortality rate, and in programs that lead to high rates of smoking cessation.

Screening in the real world as opposed to a clinical trial may involve different risks, benefits, and costs. Compliance with screening and with nodule management algorithms may be lower outside of a study. One study suggested that those at highest risk of developing lung cancer would be the least likely to enroll in a screening program and the least likely to accept curative-intent surgery for screening-detected cancer.²¹

We expect that the NLST data will be analyzed for cost-effectiveness. This should provide the most accurate estimates for the group that was studied.

 

WE SET OUT TO DESIGN A SCREENING PROGRAM

With the evidence supporting a reduction in the rate of lung cancer mortality, and knowing the remaining challenges, we set out to provide a lung cancer screening program within Cleveland Clinic. In the design of our program, we considered several questions, outlined below.

Who should be offered low-dose CT screening?

The results of the NLST led to a great deal of excitement about lung cancer screening in both the medical community and the general public. The positive side of this publicity is that lung cancer is receiving attention that may lead to support for further advances. The negative side is that many patients who may seek out lung cancer screening are not at high enough risk of lung cancer to clearly benefit from it.

In the NLST, a very high-risk cohort was studied, as defined by clinical variables (age 55 to 74, at least 30 pack-years of smoking, and if a former smoker, had quit within the past 15 years). In this high-risk group, 320 patients needed to be screened (with three yearly chest CT scans) for one life to be saved from lung cancer, and only 3.6% of all lung nodules found (4 mm or larger) were actually lung cancer. In a group at lower risk, the number that needed to be screened to save one life would be higher, and the percentage of lung nodules that truly were lung cancer would be lower. This would lead to higher risks and costs related to screening, without a proven benefit to members of the lower-risk group.

The risk of the NLST cohort developing lung cancer was approximately 0.6% per year. Lung cancer risk-prediction models have been developed and published. Up to 2011, the three most commonly used models had only moderate accuracy at predicting risk.^22–25 In 2011 a risk model based on the PLCO cohort was developed and published.²⁶ This model seemed to be more accurate but perhaps a bit harder to apply in practice.

We discussed whether using a validated risk predictor with a target of 0.6% per year (ie, the risk in the NLST trial) would be an adequate means of deciding on candidacy for lung cancer screening or if we should strictly adhere to the inclusion criteria of the NLST cohort. We feel that the NLST cohort is the only group with true evidence of benefit (a reduction in the lung cancer-specific mortality rate). Thus, for our program’s entry criteria, we decided to use the same clinical predictors used for entry in the NLST.

How will the right patients get scheduled for low-dose screening CT?

Patients who enter the lung cancer screening program from our health system will require a physician’s order.

We are fortunate to have an electronic medical record in place. We have created an order set within the electronic record for low-dose chest CT. The order will eventually be able to be entered as “CT lung screening w/o” (ie, without contrast).

For patients from outside of our health system who would like to enter the lung cancer screening program, the entry criteria will be the same (see above). We will ask for the name of the patient’s primary care practitioner. If the patient does not have one, a member of our Respiratory Institute will see and enroll the patient.

How often should patients be screened, and for how many years?

Unfortunately, questions about the frequency of screening and how many years it should continue remain unanswered.

In the NLST, a similar number of early-stage lung cancers were detected during each of the three screening rounds. In both the NLST and PLCO trials, differences in the mortality rate curves began to narrow during the observation period, when active screening was no longer occurring. Thus, it is possible that a longer duration of screening could lead to a further reduction in mortality rates. Others have questioned whether a similar benefit, with less cost and risk, could be obtained by screening every 2 years.

The large amount of data obtained from the NLST and other CT-based studies is being reviewed so that models can be developed to help answer these questions. For now, we suggest at least three yearly CT screenings, with the hope that we will have clearer answers to these questions over time.

How will low-dose CT be performed and interpreted?

