Comparative accuracy and cost-effectiveness of dynamic contrast-enhanced CT and positron emission tomography in the characterisation of solitary pulmonary nodules.

INTRODUCTION: Dynamic contrast-enhanced CT (DCE-CT) and positron emission tomography/CT (PET/CT) have a high reported accuracy for the diagnosis of malignancy in solitary pulmonary nodules (SPNs). The aim of this study was to compare the accuracy and cost-effectiveness of these. METHODS: In this prospective multicentre trial, 380 participants with an SPN (8-30 mm) and no recent history of malignancy underwent DCE-CT and PET/CT. All patients underwent either biopsy with histological diagnosis or completed CT follow-up. Primary outcome measures were sensitivity, specificity and overall diagnostic accuracy for PET/CT and DCE-CT. Costs and cost-effectiveness were estimated from a healthcare provider perspective using a decision-model. RESULTS: 312 participants (47% female, 68.1±9.0 years) completed the study, with 61% rate of malignancy at 2 years. The sensitivity, specificity, positive predictive value and negative predictive values for DCE-CT were 95.3% (95% CI 91.3 to 97.5), 29.8% (95% CI 22.3 to 38.4), 68.2% (95% CI 62.4% to 73.5%) and 80.0% (95% CI 66.2 to 89.1), respectively, and for PET/CT were 79.1% (95% CI 72.7 to 84.2), 81.8% (95% CI 74.0 to 87.7), 87.3% (95% CI 81.5 to 91.5) and 71.2% (95% CI 63.2 to 78.1). The area under the receiver operator characteristic curve (AUROC) for DCE-CT and PET/CT was 0.62 (95% CI 0.58 to 0.67) and 0.80 (95% CI 0.76 to 0.85), respectively (p<0.001). Combined results significantly increased diagnostic accuracy over PET/CT alone (AUROC=0.90 (95% CI 0.86 to 0.93), p<0.001). DCE-CT was preferred when the willingness to pay per incremental cost per correctly treated malignancy was below £9000. Above £15 500 a combined approach was preferred. CONCLUSIONS: PET/CT has a superior diagnostic accuracy to DCE-CT for the diagnosis of SPNs. Combining both techniques improves the diagnostic accuracy over either test alone and could be cost-effective. TRIAL REGISTRATION NUMBER: NCT02013063.

Tracking the Evolution of Non-Small-Cell Lung Cancer.

BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC. METHODS: In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival. RESULTS: We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10-4), which remained significant in multivariate analysis. CONCLUSIONS: Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).

Spirometry performed as part of the Manchester community-based lung cancer screening programme detects a high prevalence of airflow obstruction in individuals without a prior diagnosis of COPD.

BACKGROUND: COPD is a major cause of morbidity and mortality in populations eligible for lung cancer screening. We investigated the role of spirometry in a community-based lung cancer screening programme. METHODS: Ever smokers, age 55-74, resident in three deprived areas of Manchester were invited to a 'Lung Health Check' (LHC) based in convenient community locations. Spirometry was incorporated into the LHCs alongside lung cancer risk estimation (Prostate, Lung, Colorectal and Ovarian Study Risk Prediction Model, 2012 version (PLCOM2012)), symptom assessment and smoking cessation advice. Those at high risk of lung cancer (PLCOM2012 ≥1.51%) were eligible for annual low-dose CT screening over two screening rounds. Airflow obstruction was defined as FEV1/FVC<0.7. Primary care databases were searched for any prior diagnosis of COPD. RESULTS: 99.4% (n=2525) of LHC attendees successfully performed spirometry; mean age was 64.1±5.5, 51% were women, 35% were current smokers. 37.4% (n=944) had airflow obstruction of which 49.7% (n=469) had no previous diagnosis of COPD. 53.3% of those without a prior diagnosis were symptomatic (n=250/469). After multivariate analysis, the detection of airflow obstruction without a prior COPD diagnosis was associated with male sex (adjOR 1.84, 95% CI 1.37 to 2.47; p<0.0001), younger age (p=0.015), lower smoking duration (p<0.0001), fewer cigarettes per day (p=0.035), higher FEV1/FVC ratio (<0.0001) and being asymptomatic (adjOR 4.19, 95% CI 2.95 to 5.95; p<0.0001). The likelihood of screen detected lung cancer was significantly greater in those with evidence of airflow obstruction who had a previous diagnosis of COPD (adjOR 2.80, 95% CI 1.60 to 8.42; p=0.002). CONCLUSIONS: Incorporating spirometry into a community-based targeted lung cancer screening programme is feasible and identifies a significant number of individuals with airflow obstruction who do not have a prior diagnosis of COPD.

Attendees of Manchester's Lung Health Check pilot express a preference for community-based lung cancer screening.

Manchester's 'Lung Health Check' pilot utilised mobile CT scanners in convenient retail locations to deliver lung cancer screening to socioeconomically disadvantaged communities. We assessed whether screening location was an important factor for those attending the service. Location was important for 74.7% (n=701/938) and 23% (n=216/938) reported being less likely to attend an equivalent hospital-based programme. This preference was most common in current smokers (27% current smokers vs 19% former smokers; AdjOR 1.46, 95% CI 1.03 to 2.08, p=0.036) and those in the lowest deprivation quartile (25% lowest quartile vs 17.6% highest quartile; AdjOR 2.0, 95% CI 1.24 to 3.24, p=0.005). Practical issues related to travel were most important in those less willing to attend a hospital-based service, with 83.3% citing at least one travel related barrier to non-attendance. A convenient community-based screening programme may reduce inequalities in screening adherence especially in those at high risk of lung cancer in deprived areas.

Implementing lung cancer screening: baseline results from a community-based 'Lung Health Check' pilot in deprived areas of Manchester.

