Gerard A. Silvestri, MD, MS
Gerard A. Silvestri, MD, MS, the Hillenbrand Professor of Thoracic Oncology at the Medical University of South Carolina, Charleston, praised the investigators of the Taiwan National Lung Cancer Screening Program for their accomplishment. “It’s incredible that they screened almost 50,000 individuals in a very short period [1 year] following an incredibly compulsive algorithm,” he said. However, he noted, lung cancer in Asia is very different from lung cancer in Western countries; therefore, the screening issues are different and not directly applicable to Western populations.
Especially outside of Asia, the screening of nonsmokers and persons with a positive family history has become “an area of intense debate, with little equipoise among those for or against the practice,” Dr. Silvestri said. “Stakeholders find echo chambers that support their opinion, which stifles the advancement of science in this arena.”
Biology and Family History
The difference begins with biology. Lung cancers in Asian patients are significantly more likely to occur in never-smokers, particularly women, and to be adenocarcinoma with mutations of the epidermal growth factor receptor, he pointed out. In the Taiwan National Lung Cancer Early Detection Program, of 531 lung cancers detected, 62% were in women (despite fewer female participants), of whom 92% had a positive family history alone and were never-smokers.
Stage distribution differed between the sexes: although 90% of tumors in females were stage 0 to I, this was true for just 77% of tumors found in males. The 5-year survival, by stage and based on an earlier analysis,1 was 100% for stage 0 disease and 94% for stage I disease—significantly higher than the rates seen in the National Lung Screening Trial (NLST)2 and the NELSON trial.3
“The authors conclude that family history is a risk factor based on a higher cancer detection rate among this population dominated largely by females with a family history; on a high proportion of patients with stage I disease—even greater than was seen in the NLST; and on their [high] 5-year survivorship,” Dr. Silvestri said. “While this is encouraging, these measures cannot tell us whether it is efficacious to screen this group, because these measures may suffer from bias, including lead time, length, and overdiagnosis.”
“Family history may be an important risk factor for the development of lung cancer. But it also is possible that it’s merely a genetic marker for families destined to develop indolent lung cancer. Remember, in the United States, genetics-related lung cancer risk is about 3-fold, whereas the risk associated with smoking is about 40-fold,” he said.
Other Screening Considerations
Some investigators have maintained that a 6-year risk of at least 1.5% should be required for screening; in Western modeling studies, “there is basically no situation” where this magnitude of risk is seen in never-smokers, as harms can offset small benefits, Dr. Silvestri continued, “but you can’t apply this to the Asian population,” who may have different risk factors.
The most informative research, he maintained, would come from a randomized controlled trial of nonsmokers and individuals with a positive family history. Such an approach, comparing screened vs unscreened persons, is the best way to prove the efficacy of screening by demonstrating a relative risk reduction in mortality. A randomized trial might also give a sense of the lethal vs nonlethal cancers in this population, might capture variables for improved risk/benefit calculations, could create a biobank of biomarkers to distinguish aggressive tumors from indolent ones, and could determine the true cost-efficacy of screening outside standard parameters.
“You can’t have a cost-efficacy analysis until you prove efficacy, which is a relative reduction in mortality from lung cancer. Cancer incidence and detection of early-stage disease are not surrogates for mortality reduction,” Dr. Silvestri said. “Unlike Europe and the United States, Asia has not performed a randomized trial for screening, and it is imperative that this be done before exposing large populations of never-smokers to potential harm without the knowledge they will benefit.”
DISCLOSURE: Dr. Silvestri reported financial relationships with Delfi, Nucleix, Biodesix, PrognomiQ, Amgen, and Olympus.
REFERENCES
1. Tammemägi MC, Church TR, Hocking WG, et al: Evaluation of the lung cancer risks at which to screen ever- and never-smokers: Screening rules applied to the PLCO and NLST cohorts. PLoS Med 11:e1001764, 2014.
2. National Lung Screening Trial Research Team: Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365:395-409, 2011.
3. de Koning HJ, van der Aalst CM, de Jong PA, et al: Reduced lung-cancer mortality with volume CT screening in a randomized trial. N Engl J Med 382:503-513, 2020.