The parameters for low-dose CT were very tightly controlled and monitored during the NLST. This quality-control effort, designed to improve consistency across sites and to minimize risk to patients, should be carried into lung cancer screening programs.

Our program will closely mimic the CT performance criteria used in the NLST (tube current-time product 40 mAs for all patients, field of view lungs only, lung kernel images 3 mm at 1.5-mm intervals, and soft-tissue kernel images 5 mm at 2.5-mm intervals).²⁷ In the initial phase of the program, all screening scans will be performed at Cleveland Clinic’s main imaging facility.

Small lung nodules remain quite challenging to detect and measure. To minimize variability in scan interpretation, the NLST readers were all expertly trained radiologists. Despite this, much variability was noted in the number of nodules detected, their measured size, and the follow-up recommendations. All of the screening CT images for our program will be interpreted by board-certified radiologists with expertise in chest imaging.

Other screening studies have included novel imaging assessment in their testing algorithms, particularly volumetric analysis of lung nodules.²⁸ These tools may prove to assist in nodule detection, measurement, and management over time. At this point, we do not think they have been studied and standardized enough to include them in a standard-of-care screening program. We hope that they will evolve to the point of clinical utility in the near future.

Lung cancer screening is not currently covered by most insurers, including Medicare, although one major insurer has recently started to cover it. We expect decisions on coverage from other insurers in the next 12 months. In the meantime, we offer a low-dose screening chest CT to our patients for $125, which includes the radiologist’s fee for interpreting the scan.

Smoking cessation

The NLST showed that low-dose CT screening can reduce lung cancer mortality rates by 20% in a high-risk group. A 50-year-old active smoker who quits smoking reduces his or her risk of dying of lung cancer by more than 50%.²⁹ Entry into a lung cancer screening program provides an opportunity for education and assistance with tobacco dependency.

At Cleveland Clinic, we have an active Tobacco Treatment Center within our Wellness Institute. All lung cancer screening participants who are identified as active smokers will be given a program brochure and will be offered a consult in the program.

 

 

What do we identify as a lung nodule, and how should they be managed?

Studies of CT-based screening have highlighted the tremendous number of lung nodules that are identified and the low likelihood of malignancy in those that are less than 1 cm in diameter. Many screening studies define a positive result as a lung nodule above a particular size. The NLST used 4 mm or greater as the cutoff. The lower the cutoff, the greater the number of nodules found, and the lower the overall likelihood of malignancy in the nodules.

Studies in which annual CT screening was the intervention are able to use size criteria in part because the study design ensures another CT will be performed 12 months later. Current nodule management guidelines suggest 12-month CT follow-up of incidentally discovered lung nodules, 4 mm or smaller, in at-risk patients.³⁰ In a screening program, particularly one for which the patient must pay, the 12-month screening CT cannot be guaranteed. This makes it more difficult to ignore the smallest nodules identified on CT screening. Given this, we will be reporting all lung nodules identified, regardless of size on the initial screening.

Most studies of CT screening have reported any new nodule identified in subsequent screening rounds regardless of size. Though it is intuitive that a new nodule would have a high likelihood of malignancy in a high-risk cohort, malignancy rates have been reported to be as low as 1% for new nodules. As with the initial round of screening, we will report all new lung nodules identified in subsequent screening rounds.

All screening CT scans will be read and reported by board-certified radiologists with expertise in chest imaging. The report generated will be in a standard format and sent to the ordering physician (Table 2). The ordering physician will choose to manage the evaluation of any nodule that is detected or refer the patient to a specialty lung nodule clinic within the Respiratory Institute. A reminder of the availability of the lung nodule clinic will be present within the templated report. A consult to the lung nodule clinic is an order available within the electronic medical record.

