"Lancet" blockbuster review: what is the chance of malignant transformation of lung nodules? What should I do if I find a lung nodule?

Lung cancer is one of the malignancies with the highest morbidity and mortality worldwide. Screening and early diagnosis and treatment are effective measures to reduce lung cancer mortality in all populations. RECENTLY, THE LANCET PUBLISHED ITS ANNUAL BLOCKBUSTER REVIEW, FOCUSING ON THE MILESTONE CLINICAL TRIAL OF LUNG CANCER SCREENING, THE SELECTION OF SCREENING BENEFICIARIES, THE MANAGEMENT OF PATIENTS WITH LUNG NODULES, AND THE COST-EFFECTIVENESS OF SCREENING.

SCREENSHOT CREDIT: THE LANCET

Lung Cancer Screening Milestone Study: NLST

Chest X-ray (CXR) screening was one of the first tests used for lung cancer screening, but early studies on CXR±sputum cytology screening in the 70s of the 20th century did not prove that this method could reduce the incidence of lung cancer-specific deaths. The National Lung Screening Trial (NLST) was the first large-scale screening study to use a randomized controlled trial design and the first to achieve a positive result. In NLST, a total of 26,722 high-risk subjects for lung cancer were screened for low-dose spiral CT (LDCT) and 26,732 subjects at high risk for lung cancer were screened for CXR.

The results of this study proved that the detection rate of lung cancer in the LDCT group was higher than that in the CXR group (RR=1.13; 95%CI=1.03~1.23). Compared with annual CXR screening, participants who underwent LDCT screening had a relative reduction in lung cancer mortality of 20% and all-cause mortality by 6.7%, with an absolute risk reduction of 62 cancer-related deaths per 100,000 person-years. Overall, screening of 320 participants at high risk of lung cancer with LDCT prevented 1 lung cancer-related death.

What are the risk factors for lung cancer?

At present, it is generally believed that it is necessary for people at high risk of lung cancer to undergo lung cancer screening. It should be pointed out that the high-risk people for lung cancer included in the NLST study were 55~74 years old and had a smoking history of at least 30 pack-years (number of packs smoked per day× number of years of smoking) (current smoking or smoking cessation time within 15 years). At present, the criteria for determining high-risk groups in NLST have also been applied to lung cancer screening guidelines in many countries (there may be slight differences between different guidelines). The U.S. Preventive Services Task Force (USPSTF) has expanded the definition criteria for people at high risk of lung cancer, covering people aged 50~80 and with a smoking history of at least 20 pack-years.

So do people who have never smoked need to be screened for lung cancer? The review notes that at least a quarter of lung cancer patients worldwide have never smoked before becoming ill. South Asia has the highest prevalence of lung cancer among women who have never smoked (83% of women with lung cancer have never smoked), followed by East Asia (61%), and only 15% of women with lung cancer in the United States have never smoked.

Interestingly, an analysis of screening cohorts in Asia showed that lung cancer rates may not be much lower in never-smokers than in smokers. However, it has also been suggested that a significant proportion of lung cancer diagnosed in people who have never smoked (such as Asian women) may be related to overdiagnosis (i.e., the associated nodules do not cause symptoms or death). Overall, in addition to age and smoking history, the selection of lung cancer screening populations should also consider occupational and environmental risk factors such as exposure to radon, asbestos, chromium, arsenic, and air pollution.

Image source: 123RF

The possibility of malignant progression of pulmonary nodules

The potential physiological/psychological harm caused by LDCT screening is mainly associated with nonspecific pulmonary nodules and other incidental conditions. In addition, lung cancer screening also provides an opportunity to evaluate chronic obstructive pulmonary disease and cardiovascular disease. Current evaluations of lung nodules detected by screening are based on their size, morphology, location, and degree of change over time. It should be emphasized that the size and growth speed of nodules are the most important predictors of its malignancy. Nodules can be solid, ground-glass (or non-solid), or partially solid. Among them, nodules close to the pleura are usually benign, and irregular nodules within or in contact with cystic cavity walls may be cancerous nodules.

Many nodules detected by screening may develop calcifications, and no additional evaluation is required if the calcification pattern is central, diffuse, lamellad, or popcorn; Isolated ground-glass attenuated nodules are generally more likely to be adenocarcinoma in situ; Nodules with irregular borders, lobulations, or burrs are more likely to become malignant than those with smooth borders. In addition, ground-glass lesions that progress to solid structures require caution and prompt evaluation.

Overall, data from LDCT-related screening studies showed that the overall malignancy probability of nodules with a diameter of < 5 mm was 0~1%; Nodules with a diameter of 5 mm~10 mm are 6%~28%; Nodules with a diameter of 11 mm~20 mm are 33%~64%; Nodules with a diameter of > 20 mm are 64%~82%.

What should I do if screening reveals lung nodules?

Patients with pulmonary nodules detected by screening require pulmonary function assessment (e.g., local perfusion scan and/or pulmonary stress testing). In addition, these patients need to be assessed for the possibility of carcinogenesis and surgical risk assessment based on risk stratification (based on factors such as advanced age, previous cancer history, duration and amount of smoking, number of years of smoking cessation, concomitant chronic obstructive pulmonary disease, asbestos exposure, etc.). Clinicians should choose appropriate intervention strategies for management, such as close monitoring, further diagnosis by other means (e.g., PET-CT), or direct surgery.

If screening finds that participants are at high risk of cancer, such as positive biopsy, positive PET scan, and nodule growth on follow-up CT, surgery is necessary, and surgery can be used to further diagnose and clarify the treatment plan. In general, the risk of surgery depends on whether the nodule is malignant or not. If nodules are found to be benign in cryosections, participants need to undergo wedge resection (surgical mortality of 0.5%). If the nodule is found to be malignant by surgery, the subject will need to undergo lobectomy and lymph node dissection (surgical mortality is about 1%~4%).

Results from observational studies and randomized controlled studies related to LDCT screening have shown that LDCT screening detects many non-clinically significant nodules (the vast majority benign). Participants may require long-term follow-up testing of these nodules, which may cause long-term anxiety and excessive radiation exposure. Therefore, the cost-effective characteristics of LDCT have also become the focus of attention. The review noted that the cost-benefit profile of lung cancer screening differed in different populations. In addition, differences in the population included in screening, screening interval, and smoking cessation intervention will have a significant impact on the cost-effectiveness of lung cancer screening. Future personalized screening intervals and the choice of risk stratification strategies may significantly improve the cost-effectiveness of lung cancer screening.

Summary

Overall, LDCT has been shown to be an effective screening tool for lung cancer. The conclusion of the NLST study suggests that LDCT screening is beneficial for people aged 55~74 years with a smoking history of at least 30 years (current smoking or quitting within 15 years).

The review highlights that smoking cessation is the most effective intervention to reduce lung cancer-related mortality, and lung cancer screening offers many opportunities to support individuals to quit smoking. In addition, the frontier exploration of artificial intelligence technology (such as imaging-assisted diagnosis, image reconstruction technology, etc.) and biomarkers (such as microRNA, cancer-associated antigens, ctDNA, DNA methylation, circulating protein markers, etc.) is also expected to bring new and effective means for lung cancer screening.

Resources

[1] Scott J Adams, et al. Lung cancer screening. THE LANCET, doi: 10.1016/S0140-6736(22)01694-4