Lung cancer is the most common malignant tumor in the world, and the incidence and mortality rate are the first among malignant tumors, which has become a recognized killer of human health. The prognosis of lung cancer is closely related to the clinical stage. Due to the late appearance of symptoms and signs, 80% of patients have metastasis by the time they are first diagnosed, resulting in a 5-year survival rate of only 16% due to the loss of surgical opportunities, in contrast, the 5-year survival rate of stage I patients can reach 90%. In contrast, the 5-year survival rate of stage I patients can reach 90%. Early detection of lung cancer may effectively improve the prognosis of lung cancer patients.
Therefore, the establishment of a reasonable and effective screening program to provide simple and effective screening for high-risk groups is the focus of clinical work. The screening methods currently used are mainly as follows.
1.Sputum cytology test
Among lung cancer screening methods, sputum cytology test is the most traditional and the earliest one, which has been used since 1930. However, because cytology is affected by many factors, its sensitivity is low, and it is related to the location of the lesion and the type of pathology, so the role of sputum cytology test in screening is greatly limited.
2.X-ray chest film
Since the 1950s, clinical trials using chest X-ray for lung cancer screening have been conducted around the world. In 1970, the role of chest X-ray in lung cancer screening was recognized because of the relatively early stage of lung cancer detection and the relatively good prognosis compared to control subjects. These conflicting clinical data led to the widespread perception that x-ray chest radiographs were ineffective in lung cancer screening, given the more obvious methodological shortcomings of early clinical trials. The American Cancer Society recommended lung cancer screening with X-rays in current and former smokers in 1970, but rescinded this recommendation in 1980, and the results of the Prostate, Lung, Colorectal, and Ovarian Tumor Screening Trial, which began in 1990 and was published in 2011, again showed that annual screening with X-rays was not effective in reducing lung cancer mortality.
The sensitivity of X-rays depends on the size and location of the lesion, the quality of the images, and the skill of the physician. If the lung lesion is small or close to the mediastinum, or if the error of the film-reading physician himself, it will lead to a decrease in the sensitivity of X-ray chest film detection. Therefore, clinical staffs are gradually searching for suitable means for lung cancer screening among newer and more sensitive imaging technologies.
3.Low-dose spiral CT scan
Low-dose spiral computed tomography (LDCT) is a new technology for lung cancer screening since X-ray chest radiography, and has been a hot spot of clinical research at home and abroad in recent years. Compared with ordinary CT plain film, the advantage of LDCT is that its radiation dose is only 1/6, but it can detect lung nodules with a diameter of nearly 2 mm, which is 10 times more sensitive than X-ray chest film. Overall, LDCT is becoming the main method of lung cancer screening because it can reduce the radiation exposure time of the examinees and obtain sufficient images of the chest.
Since 1990, clinical studies on LDCT screening for lung cancer have been conducted in Europe and the United States. The major studies currently include the DEPISCAN New Imaging Technique with Molecular Diagnostic Detection and Screening for Early Lung Cancer in France, the Multicenter Lung Detection Trial (MILD) in Italy, the Danish Lung Cancer Screening Trial (DLCST), the Italian CT Lung Cancer Screening Trial (ITALUNG), the Netherlands Belgium’s Lung Cancer Screening Trial (NELSON), and the National Cancer Institute’s (NCI) National Lung Cancer Screening Trial (NLST).
The NCI published the results of the NLST at 6.5 years of follow-up in the New England Journal in August 2011. This multicenter, prospective meta-analysis of lung cancer screening included a total of 53,454 subjects who were screened for regular lung cancer using LDCT with X-ray chest radiographs in smokers. The results of the study confirmed that LDCT screening in high-risk groups for three consecutive years at I times a year reduced lung cancer mortality by 20%, thus confirming the importance of LDCT in lung cancer screening and providing an important basis for clinical application.
Based on the results of the NLST, the National Comprehensive Cancer Network first published guidelines for lung cancer screening in October 2011, recommending annual LDCT screening in people at high risk for lung cancer. 2013 latest NCCN guidelines recommend LDCT screening for lung cancer in people at high risk who are older than 50 years, have a smoking history of more than 30 pack years, and have not yet smoked or quit smoking for less than 15 years, with evidence level Class I. According to the NLST, these high-risk individuals should undergo LDCT screening at I times per year for 2 consecutive years and then be re-evaluated based on their medical condition.
In addition to the NLST, three other studies have published their results, and the results of DANTE, DLCST and MILD do not support that LDCT screening for lung cancer is associated with a survival benefit. However, it is worth looking forward to the fact that several European clinical trials are still ongoing, including DLCST, ITALUNG and the largest one, the NELSON trial, which enrolled 15822 subjects and randomized LDCT versus general observation of the difference in lung cancer diagnosis and its morbidity and mortality rate, with final results to be published in 2016, and it is hoped that the data from these clinical trials will provide insight into the role of LDCT in lung cancer screening by providing a stronger rationale for the role of LDCT in lung cancer screening.
Based on the current clinical data, the 2013 U.S. Preventive Services Task Force (USPSTF) recommended guidelines for lung cancer screening re-emphasize that high-risk individuals aged 55-80 years with a smoking index of 30 pack-years and who are currently still smoking or have quit smoking for less than 15 years should undergo annual LDCT lung cancer screening. Screening may be discontinued once the patient has quit smoking for 15 years or has another condition that affects life expectancy or interferes with performing lung cancer surgery.