The recommendations for the evaluation of lung nodules, both within the report and at the lung nodule clinic, are in keeping with currently available guidelines, such as those from the Fleischner Society³⁰ and the American College of Chest Physicians.³¹ For incidentally discovered lung nodules in patients at high risk, the Fleischner Society recommendations are as follows³⁰:

• For nodules 4 mm or smaller, follow-up in 12 months; if no growth, then no further follow-up
• For nodules 4 to 6 mm, follow-up at 6 to 12 months, then 18 to 24 months if no growth
• For nodules 6 to 8 mm, follow-up at 3 to 6 months, then 9 to 12 months, then 24 months if no growth
• For nodules 8 mm or larger, follow-up at 3, 9, and 24 months, or positron emission tomography, or biopsy, or both.

If the nodule is large enough or is deemed to be of high enough risk, adjuvant testing with diagnostic imaging, guided bronchoscopy, transthoracic needle aspiration, or minimally invasive resection will be offered. All patients with nodules believed to require biopsy will be discussed at our multidisciplinary lung cancer tumor board before biopsy.

How do we make practitioners and patients aware of the program and its indications, risks, and benefits?

Education will be the key to having lung cancer screening adopted as the standard of care, to lung cancer screening being provided within a well-designed and capable system, and to ensuring that patients have realistic expectations about screening. Articles such as this and grand rounds presentations within our health system will help provide education to our colleagues. Broader marketing campaigns will be considered in the future once demand and system capabilities are clearly identified. A patient information brochure will be provided at the time of the screening test (see the patient information sheet that accompanies this article).

How do we help to advance best practice?

As excited as we are that low-dose CT-based lung cancer screening has been proven to reduce lung cancer mortality rates, it is clear that there is a lot of room to improve the programs that are developed based on current data.

Advances in our ability to accurately predict an individual’s risk of developing lung cancer will allow us to offer screening to those it is most likely to benefit.

Advances in smoking cessation and chemoprevention will help to minimize the number of lung cancers that develop.

Advances in our ability to determine the nature of lung nodules will allow us to accelerate treatment of very early lung cancer while minimizing additional testing on benign nodules; advances in our ability to treat localized and advanced disease will improve the outcome for those identified as having lung cancer.

To help move the science of screening forward, we will develop a screening program registry that can be populated from the order set and the templated report. The registry can be used to ensure appropriate patient care, while studying relevant epidemiologic, quality, and cost-related questions.

We hope to assess novel imaging software capable of assisting with the detection and characterization of lung nodules.

We have an active biomarker development program to assess the ability of breath and blood-based biomarkers to identify those at risk of developing lung cancer; to assist with the management of screening-detected lung nodules; to assist with the diagnosis of early stage lung cancer; and to characterize the nature of the cancers identified. Accurate biomarkers could lead to further decreases in mortality rates while reducing the risks and costs of a screening program.

We have strong surgical, medical, and radiation oncology programs, actively pursuing advances in minimally invasive resection procedures and ablative and targeted therapies.

ENTERING A NEW ERA

We are entering a new era of lung cancer screening. The NLST has shown that lung cancer morality rates can be reduced through low-dose CT screening in a high-risk population. Many challenges remain, such as managing the nodules that are discovered, determining if the program is cost-effective, and minimizing radiation exposure. These need to be considered when designing a lung cancer screening program. Advances over time will help us optimize the programs that are developed.

In 2011, two papers were published that will shape the way we think about lung cancer screening for years to come.

See related patient information sheet

In one, the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized controlled trial of chest radiography for lung cancer screening,¹ researchers found that chest radiography was not an effective lung cancer screening tool. However, the National Lung Screening Trial (NLST)² has transformed medicine by finding that screening with low-dose computed tomography (CT) reduced the lung cancer mortality rate (Table 1).

While the ability to screen for lung cancer is a major positive change, it also raises many thorny questions, such as who should be screened, how often should they be screened, and how should we respond when a nodule is detected.

To answer some of these questions, we will outline how Cleveland Clinic has structured its lung cancer screening program, and the rationale we used for making pragmatic patient-care decisions within this program. We will conclude with our thoughts about the potential evolution of lung cancer screening programs.

