In the past decade, the introduction of molecularly targeted agents and immune-checkpoint inhibitors has led to improved survival outcomes for patients with advanced-stage lung cancer; however, this ...disease remains the leading cause of cancer-related mortality worldwide. Two large randomized controlled trials of low-dose CT (LDCT)-based lung cancer screening in high-risk populations - the US National Lung Screening Trial (NLST) and NELSON - have provided evidence of a statistically significant mortality reduction in patients. LDCT-based screening programmes for individuals at a high risk of lung cancer have already been implemented in the USA. Furthermore, implementation programmes are currently underway in the UK following the success of the UK Lung Cancer Screening (UKLS) trial, which included the Liverpool Health Lung Project, Manchester Lung Health Check, the Lung Screen Uptake Trial, the West London Lung Cancer Screening pilot and the Yorkshire Lung Screening trial. In this Review, we focus on the current evidence on LDCT-based lung cancer screening and discuss the clinical developments in high-risk populations worldwide; additionally, we address aspects such as cost-effectiveness. We present a framework to define the scope of future implementation research on lung cancer screening programmes referred to as Screening Planning and Implementation RAtionale for Lung cancer (SPIRAL).
The present review is an update of the research and development efforts regarding the use of molecular biomarkers in the lung cancer screening setting. The two main unmet clinical needs, namely, the ...refinement of risk to improve the selection of individuals undergoing screening and the characterization of undetermined nodules found during the computed tomography–based screening process are the object of the biomarkers described in the present review. We first propose some principles to optimize lung cancer biomarker discovery projects. Then, we summarize the discovery and developmental status of currently promising molecular candidates, such as autoantibodies, complement fragments, microRNAs, circulating tumor DNA, DNA methylation, blood protein profiling, or RNA airway or nasal signatures. We also mention other emerging biomarkers or new technologies to follow, such as exhaled breath biomarkers, metabolomics, sputum cell imaging, genetic predisposition studies, and the integration of next-generation sequencing into study of circulating DNA. We also underline the importance of integrating different molecular technologies together with imaging, radiomics, and artificial intelligence. We list a number of completed, ongoing, or planned trials to show the clinical utility of molecular biomarkers. Finally, we comment on future research challenges in the field of biomarkers in the context of lung cancer screening and propose a design of a trial to test the clinical utility of one or several candidate biomarkers.
•PD-L1 expression was assessed for heterogeneity in 107 NSCLC patients.•Intra-tumoural heterogeneity was observed in 78% of cases.•Inter-tumoural heterogeneity was observed in 53% of cases.•23% of ...cases had clinically relevant changes between primary and secondary tumours.•Sample site selection is an important consideration for testing PD-L1.
PD-L1 expression on tumour cells can guide the use of anti-PD-1/PD-L1 immune modulators to treat patients with non-small cell lung cancer (NSCLC). Heterogeneity of PD-L1 expression both within and between tumour sites is a well-documented phenomenon that compromises its predictive power. Our aim was to better characterise the pattern and extent of PD-L1 heterogeneity with a view to optimising tumour sampling and improve its accuracy as a biomarker.
Expression of PD-L1 was assessed by immunochemistry using the SP263 clone in 107 resected primary NSCLCs and their nodal metastases. Intra-tumoural heterogeneity, defined as ‘small-scale’ (mm²), ‘medium-scale’ (cm²) and ‘large-scale’ (between tumour blocks), was assessed by digital imaging using a novel ‘squares method’. Inter-tumoural heterogeneity between the primary tumours and their nodal metastases and between N1 and N2 nodal stages was also assessed.
The majority of tumours demonstrated intra-tumoural heterogeneity (small-scale 78%, medium-scale 50%, large-scale 46%). Inter-tumoural heterogeneity between the primary and nodal metastases was present in 53% of cases and, in 17%, between N1 and N2 disease. These differences were occasionally sufficient to lead to discrepancy across the ≥1%, ≥25% and ≥50% cut-offs used to guide therapy.
Heterogeneity of PD-L1 expression is common, variable in scale and extent, and carries significant implications for its accuracy as a predictive biomarker. Extensive sampling reduces, but cannot eliminate, this inaccuracy.