When a lung nodule is detected on LDCT, a risk assessment based on the presence or absence of lung cancer-related risk factors is required, and different follow-up testing options are selected depending on the probability of malignancy of the nodule.
The USPSTF 2013 recommended guidelines for lung cancer screening state that age, total cumulative tobacco exposure, and time to quit smoking are the most important risk factors for lung cancer. Other risk factors include specific occupational exposure, exposure to radon, family history, and history of pulmonary fibrosis or chronic obstructive pulmonary disease.
Clinicians calculate the probability of malignancy of a nodule based on these risk factors, the imaging characteristics of the nodule, and certain models for calculating the probability of malignancy. 2013 latest edition of the American College of Chest Physicians guidelines recommends the selection of follow-up CT scan surveillance, non-surgical biopsy (including functional-imaging tests and puncture biopsy), and surgical diagnosis based on the probability.
In recent years, in addition to the United States, Japan and other countries are similarly conducting trials of LDCT to screen for early lung cancer. The results point out that the rate of early lung cancer detected is as high as 80%, and 80% to 90% of these patients can be removed through minimally invasive surgery without further radiotherapy and chemotherapy. The latest 5-year survival rate for lung cancer published by the Japanese Lung Cancer Association in 2009 increased from 47.8% in 1989 to 62.0% in 1999, which was mainly due to the improvement in screening and diagnosis of early-stage lung cancer, especially those <50mm in diameter.
It should be noted that LDCT has some drawbacks as an imaging method, the most important of which is overdiagnosis and overtreatment due to false positives, and the resulting financial and psychological burden. Current clinical studies indicate that the nodal screening rate of LDCT is approximately 20%, with the screening probability of RCT ranging from 3% to 30% and the probability of cohort studies ranging from 5% to 51%.
Most studies found >90% of nodules to be benign. Therefore, it is the future direction of lung cancer screening technology to further improve the resolution of LDCT, increase the screening accuracy, and reduce the problems caused by false positives. Positron emission tomography (PET), which has the dual role of combining imaging and metabolic information of lesions, is significantly more accurate than LDCT in screening and diagnosis of small nodules, but due to the high cost, screening of large samples still lacks certain feasibility, but for lesions with maximum diameter <25 mm, the diagnostic value of PET/CT is obviously limited.
4.Hematological oncology markers
In addition to chest imaging, tumor markers are active substances secreted by cells when they become cancerous and exist in cancerous tissues and host body fluids, which are important for early screening and diagnosis of lung cancer. From early sputum cytology testing to current genetic testing of blood specimens, clinical staff have also made efforts to find suitable biological markers in molecular biology.
Carcinoembryonic antigen, neuron-specific enolase and cytokeratin 19 fragment are currently commonly used and considered to be the most valuable lung cancer markers in clinical practice. The single detection of these markers may have certain limitations, but the positive rate of lung cancer detection is significantly higher when combined, which is of great clinical significance for early diagnosis.
Telomerase expression is upregulated in malignant tumors such as breast, prostate, lung, liver, and pancreatic cancers, and the level of telomerase activity can begin to rise early in the development of theoma compared to other tumor markers, thus suggesting that telomerase activity may be a favorable biological marker for early tumor screening.
Circulating tumor cells (CTCs) are malignant tumor cells that are freely present in the circulation, detached from the primary tumor or metastatic site and entering the bloodstream. In recent years, new techniques have been developed to identify, isolate and characterize these CTCs from peripheral blood. unlike traditional invasive methods such as biopsy, CTCs represent a convenient class of resources that can aid in tumor diagnosis and are now considered to be metastatic markers of primary lung cancer. Clinical trials to further confirm the role of CTCs in early lung cancer screening are still underway.
In addition to the above markers, P53 oncogene, plasma proteomics, circulating DNA, SURVIVIN protein, and P16 gene are also currently reported as markers for lung cancer screening. However, it is worth noting that the sensitivity of single tumor markers is low and their usefulness in large sample screening is limited, and the combined use of tumor markers may increase the screening rate of early lung cancer, which also needs to be confirmed by the results of further clinical studies.
5. Problems and outlook
A good screening tool should work in the early stages of the disease, identifying patients with disease without symptoms in the population at risk for a given disease, and those who screen positive should then undergo evaluation testing to determine whether they actually have the disease. Although controversial, the available clinical data support the importance of LDCT in early lung cancer screening, and more data are expected to confirm its role.
As mentioned above, the main problems with lung cancer screening currently are.
(1) How to identify high-risk groups for screening, such as how to determine the threshold for screening in nonsmokers and women, and how to consider the effects of occupational exposure and air pollution;
(2) How to improve the efficiency and accuracy of screening, and avoid and reduce overdiagnosis and false positives;
(3) How to cover health insurance and other health economics considerations.
In the future, if traditional detection techniques can be effectively combined with new technologies, the specificity of early lung cancer screening and diagnosis will definitely be improved. Therefore, the precise targeting of high-risk groups and the influence of multiple risk factors (air pollution, etc.) are issues that should be emphasized in the future. In terms of screening technology, the use of lower radiation dose combined with sensitive serum molecular marker detection technology will make lung cancer screening earlier, faster, more accurate and safer!