THE 40-YEAR QUEST FOR EFFECTIVE LUNG CANCER SCREENING

Lung cancer kills more people in the United States than the next four most lethal types of cancer combined.³ It is curable if found early in its course. Unfortunately, most people who develop lung cancer feel no symptoms when it is early in its course, and therefore it is too often diagnosed at a late stage. Treatment for late-stage lung cancer is effective, but it is rarely curative.

Screening refers to testing people at risk of developing a disease before its symptoms or signs have appeared. The goal of screening is to reduce the disease-specific mortality rate. For this to happen, the disease must be detectable in a preclinical form, and treatment must be more successful when applied early. Ideally, the screening test should pose little risk to the patient, be sensitive for detecting the disease early in its course, give few false-positive results, be acceptable to the patient, and be relatively inexpensive to the health system.

Over the past 4 decades, a large volume of research has been done in the hope of proving that conventional radiography or CT could be an effective screening test for lung cancer.^4,5

Cohort studies (ie, in which all the patients were screened) of radiography or CT have shown a longer survival from the time of lung cancer diagnosis than would be expected without screening. These studies were not designed to prove a reduction in the lung cancer-specific mortality rate.

Controlled trials (in which half the patients received the screening and the other half did not) of chest radiography have been interpreted as not showing a reduction in lung cancer mortality rates, though debate about the interpretation of these trials persisted until this past year. Biases inherent in using duration of survival rather than the mortality rate as an end point have been suggested as the reason for the apparent benefit in survival without a reduction in the mortality rate.

Controlled trials of CT screening were started nearly a decade ago. Until 2011, the results of these trials were not mature enough to comment on.

THE PROSTATE, LUNG, COLORECTAL, AND OVARIAN TRIAL

The lung cancer screening portion of the PLCO trial aimed to determine the effect of screening chest radiography on lung cancer-specific mortality rates.¹

In this trial, 154,901 people were randomized to undergo either posteroanterior chest radiography every year for 4 years or usual care, ie, no lung cancer screening. Participants were men and women age 55 to 74 with no history of prostate, lung, colorectal, or ovarian cancer. They did not need to be a smoker to participate. Those who had never smoked and who were randomized to the screening group received only 3 years of testing. All were followed for 13 years or until the conclusion of the study (8 years after the final participant was enrolled). About half were women, and nearly two-thirds were age 55 through 64. Only 10% were current smokers, while a full 45% had never smoked.

Results. Adherence to screening in the screening group ranged from 79% to 86.6% over the years of screening, and 11% of the usual-care group was estimated to have undergone screening chest radiography.

Cumulative lung cancer incidence rates were 201 per 100,000 person-years in the screening group and 192 in the usual-care group.

In the screening group, there were a total of 1,696 lung cancers during the entire study. Of these, 307 (18%) were detected by screening, 198 (12%) were interval cancers (diagnosed during the screening period but not by the screening test), and the remainder were diagnosed after the screening period during the years of follow-up. In the screening group, the cancers detected by screening were more likely to be adenocarcinomas and less likely to be small-cell carcinomas than those not detected by screening. Also in the screening group, the cancers detected by screening were more likely to be stage I (50%) than those not detected by screening.

The cumulative number of deaths from lung cancer was slightly but not significantly lower in the screening group from years 4 through 11. However, by the end of follow-up, the number of lung cancer deaths was equal between the groups (1,213 in the screening group vs 1,230 in the usual-care group). The cumulative overall mortality rate was also similar between the groups. For the subgroup who would have qualified for the NLST (see below), the lung cancer mortality rate was statistically similar between the two groups.

Comments. The results of the PLCO screening trial will be interpreted as the final word in lung cancer screening with standard chest radiography. The conclusion is that annual screening with chest radiography does not reduce lung cancer mortality rates and thus should not be performed in this context.