Lung cancer kills more people than any other cancer in the UK (5-year survival < 13%). Early diagnosis can save lives. The USA-based National Lung Cancer Screening Trial reported a 20% relative ...reduction in lung cancer mortality and 6.7% all-cause mortality in low-dose computed tomography (LDCT)-screened subjects.
To (1) analyse LDCT lung cancer screening in a high-risk UK population, determine optimum recruitment, screening, reading and care pathway strategies; and (2) assess the psychological consequences and the health-economic implications of screening.
A pilot randomised controlled trial comparing intervention with usual care. A population-based risk questionnaire identified individuals who were at high risk of developing lung cancer (≥ 5% over 5 years).
Thoracic centres with expertise in lung cancer imaging, respiratory medicine, pathology and surgery: Liverpool Heart & Chest Hospital, Merseyside, and Papworth Hospital, Cambridgeshire.
Individuals aged 50-75 years, at high risk of lung cancer, in the primary care trusts adjacent to the centres.
A thoracic LDCT scan. Follow-up computed tomography (CT) scans as per protocol. Referral to multidisciplinary team clinics was determined by nodule size criteria.
Population-based recruitment based on risk stratification; management of the trial through web-based database; optimal characteristics of CT scan readers (radiologists vs. radiographers); characterisation of CT-detected nodules utilising volumetric analysis; prevalence of lung cancer at baseline; sociodemographic factors affecting participation; psychosocial measures (cancer distress, anxiety, depression, decision satisfaction); and cost-effectiveness modelling.
A total of 247,354 individuals were approached to take part in the trial; 30.7% responded positively to the screening invitation. Recruitment of participants resulted in 2028 in the CT arm and 2027 in the control arm. A total of 1994 participants underwent CT scanning: 42 participants (2.1%) were diagnosed with lung cancer; 36 out of 42 (85.7%) of the screen-detected cancers were identified as stage 1 or 2, and 35 (83.3%) underwent surgical resection as their primary treatment. Lung cancer was more common in the lowest socioeconomic group. Short-term adverse psychosocial consequences were observed in participants who were randomised to the intervention arm and in those who had a major lung abnormality detected, but these differences were modest and temporary. Rollout of screening as a service or design of a full trial would need to address issues of outreach. The health-economic analysis suggests that the intervention could be cost-effective but this needs to be confirmed using data on actual lung cancer mortality.
The UK Lung Cancer Screening (UKLS) pilot was successfully undertaken with 4055 randomised individuals. The data from the UKLS provide evidence that adds to existing data to suggest that lung cancer screening in the UK could potentially be implemented in the 60-75 years age group, selected via the Liverpool Lung Project risk model version 2 and using CT volumetry-based management protocols.
The UKLS data will be pooled with the NELSON (Nederlands Leuvens Longkanker Screenings Onderzoek: Dutch-Belgian Randomised Lung Cancer Screening Trial) and other European Union trials in 2017 which will provide European mortality and cost-effectiveness data. For now, there is a clear need for mortality results from other trials and further research to identify optimal methods of implementation and delivery. Strategies for increasing uptake and providing support for underserved groups will be key to implementation.
Current Controlled Trials ISRCTN78513845.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 40. See the NIHR Journals Library website for further project information.
European position statement on lung cancer screening Oudkerk, Matthijs; Devaraj, Anand; Vliegenthart, Rozemarijn ...
The lancet oncology,
December 2017, 2017-12-00, 20171201, Letnik:
18, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Lung cancer screening with low-dose CT can save lives. This European Union (EU) position statement presents the available evidence and the major issues that need to be addressed to ensure the ...successful implementation of low-dose CT lung cancer screening in Europe. This statement identified specific actions required by the European lung cancer screening community to adopt before the implementation of low-dose CT lung cancer screening. This position statement recommends the following actions: a risk stratification approach should be used for future lung cancer low-dose CT programmes; that individuals who enter screening programmes should be provided with information on the benefits and harms of screening, and smoking cessation should be offered to all current smokers; that management of detected solid nodules should use semi-automatically measured volume and volume-doubling time; that national quality assurance boards should be set up to oversee technical standards; that a lung nodule management pathway should be established and incorporated into clinical practice with a tailored screening approach; that non-calcified baseline lung nodules greater than 300 mm3, and new lung nodules greater than 200 mm3, should be managed in multidisciplinary teams according to this EU position statement recommendations to ensure that patients receive the most appropriate treatment; and planning for implementation of low-dose CT screening should start throughout Europe as soon as possible. European countries need to set a timeline for implementing lung cancer screening.
