The challenges of implementing low-dose computed tomography for lung cancer screening in low- and middle-income countries

Review Article https://doi.org/10.1038/s43018-020-00142-z The challenges of implementing low-dose computed tomography for lung cancer screening in low- and middle-income countries Eduardo Edelman Saul 1 ✉, Raquel B. Guerra2, Michelle Edelman Saul3, Laercio Lopes da Silva4, Gabriel F. P. Aleixo5, Raquel M. K. Matuda6 and Gilberto Lopes7 Lung cancer accounts for an alarming human and economic burden in low- and middle-income countries (LMICs). Recent landmark trials from high-income countries (HICs) by demonstrating that low-dose computed tomography (LDCT) screening effectively reduces lung cancer mortality have engendered enthusiasm for this approach. Here we examine the effectiveness and affordability of LDCT screening from the viewpoint of LMICs. We consider resource-restricted perspectives and discuss implementation challenges and strategies to enhance the feasibility and cost-effectiveness of LDCT screening in LMICs. L ung cancer is the most frequently diagnosed malignancy and the leading cause of cancer death worldwide: GLOBOCAN estimated 2,093,876 new cases and a total of 1,761,007 deaths in 2018, with 61% of incidence and 65.3% of mortality occurring in LMICs1. The human and economic burden of this cancer type in resource-scarce populations is an urgent public health crisis with an expected upward trend, given the steadily increasing prevalence of smoking and air pollution in those countries2. Non–small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers1. Related symptoms are nonspecific, usually manifested as lasting cough and dyspnea3. Roughly 75% of the cases present when the disease is locally advanced (stage IIIC) or metastatic (stage IV), when it has 5-year survival rates of 13% and 0%, respectively. In contrast, when detected at stage IA, usually in asymptomatic individuals, NSCLC can be treated with curative intent, with overall survival of up to 92% (ref. 4). These stark differences provide the opportunity to improve survival in the high-risk population by early detection through lung cancer screening (LCS). However, chest X-ray (CXR) with and without sputum cytology as a screening strategy has failed to demonstrate benefit for lung cancer mortality5,6. Renewed enthusiasm arose when the National Lung Screening Trial (NLST) showed a 20% mortality reduction in high-risk individuals using LDCT screening7, which was recently buoyed by results of the Dutch-Belgian Lung Cancer Screening Trial (NELSON)8. LCS programs require the availability of a complex healthcare infrastructure and considerable economic resources, making LDCT screening efficacy and affordability highly variable2, especially in emerging economies with fragmented and underfinanced health systems. Herein, we present the LCS development and LMIC perspective of lung cancer epidemiology, discussing cost-effectiveness and strategies for LDCT screening implementation in the daily LMIC oncology practice. LCS development The first study to assess LCS, in the 1960s, evaluated 55,034 men ≥40 years of age and compared CXR results every 6 months for 3 years, with a control group receiving CXR at the beginning and end of the study9. Subsequently, a cooperative study at three different US sites, including over 30,000 male smokers, evaluated dual-screening (CXR plus sputum cytology) versus control groups undergoing CXR or no intervention6. In Czechoslovakia, semiannual or 3-year-interval dual screening was compared with no screening, including high-risk men aged 40–64 years with lifetime cigarette consumption of ≥150,000 (ref. 5). Finally, the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial randomized 154,091 participants 55–74 years of age to annual CXR versus standard care, substantiating the lack of mortality benefit of these strategies10. The Early Lung Cancer Action Program (ELCAP), initiated in 1992, was the first to gauge the use of LDCT for LCS. One thousand participants with a cigarette smoking history of ≥10 packs per year underwent baseline11 and annual (841 individuals)12 LDCT and CXR, demonstrating an increase in early-stage diagnosis rate with LDCT. In 2006, the follow-up International Early Lung Cancer Action Program (I-ELCAP) study13 included 31,567 individuals from Japan, the United States, Europe, Israel and China, with participants >40 years old and subject to high-risk factors such as cigarette smoking, occupational exposure (asbestos, beryllium, uranium or radon) or second-hand smoke exposure. This study reported an 85% screening detection rate of stage I lung cancer, with 80% estimated overall 10-year survival, which increased to 92% if resection occurred within 1 month of diagnosis. Likewise, observational studies ultimately suggested that screening with LDCT could potentially detect curable lung cancer14–19. This growing body of evidence encouraged further confirmatory randomized controlled trials (RCTs)20. Department of Medicine, Jackson Memorial Hospital/University of Miami, Miami, FL, USA. 2Centro Paulista de Oncologia–Oncoclinicas Group, São Paulo, Brazil. 3Department of Medicine, Universidade Estácio de Sá, Rio de Janeiro, Brazil. 4Department of Medicine, Metrowest Medical Center/Tufts University School of Medicine, Framingham, MA, USA. 5Department of Hematology-Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 6Division of Oncology, Oncoclinicas Group, Brasilia, Brazil. 7Division of Hematology-Oncology, Department of Medicine, Miller School of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA. ✉e-mail: 1 1140 NatUre Cancer | VOL 1 | December 2020 | 1140–1152 | www.nature.com/natcancer NaTuRe CanceR The landmark NLST, in 2011, was the first to demonstrate mortality reduction with LDCT screening. This trial randomized 53,454 high-risk participants to undergo three annual screenings with LDCT versus CXR. Eligible participants were current or former smokers 55–74 years of age with a ≥30-pack-per-year smoking history and <15 years since quitting. Cases were detected at either stage IA or IB in 63% of patients in the screening arm, characterizing stage migration. A reduction of 20% and 6.7% in lung cancer and all-cause relative mortality, respectively, was observed7. After a sequence of RCTs with limited power raised uncertainties by publishing inconclusive and heterogeneous results21–26, the NELSON trial8, the only fully powered RCT following the NLST, assuaged doubts about the potential mortality benefit of LDCT screening27. The NELSON trial randomized 15,792 current or former smokers 50–75 years of age, with smoking history of >15 cigarettes daily for >25 years or >10 cigarettes daily for >30 years and ≤10 years after quitting, to four rounds of LDCT at baseline and 1-, 2- and 2.5-year intervals versus no screening. Results showed that 58.6% of the screening-detected cases were in the early stages (IA and IB). At the 10-year follow-up, the reduction in lung cancer (...truncated)