 

THE NATIONAL LUNG SCREENING TRIAL

The NLST aimed to determine if screening with low-dose chest CT could reduce lung cancer mortality rates.²

This controlled trial enrolled 53,454 people, who were randomized to undergo either low-dose chest CT or posteroanterior chest radiography at baseline and then yearly for 2 years.

Participants were men and women age 55 to 74 with at least 30 pack-years of cigarette smoking. If they had quit smoking, they had to have quit within the past 15 years. All were followed until study conclusion (median 6.5 years, maximum 7.4). About 41% were women, and nearly three-quarters were age 55 through 64. More than 48% were current smokers, with the rest being former smokers.

Results. Adherence to screening was 95% in the CT group and 93% in the radiography group, with a 4.3% annual rate of CT outside the study during the screening phase.

Cumulative lung cancer incidence rates were 645 per 100,000 person-years in the CT group and 572 in the radiography group.

In the CT group there were a total of 1,060 lung cancers during the entire study. Of these, 649 (61%) were detected by screening, 44 (4%) were interval cancers, and the rest were diagnosed after the screening period during follow-up.

In the chest radiography group, there were a total of 941 lung cancers during the entire study. Of these, 279 (30%) were detected by screening, 137 (15%) were interval cancers, and the rest were diagnosed after the screening period. Within the CT group, the cancers detected by screening were more likely to be adenocarcinomas and less likely to be small-cell carcinomas than those not detected by screening. Also within the CT group, the cancers detected by screening were more likely to be stage I (63%) than those not detected by screening.

The cumulative number of deaths from lung cancer was 443 in the radiography group, but only 356 in the CT group—20.0% lower (P =.004). The cumulative overall mortality rate was 6.7% lower in the CT group (P = .02).

Comments. The results of the NLST provide the first evidence that lung cancer mortality rates can be reduced by screening. Though many questions remain, the conclusions of this study are that screening a well-defined high-risk group with low-dose CT reduces the rate of death from lung cancer.

REMAINING CHALLENGES

The NLST showed that lung cancer screening with low-dose CT can meet the most important criterion for a successful screening program, ie, a reduction in the disease-specific mortality rate. Many challenges remain in meeting the other criteria for a successful or ideal screening program (low risk, few false-positive results, acceptability to the patient, and affordability). The issues with low-dose CT-based screening that challenge these ideals are outlined in this section.

Lung nodules: Benign or malignant?

Imaging-based lung cancer screening is designed to find lung nodules. CT has been more successful than radiography largely because it is more sensitive at finding lung nodules. Unfortunately, most lung nodules found by modern CT are not cancerous, but rather are benign. Distinguishing between a nodule that is an early malignancy and one that is benign remains challenging (Figure 1).

A meta-analysis of CT screening studies found that for every 1,000 people screened at baseline, 9 were found to have stage I non-small-cell lung cancer, 235 had false-positive nodules, and 4 underwent thoracotomy for benign lesions.⁶

The NLST results were similar. In this trial, only nodules that were 4 mm or greater in diameter were reported. Using these criteria, over 27% of all study participants were found to have a lung nodule on CT at baseline and at year 1. The rate fell to nearly 17% at year 2, as nodules present from baseline were not reported. Of all the lung nodules detected, only 3.6% were ultimately proven to represent lung cancer.²

Many issues with small lung nodules need to be considered. The nodules are difficult to find, with highly variable reporting even by expert radiologists.⁷ They are difficult to measure accurately and thus are difficult to assess for growth.⁸ Adjunctive imaging and nonsurgical biopsy have a low yield for small nodules.^9–11 Follow-up of these lung nodules includes additional imaging and nonsurgical and surgical biopsy procedures, adding expense to the program and risk to the patient. Finally, knowing that they have a lung nodule makes patients feel anxious and thus negatively affects their quality of life.^12,13

Radiation exposure: How great is the risk?

There is a great deal of concern about radiation exposure from medical imaging, as many people receive a substantial amount of radiation each year from medical testing.¹⁴ A single low-dose scan with chest CT delivers a whole-body effective dose of about 1.5 mSv—less than one-fifth of the radiation dose of a typical diagnostic CT scan.