Since the publication of the first mortality results from the National Lung Screening Trial (NLST), which showed a 20% reduction in lung-cancer mortality with low-dose computed tomographic (CT) ...screening,
1
the intervention has been adopted as policy in the United States, and there has been considerable discussion of the possibilities for its adoption in Europe.
2,3
Policy decisions are still awaited in many countries, despite the unequivocal nature of the original NLST results.
1
This is likely to be partly due to doubts fostered by the early publication of inconclusive results of a number of smaller trials in Europe.
4,5
These doubts should be . . .
Objective Lung cancer is the leading cause of cancer death in North America. Low-dose computed tomography screening can reduce lung cancer–specific mortality by 20%. Method The American Association ...for Thoracic Surgery created a multispecialty task force to create screening guidelines for groups at high risk of developing lung cancer and survivors of previous lung cancer. Results The American Association for Thoracic Surgery guidelines call for annual lung cancer screening with low-dose computed tomography screening for North Americans from age 55 to 79 years with a 30 pack-year history of smoking. Long-term lung cancer survivors should have annual low-dose computed tomography to detect second primary lung cancer until the age of 79 years. Annual low-dose computed tomography lung cancer screening should be offered starting at age 50 years with a 20 pack-year history if there is an additional cumulative risk of developing lung cancer of 5% or greater over the following 5 years. Lung cancer screening requires participation by a subspecialty-qualified team. The American Association for Thoracic Surgery will continue engagement with other specialty societies to refine future screening guidelines. Conclusions The American Association for Thoracic Surgery provides specific guidelines for lung cancer screening in North America.
Deaths from lung cancer exceed those from any other type of malignancy, with 1·5 million deaths in 2010. Prevention and smoking cessation are still the main methods to reduce the death toll. The US ...National Lung Screening Trial, which compared CT screening with chest radiograph, yielded a mortality advantage of 20% to participants in the CT group. International debate is ongoing about whether sufficient evidence exists to implement CT screening programmes. When questions about effectiveness and cost-effectiveness have been answered, which will await publication of the largest European trial, NELSON, and pooled analysis of European CT screening trials, we discuss the main topics that will need consideration. These unresolved issues are risk prediction models to identify patients for CT screening; radiological protocols that use volumetric analysis for indeterminate nodules; options for surgical resection of CT-identified nodules; screening interval; and duration of screening. We suggest that a demonstration project of biennial screening over a 4-year period should be undertaken.
Smoking cessation was examined among high-risk participants in the UK Lung Cancer Screening (UKLS) Pilot Trial of low-dose CT screening.
High-risk individuals aged 50-75 years who completed baseline ...questionnaires were randomised to CT screening (intervention) or usual care (no screening control). Smoking habit was determined at baseline using self-report. Smokers were asked whether they had quit smoking since joining UKLS at T
(2 weeks after baseline scan results or control assignment) and T
(up to 2 years after recruitment). Intention-to-treat (ITT) regression analyses were undertaken, adjusting for baseline lung cancer distress, trial site and sociodemographic variables.
Of a total 4055 individuals randomised to CT screening or control, 1546 were baseline smokers (759 intervention, 787 control). Smoking cessation rates were 8% (control n=36/479) versus 14% (intervention n=75/527) at T
and 21% (control n=79/377) versus 24% (intervention n=115/488) at T
. ITT analyses indicated that the odds of quitting among screened participants were significantly higher at T
(adjusted OR (aOR) 2.38, 95% CI 1.56 to 3.64, p<0.001) and T
(aOR 1.60, 95% CI 1.17 to 2.18, p=0.003) compared with control. Intervention participants who needed additional clinical investigation were more likely to quit in the longer term compared with the control group (aOR 2.29, 95% CI 1.62 to 3.22, p=0.007) and those receiving a negative result (aOR 2.43, 95% CI 1.54 to 3.84, p<0.001).
CT lung cancer screening for high-risk participants presents a teachable moment for smoking cessation, especially among those who receive a positive scan result. Further behavioural research is needed to evaluate optimal strategies for integrating smoking cessation intervention with stratified lung cancer screening.
Results, ISRCTN 78513845.
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