A fundamental goal of any lung cancer screening program is to discern people who are at high risk for progression to lung cancer. Although smoking is a gold standard risk factor, other environmental and genetic factors also appear to increase the risk. The following is a review of the newly known risk factors for progression to lung cancer in order to identify the high-risk groups that should be targeted for screening.
Smoking
1. Active smoking
Tobacco smoke is the major variable risk factor for the development of lung cancer, accounting for 85% of all lung cancers associated with death The causal relationship between tobacco smoke and lung cancer was first reported in 1939. Since then, the risk of lung cancer from tobacco smoke has been firmly established. Tobacco smoke contains more than 4,500 compounds; more than 50 of these are known to be carcinogens that increase the risk of carcinogenic mutations at the molecular level, particularly in genetically predisposed populations. There is a dose-effect relationship between tobacco smoke and the risk of lung cancer; however, there is no risk-free level of tobacco smoke exposure, and the relative risk of lung cancer in smokers is nearly 20-fold compared to nonsmokers. Stopping tobacco smoke reduces the risk of lung cancer. However, ex-smokers who changed also had a higher risk of lung cancer compared to never-smokers. The result was that both current and former smoking were considered risk factors for lung cancer, regardless of the intensity of exposure (to tobacco smoke) and the length of time since cessation of smoking.
In the NCCN lung cancer screening rules, those with a smoking history of 30 pack-years or more (age 55-74 years) were selected as the highest risk group for lung cancer and were recommended for screening based on the criteria for inclusion in the NSLT (Tier 1). Pack-years of smoking history was defined as the number of packs smoked per day multiplied by the number of years of smoking. People with a smoking history of 30 pack-years who have stopped smoking for less than 15 years are still in the highest risk group.
2. Secondhand smoke exposure
(a) The relationship between lung cancer and exposure to secondhand smoke (also known as environmental tobacco smoke, “passive smoking,” and reluctant smoking) was first suggested in an epidemiologic study published in 1981. Since then, several studies and synthetic relative risk predictions have suggested that secondhand smoke causally increases the risk of lung cancer in nonsmokers. However, the NCCN panel did not consider secondhand smoke to be an independent risk factor because its association was both weak and variable. Therefore, in this NCCN guideline, secondhand smoke does not place the exposed population at a sufficiently high risk to warrant consideration of lung cancer screening.
A synthetic analysis of 37 published studies found that for adult nonsmokers living with smokers, the estimated relative risk was 1.24 (95% CI, 1.13-1.36). A synthetic prognosis of 25 studies found that the RR (relative risk) of lung cancer risk was 1.22 (95% CI, 1.13-1.33) for exposure to secondhand smoke in the work environment. Synthetic pretesting of six studies suggested a dose-effect relationship between years of secondhand smoke exposure and lung cancer risk. For secondhand smoke exposure in childhood and lung cancer risk in adulthood (the relationship), the information is contradictory. For childhood exposure to tobacco smoke, the synthetic RR prediction for causing lung cancer was 0.93 (95% CI, 0.71-0.92) in several studies led by the United States, 0.81 (95% CI, 0.71-0.92) in studies led by European countries, and 1.59 (95% CI, 1.18-2.15) in studies led by Asian countries.
(ii) Occupational exposure About 150 factors were classified as known or probable human carcinogens (IARC 2002). 8 factors were identified as carcinogens specifically targeting the lung i.e. arsenic, chromium, asbestos, nickel, cadmium, beryllium, silica and diesel fumes. These factors are listed in the order of their presumed risk. In the United States, the calculated average relative risk of causing lung cancer in exposed populations with known occupations for these factors is 1.59. For those exposed to these carcinogens, smokers have a greater risk of lung cancer than nonsmokers.
(iii) Residential radon exposure Radon (gaseous decay substance of uranium-238 and radium-226) is associated with the occurrence of lung cancer. The lung cancer risk of occupational exposure from uranium miners is well established. However, the risk regarding residential radon is uncertain. a meta-analysis of eight studies in 1997 yielded a predicted relative risk of 1.14 (95% CI, 1.0-1.3). However, a 2005 meta-analysis of 13 studies (using individual patient data) reported a linear relationship between radon concentration detected in the home and the development of lung cancer. For those exposed to radon gas, smokers have a greater risk of lung cancer than nonsmokers.
(iv) Cancer history There is evidence of an increased risk of new primary cancers in survivors of lung, lymphoma, head and neck, or smoking-related cancers (e.g., esophageal cancer). Among surviving small cell lung cancer patients, there is a 3-fold increased risk of developing new primary cancers (primarily NSCLC).
For patients who continued to smoke and who had previous chest radiotherapy or alkylating agent therapy, there was an increased risk of subsequent lung cancer. For patients previously treated with chest radiotherapy, the risk of new primary lung cancer was increased 13-fold, and the relative risk for patients previously treated with alkylating agents was estimated to be 9.4. For patients with previously treated Hodgkin’s lymphoma, the relative risk of new primary lung cancer was 4.2 if previously treated with alkylating agents and 5.9 if previously treated with 5 Gy or higher (dose) radiation.
In head and neck cancers, subsequent new primary lung cancer may or may not occur concurrently. New primary cancers are seen in approximately 9% of patients with head and neck cancers. Most of these are squamous carcinomas and one-third appear in the lung. However, the data do not suggest that previous treatment for head and neck cancer increases the risk of subsequent new primary lung cancer that is not dependent on tobacco exposure.
Evidence suggests that patients successfully treated (e.g., cured) for their first smoking-associated lung cancer and those who stop smoking have a reduced risk of subsequent smoking-associated cancer compared with continued smokers.