Many have tried to estimate the consequences of radiation exposure from low-dose CT screening. All estimates are extrapolations from unrelated radiation exposures. The increase in risk of death ranged from 0.01% to a few percent,¹⁵ and the increase in cancers was as high as 1.8% over a 25-year screening period.¹⁶ In general, the risks are felt to be very low but not negligible.

Cost-effectiveness is unknown

The cost-effectiveness of lung cancer screening is also unknown. Many highly variable estimates have been published.^17–20 The studies have differed in the perspective taken, the costs of testing assumed, and the rounds of screening included. The most cost-effective estimates are in populations with the highest risk of cancer, in programs that achieve the greatest reduction in mortality rate, and in programs that lead to high rates of smoking cessation.

Screening in the real world as opposed to a clinical trial may involve different risks, benefits, and costs. Compliance with screening and with nodule management algorithms may be lower outside of a study. One study suggested that those at highest risk of developing lung cancer would be the least likely to enroll in a screening program and the least likely to accept curative-intent surgery for screening-detected cancer.²¹

We expect that the NLST data will be analyzed for cost-effectiveness. This should provide the most accurate estimates for the group that was studied.

 

WE SET OUT TO DESIGN A SCREENING PROGRAM

With the evidence supporting a reduction in the rate of lung cancer mortality, and knowing the remaining challenges, we set out to provide a lung cancer screening program within Cleveland Clinic. In the design of our program, we considered several questions, outlined below.

Who should be offered low-dose CT screening?

The results of the NLST led to a great deal of excitement about lung cancer screening in both the medical community and the general public. The positive side of this publicity is that lung cancer is receiving attention that may lead to support for further advances. The negative side is that many patients who may seek out lung cancer screening are not at high enough risk of lung cancer to clearly benefit from it.

In the NLST, a very high-risk cohort was studied, as defined by clinical variables (age 55 to 74, at least 30 pack-years of smoking, and if a former smoker, had quit within the past 15 years). In this high-risk group, 320 patients needed to be screened (with three yearly chest CT scans) for one life to be saved from lung cancer, and only 3.6% of all lung nodules found (4 mm or larger) were actually lung cancer. In a group at lower risk, the number that needed to be screened to save one life would be higher, and the percentage of lung nodules that truly were lung cancer would be lower. This would lead to higher risks and costs related to screening, without a proven benefit to members of the lower-risk group.

The risk of the NLST cohort developing lung cancer was approximately 0.6% per year. Lung cancer risk-prediction models have been developed and published. Up to 2011, the three most commonly used models had only moderate accuracy at predicting risk.^22–25 In 2011 a risk model based on the PLCO cohort was developed and published.²⁶ This model seemed to be more accurate but perhaps a bit harder to apply in practice.

We discussed whether using a validated risk predictor with a target of 0.6% per year (ie, the risk in the NLST trial) would be an adequate means of deciding on candidacy for lung cancer screening or if we should strictly adhere to the inclusion criteria of the NLST cohort. We feel that the NLST cohort is the only group with true evidence of benefit (a reduction in the lung cancer-specific mortality rate). Thus, for our program’s entry criteria, we decided to use the same clinical predictors used for entry in the NLST.

How will the right patients get scheduled for low-dose screening CT?

Patients who enter the lung cancer screening program from our health system will require a physician’s order.

We are fortunate to have an electronic medical record in place. We have created an order set within the electronic record for low-dose chest CT. The order will eventually be able to be entered as “CT lung screening w/o” (ie, without contrast).

For patients from outside of our health system who would like to enter the lung cancer screening program, the entry criteria will be the same (see above). We will ask for the name of the patient’s primary care practitioner. If the patient does not have one, a member of our Respiratory Institute will see and enroll the patient.

How often should patients be screened, and for how many years?