We report baseline results of a community-based, targeted, low-dose CT (LDCT) lung cancer screening pilot in deprived areas of Manchester. Ever smokers, aged 55-74 years, were invited to 'lung health checks' (LHCs) next to local shopping centres, with immediate access to LDCT for those at high risk (6-year risk ≥1.51%, PLCOM2012 calculator). 75% of attendees (n=1893/2541) were ranked in the lowest deprivation quintile; 56% were high risk and of 1384 individuals screened, 3% (95% CI 2.3% to 4.1%) had lung cancer (80% early stage) of whom 65% had surgical resection. Taking lung cancer screening into communities, with an LHC approach, is effective and engages populations in deprived areas.

Second round results from the Manchester 'Lung Health Check' community-based targeted lung cancer screening pilot.

We report results from the second annual screening round (T1) of Manchester's 'Lung Health Check' pilot of community-based lung cancer screening in deprived areas (undertaken June to August 2017). Screening adherence was 90% (n=1194/1323): 92% of CT scans were classified negative, 6% indeterminate and 2.5% positive; there were no interval cancers. Lung cancer incidence was 1.6% (n=19), 79% stage I, treatments included surgery (42%, n=9), stereotactic ablative radiotherapy (26%, n=5) and radical radiotherapy (5%, n=1). False-positive rate was 34.5% (n=10/29), representing 0.8% of T1 participants (n=10/1194). Targeted community-based lung cancer screening promotes high screening adherence and detects high rates of early stage lung cancer.

"To know or not to know ?" Push and pull in ever smokers lung screening uptake decision-making intentions.

BACKGROUND: In the United States, lung cancer screening aims to detect cancer early in nonsymptomatic current and former smokers. A lung screening pilot service in an area of high lung cancer incidence in the United Kingdom has been designed based on United States trial evidence. However, our understanding of acceptability and reasons for lung screening uptake or decline in a United Kingdom nontrial context are currently limited. OBJECTIVE: To explore with ever smokers the acceptability of targeted lung screening and uptake decision-making intentions. DESIGN: Qualitative study using semistructured focus groups and inductive thematic analysis to explore acceptability and uptake decision-making intentions with people of similar characteristics to lung screening eligible individuals. SETTING AND PARTICIPANTS: Thirty-three participants (22 ex-smokers; 11 smokers) men and women, smokers and ex-smokers, aged 50-80 were recruited purposively from community and health settings in Manchester, England. RESULTS: Lung screening was widely acceptable to participants. It was seen as offering reassurance about lung health or opportunity for early detection and treatment. Participant's desire to know about their lung health via screening was impacted by perceived benefits; emotions such as worry about a diagnosis and screening tests; practicalities such as accessibility; and smoking-related issues including perceptions of individual risk and smoking stigma. DISCUSSION: Decision making was multifaceted with indications that current smokers faced higher participation barriers than ex-smokers. Reducing participation barriers through careful service design and provision of decision support information will be important in lung screening programmes to support informed consent and equitable uptake.

The cost-effectiveness of the Manchester 'lung health checks', a community-based lung cancer low-dose CT screening pilot.

BACKGROUND: Previous evaluations of low-dose CT (LDCT) lung cancer screening programmes have taken very different approaches in the design of the informative trials and the methods applied to determine cost-effectiveness. Therefore, it has not been possible to determine if differences in cost-effectiveness are due to different screening approaches or the evaluation methodology. This study reports the findings of an evaluation of the first round of a community-based, LDCT screening pilot Manchester, applying previously published methodology to ensure consistency. METHODS: Using the economic evaluation method reported in the UKLS trial, applying Manchester specific evidence where possible, we estimate the cost-effectiveness of LDCT for lung cancer. Estimates of the total costs and quality adjusted life years (QALYs) were calculated. RESULTS: The Manchester programme cost £663,076, diagnosed 42 patients with lung cancer resulting in a gain in population health of 88.13 discounted life years, equivalent to 65.85 QALYs. This implied an incremental cost-effectiveness ratio of £10,069/QALY. CONCLUSIONS: We found the Manchester programme to be a cost-effective use of limited NHS resources. The findings suggest that further research is now needed not as to whether LDCT screening is cost-effective but under what conditions can it improve patient health by the most while remaining cost-effective.

Progress and prospects of early detection in lung cancer.

Lung cancer is the leading cause of cancer-related death in the world. It is broadly divided into small cell (SCLC, approx. 15% cases) and non-small cell lung cancer (NSCLC, approx. 85% cases). The main histological subtypes of NSCLC are adenocarcinoma and squamous cell carcinoma, with the presence of specific DNA mutations allowing further molecular stratification. If identified at an early stage, surgical resection of NSCLC offers a favourable prognosis, with published case series reporting 5-year survival rates of up to 70% for small, localized tumours (stage I). However, most patients (approx. 75%) have advanced disease at the time of diagnosis (stage III/IV) and despite significant developments in the oncological management of late stage lung cancer over recent years, survival remains poor. In 2014, the UK Office for National Statistics reported that patients diagnosed with distant metastatic disease (stage IV) had a 1-year survival rate of just 15-19% compared with 81-85% for stage I.

Circulating Tumor Cells Detected in the Tumor-Draining Pulmonary Vein Are Associated with Disease Recurrence after Surgical Resection of NSCLC.

Tumor recurrence after surgical resection of NSCLC obstructs long-term disease-free survival in approximately 50% of cases. Our data suggest that combining circulating tumor cell enumeration (as single cells or clusters) in tumor-draining pulmonary vein and peripheral blood (assessed by CellSearch) at the time of NSCLC surgery better identifies those patients at higher risk for lung cancer recurrence than does peripheral circulating tumor cell number alone.