(v) Family history of lung cancer Several studies suggest an increased risk of lung cancer among first-degree relatives of lung cancer patients, even after adjustment for age, sex, and smoking habits, with a meta-analysis of 28 case-control studies and 17 observational cohort studies showing a relative risk of 1.8 (95% CI, 1.6-2.0) for a sibling/parent or (other) one first-degree relative with lung cancer . The risk was greater for those with multiple family members with the disease or cancer diagnosed at a younger age.
Although no syndromes of high epidemiological inheritance have been described for lung cancer (small cell lung cancer or non-small cell lung cancer), several groups have identified genetic loci that may be associated with an increased risk of developing lung cancer. The Lung Cancer Epidemiology Association led a genome-wide linkage analysis of 52 families with several first-degree relatives with lung cancer. Subsequently, three groups performed genome-wideassociation studies in lung cancer and matched controls. They identified a locus at 15q24-25 that was associated with increased risk of lung cancer, nicotine dependence, and peripheral arterial disease. Interestingly, subunits of nicotinic acetylcholine receptor genes were noted to be located in this region (CHRNA5,CHRNA3 andCHRNB4). Other investigators have recently found that a variant of 15q24/25 is associated with bronchial obstruction and emphysema in lung volume measurements, as assessed by CT. In patients with typical familial cancer susceptibility syndromes [e.g., retinoblastoma, Li Fraumün syndrome (with mutations in the p53 gene)], their risk of lung cancer is substantially (substantively) increased in patients who smoke.
(F) The patient’s history of lung cancer (i.e., personal history of lung cancer)
1. A history of COPD with chronic obstructive pulmonary disease is associated with lung cancer risk. Much of this correlation is due to smoking; Yang et al. found COPD to account for 12% of lung cancer patients who smoked heavily. However, even after making statistical adjustments, the evidence suggests that the association between COPD and lung cancer is not exclusively due to smoking. For example, 1) a family history of chronic bronchitis and emphysema was associated with an increased risk of lung cancer, and 2) COPD was associated with lung cancer in never-smokers. yang et al. found COPD in 10% of never-smoking lung cancer patients. koshiol et al. found that when limiting the analysis to adenocarcinoma (which is more common in non-smokers, especially women). copd was still associated with an increased risk of lung cancer. increased risk.
2, Pulmonary fibrosis Patients with diffuse pulmonary fibrosis appear to be at a higher risk of lung cancer even after accounting for age, sex and smoking history (RR=8.25,95%
CI,4.7-11.48). Among patients with a history of asbestos exposure, those who developed interstitial fibrosis were at a higher risk of developing lung cancer than those without fibrosis.
(vii) Hormone replacement therapy It is unclear whether HRT use affects lung cancer risk in women. More than 20 studies have been published, and the results are inconsistent. Most of the currently available information is derived from case-control studies and cohort studies. Cumulatively, these studies are iteratively variable; they have found correlations with increased lung cancer risk, no effect, and a protective effect of HRT on lung cancer risk. However, in a large randomized controlled study, no increase in lung cancer incidence was found in postmenopausal women treated with estrogen and progestin replacement therapy, but mortality from lung cancer (especially NSCLC) was higher in patients receiving HRT.
(viii) Selection of high-risk screening populations As previously mentioned, there are multiple well-known factors for lung cancer development, especially tobacco. Results from the newly concluded NLST support screening of selective populations at high risk for lung cancer, and the NCCN panel recommends that high-risk populations be screened; those at moderate and low risk should not be screened at this time. Patient selection was performed in NLST inclusion criteria, non-randomized trials, and/or observational studies using different risk criteria. Based on the available information, the NCCN Lung Cancer Screening Panel recommends using the following criteria to determine whether a population is at high, intermediate, or low risk for lung cancer.
1. High-risk populations The NCCN expert panel recommends lung cancer screening using spiral LDCT for people with the following high-risk factors
2. Screening is recommended for high-risk groups (Level 1): 55-74 years of age; ≥30 pack-years of smoking history; and if a former smoker, have stopped smoking in 15 years. certain high-risk groups in the NLST also have COPD and other risk factors. This is a level 1 recommendation because these populations were selected based on NLST inclusion criteria. As previously described (see the beginning of this discussion), a NCCN Level 1 recommendation is based on a high level of evidence (e.g., randomized controlled trials) and consensus among members of the NCCN expert panel.
According to the NLST, screening is recommended once a year until age 74 years for these high-risk populations. However, there is uncertainty regarding the appropriate duration of screening and the age at which screening is no longer appropriate.
3. Screening is also recommended in (the following) high-risk groups (Class 2B): ≥50 years of age, smoking history ≥20 pack-years, plus one additional risk factor. This is a NCCN expert panel level 2B recommendation because these populations were selected based on non-randomized studies and observational information. These additional risk factors have been described previously and include: history of cancer, history of lung disease, family history of lung cancer, radon gas exposure, and occupational exposure. Note that the NCCN expert panel does not currently feel that exposure to secondhand smoke is an independent risk factor, as the information is both weak and inconsistent.
4. intermediate-risk populations The NCCN defines intermediate-risk populations as those aged ≥50 years and a history of smoking and smoking ≥20 pack-years or secondhand smoke exposure without additional risk factors for lung cancer. the NCCN Lung Cancer Screening Panel does not recommend lung cancer screening for these intermediate-risk populations. This is a level 2A recommendation based on non-randomized studies and observational data.
The NCCN Lung Cancer Screening Panel does not recommend lung cancer screening for low-risk populations. This is a level 2A recommendation based on non-randomized studies and observational data.