Unfortunately, questions about the frequency of screening and how many years it should continue remain unanswered.

In the NLST, a similar number of early-stage lung cancers were detected during each of the three screening rounds. In both the NLST and PLCO trials, differences in the mortality rate curves began to narrow during the observation period, when active screening was no longer occurring. Thus, it is possible that a longer duration of screening could lead to a further reduction in mortality rates. Others have questioned whether a similar benefit, with less cost and risk, could be obtained by screening every 2 years.

The large amount of data obtained from the NLST and other CT-based studies is being reviewed so that models can be developed to help answer these questions. For now, we suggest at least three yearly CT screenings, with the hope that we will have clearer answers to these questions over time.

How will low-dose CT be performed and interpreted?

The parameters for low-dose CT were very tightly controlled and monitored during the NLST. This quality-control effort, designed to improve consistency across sites and to minimize risk to patients, should be carried into lung cancer screening programs.

Our program will closely mimic the CT performance criteria used in the NLST (tube current-time product 40 mAs for all patients, field of view lungs only, lung kernel images 3 mm at 1.5-mm intervals, and soft-tissue kernel images 5 mm at 2.5-mm intervals).²⁷ In the initial phase of the program, all screening scans will be performed at Cleveland Clinic’s main imaging facility.

Small lung nodules remain quite challenging to detect and measure. To minimize variability in scan interpretation, the NLST readers were all expertly trained radiologists. Despite this, much variability was noted in the number of nodules detected, their measured size, and the follow-up recommendations. All of the screening CT images for our program will be interpreted by board-certified radiologists with expertise in chest imaging.

Other screening studies have included novel imaging assessment in their testing algorithms, particularly volumetric analysis of lung nodules.²⁸ These tools may prove to assist in nodule detection, measurement, and management over time. At this point, we do not think they have been studied and standardized enough to include them in a standard-of-care screening program. We hope that they will evolve to the point of clinical utility in the near future.

Lung cancer screening is not currently covered by most insurers, including Medicare, although one major insurer has recently started to cover it. We expect decisions on coverage from other insurers in the next 12 months. In the meantime, we offer a low-dose screening chest CT to our patients for $125, which includes the radiologist’s fee for interpreting the scan.

Smoking cessation

The NLST showed that low-dose CT screening can reduce lung cancer mortality rates by 20% in a high-risk group. A 50-year-old active smoker who quits smoking reduces his or her risk of dying of lung cancer by more than 50%.²⁹ Entry into a lung cancer screening program provides an opportunity for education and assistance with tobacco dependency.

At Cleveland Clinic, we have an active Tobacco Treatment Center within our Wellness Institute. All lung cancer screening participants who are identified as active smokers will be given a program brochure and will be offered a consult in the program.

 

 

What do we identify as a lung nodule, and how should they be managed?

Studies of CT-based screening have highlighted the tremendous number of lung nodules that are identified and the low likelihood of malignancy in those that are less than 1 cm in diameter. Many screening studies define a positive result as a lung nodule above a particular size. The NLST used 4 mm or greater as the cutoff. The lower the cutoff, the greater the number of nodules found, and the lower the overall likelihood of malignancy in the nodules.

Studies in which annual CT screening was the intervention are able to use size criteria in part because the study design ensures another CT will be performed 12 months later. Current nodule management guidelines suggest 12-month CT follow-up of incidentally discovered lung nodules, 4 mm or smaller, in at-risk patients.³⁰ In a screening program, particularly one for which the patient must pay, the 12-month screening CT cannot be guaranteed. This makes it more difficult to ignore the smallest nodules identified on CT screening. Given this, we will be reporting all lung nodules identified, regardless of size on the initial screening.

Most studies of CT screening have reported any new nodule identified in subsequent screening rounds regardless of size. Though it is intuitive that a new nodule would have a high likelihood of malignancy in a high-risk cohort, malignancy rates have been reported to be as low as 1% for new nodules. As with the initial round of screening, we will report all new lung nodules identified in subsequent screening rounds.

All screening CT scans will be read and reported by board-certified radiologists with expertise in chest imaging. The report generated will be in a standard format and sent to the ordering physician (Table 2). The ordering physician will choose to manage the evaluation of any nodule that is detected or refer the patient to a specialty lung nodule clinic within the Respiratory Institute. A reminder of the availability of the lung nodule clinic will be present within the templated report. A consult to the lung nodule clinic is an order available within the electronic medical record.

The recommendations for the evaluation of lung nodules, both within the report and at the lung nodule clinic, are in keeping with currently available guidelines, such as those from the Fleischner Society³⁰ and the American College of Chest Physicians.³¹ For incidentally discovered lung nodules in patients at high risk, the Fleischner Society recommendations are as follows³⁰:

• For nodules 4 mm or smaller, follow-up in 12 months; if no growth, then no further follow-up
• For nodules 4 to 6 mm, follow-up at 6 to 12 months, then 18 to 24 months if no growth
• For nodules 6 to 8 mm, follow-up at 3 to 6 months, then 9 to 12 months, then 24 months if no growth
• For nodules 8 mm or larger, follow-up at 3, 9, and 24 months, or positron emission tomography, or biopsy, or both.

If the nodule is large enough or is deemed to be of high enough risk, adjuvant testing with diagnostic imaging, guided bronchoscopy, transthoracic needle aspiration, or minimally invasive resection will be offered. All patients with nodules believed to require biopsy will be discussed at our multidisciplinary lung cancer tumor board before biopsy.

How do we make practitioners and patients aware of the program and its indications, risks, and benefits?

Education will be the key to having lung cancer screening adopted as the standard of care, to lung cancer screening being provided within a well-designed and capable system, and to ensuring that patients have realistic expectations about screening. Articles such as this and grand rounds presentations within our health system will help provide education to our colleagues. Broader marketing campaigns will be considered in the future once demand and system capabilities are clearly identified. A patient information brochure will be provided at the time of the screening test (see the patient information sheet that accompanies this article).

How do we help to advance best practice?

As excited as we are that low-dose CT-based lung cancer screening has been proven to reduce lung cancer mortality rates, it is clear that there is a lot of room to improve the programs that are developed based on current data.

Advances in our ability to accurately predict an individual’s risk of developing lung cancer will allow us to offer screening to those it is most likely to benefit.

Advances in smoking cessation and chemoprevention will help to minimize the number of lung cancers that develop.

Advances in our ability to determine the nature of lung nodules will allow us to accelerate treatment of very early lung cancer while minimizing additional testing on benign nodules; advances in our ability to treat localized and advanced disease will improve the outcome for those identified as having lung cancer.

To help move the science of screening forward, we will develop a screening program registry that can be populated from the order set and the templated report. The registry can be used to ensure appropriate patient care, while studying relevant epidemiologic, quality, and cost-related questions.

We hope to assess novel imaging software capable of assisting with the detection and characterization of lung nodules.

We have an active biomarker development program to assess the ability of breath and blood-based biomarkers to identify those at risk of developing lung cancer; to assist with the management of screening-detected lung nodules; to assist with the diagnosis of early stage lung cancer; and to characterize the nature of the cancers identified. Accurate biomarkers could lead to further decreases in mortality rates while reducing the risks and costs of a screening program.

We have strong surgical, medical, and radiation oncology programs, actively pursuing advances in minimally invasive resection procedures and ablative and targeted therapies.

ENTERING A NEW ERA

We are entering a new era of lung cancer screening. The NLST has shown that lung cancer morality rates can be reduced through low-dose CT screening in a high-risk population. Many challenges remain, such as managing the nodules that are discovered, determining if the program is cost-effective, and minimizing radiation exposure. These need to be considered when designing a lung cancer screening program. Advances over time will help us optimize the programs that are developed.