John A Holemans

UK Lung Cancer RCT Pilot Screening Trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening

Background Lung cancer screening using low-dose CT (LDCT) was shown to reduce lung cancer mortality by 20% in the National Lung Screening Trial. Methods The pilot UK Lung Cancer Screening (UKLS) is a randomised controlled trial of LDCT screening for lung cancer versus usual care. A population-based questionnaire was used to identify high-risk individuals. CT screen-detected nodules were managed by a pre-specified protocol. Cost effectiveness was modelled with reference to the National Lung Cancer Screening Trial mortality reduction. Results 247 354 individuals aged 50–75 years were approached; 30.7% expressed an interest, 8729 (11.5%) were eligible and 4055 were randomised, 2028 into the CT arm (1994 underwent a CT). Forty-two participants (2.1%) had confirmed lung cancer, 34 (1.7%) at baseline and 8 (0.4%) at the 12-month scan. 28/42 (66.7%) had stage I disease, 36/42 (85.7%) had stage I or II disease. 35/42 (83.3%) had surgical resection. 536 subjects had nodules greater than 50 mm3 or 5 mm diameter and 41/536 were found to have lung cancer. One further cancer was detected by follow-up of nodules between 15 and 50 mm3 at 12 months. The baseline estimate for the incremental cost-effectiveness ratio of once-only CT screening, under the UKLS protocol, was £8466 per quality adjusted life year gained (CI £5542 to £12 569). Conclusions The UKLS pilot trial demonstrated that it is possible to detect lung cancer at an early stage and deliver potentially curative treatment in over 80% of cases. Health economic analysis suggests that the intervention would be cost effective—this needs to be confirmed using data on observed lung cancer mortality reduction. Trial registration ISRCTN 78513845.

The UK Lung Screen (UKLS): demographic profile of first 88,897 approaches provides recommendations for population screening.

The UK Lung Cancer Screening trial (UKLS) aims to evaluate low-dose computed tomography (LDCT) lung cancer population screening in the United Kingdom. In UKLS, a large population sample ages 50 to 75 years is approached with a questionnaire to determine lung cancer risk. Those with an estimated risk of at least 5% of developing lung cancer in the next 5 years (using the Liverpool Lung project risk model) are invited to participate in the trial. Here, we present demographic, risk, and response rate data from the first 88,897 individuals approached. Of note, 23,794 individuals (26.8% of all approached) responded positively to the initial questionnaire; 12% of these were high risk. Higher socioeconomic status correlated positively with response, but inversely with risk (P < 0.001). The 50- to 55-year age group was least likely to participate, and at lowest cancer risk. Only 5% of clinic attendees were ages ≤60 years (compared with 47% of all 88,897 approached); this has implications for cost effectiveness. Among positive responders, there were more ex-smokers than expected from population figures (40% vs. 33%), and fewer current smokers (14% vs. 17.5%). Of note, 32.7% of current smokers and 18.4% of ex-smokers were designated as high risk. Overall, 1,452 of 23,794 positive responders (6.1%) were deemed high risk and attended a recruitment clinic. UKLS is the first LDCT population screening trial, selecting high-risk subjects using a validated individual risk prediction model. Key findings: (i) better recruitment from ex- rather than current smokers, (ii) few clinic attendees ages early 50s, and (iii) representative number of socioeconomically deprived people recruited, despite lower response rates. Cancer Prev Res; 7(3); 362–71. ©2014 AACR.

CT Quantification of Emphysema in Young Subjects with No Recognizable Chest Disease

OBJECTIVE The purpose of this prospective study was to evaluate volumetric CT emphysema quantification (CT densitovolumetry) in a young population with no recognizable lung disease. SUBJECTS AND METHODS A cohort of 30 nonsmoking patients with no recognizable lung disease (16 men, 14 women; age range, 19-41 years) underwent inspiratory and expiratory CT, after which the data were postprocessed for volumetric quantification of emphysema (threshold, -950 HU). Correlation was tested for age, weight, height, sex, body surface area (BSA), and physical activity. Normal limits were established by mean +/- 1.96 SD. RESULTS No correlation was found between the measured volumes and age or physical activity. Correlation was found between BSA and normal lung volume in inspiration (r = 0.69, p = 0.000), shrink volume (i.e., difference in total lung volume in inspiration and in expiration) (r = 0.66, p = 0.000), and percentage of shrink volume (r = 0.35, p = 0.05). For an alpha error of 5%, the limits of normality based on this sample are percentage of emphysema in inspiration, 0.35%; percentage of emphysema in expiration, 0.12%; and maximum lung volume in expiration, 3.6 L. The maximum predicted percentage of shrink volume can be calculated as %SV = 29.43% + 16.97% x BSA (+/- 1.96 x 7.61%). CONCLUSION Young healthy nonsmokers with no recognizable lung disease can also show a small proportion of emphysematous-like changes on CT densitovolumetry when a threshold of -950 HU is used. Reference values should be considered when applying the technique for early detection or grading of emphysema and when studying aging lungs.

The UK Lung Cancer Screening Trial: a pilot randomised controlled trial of low-dose computed tomography screening for the early detection of lung cancer.

BACKGROUND 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. OBJECTIVES 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. DESIGN 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). SETTING Thoracic centres with expertise in lung cancer imaging, respiratory medicine, pathology and surgery: Liverpool Heart & Chest Hospital, Merseyside, and Papworth Hospital, Cambridgeshire. PARTICIPANTS Individuals aged 50-75 years, at high risk of lung cancer, in the primary care trusts adjacent to the centres. INTERVENTIONS A thoracic LDCT scan. Follow-up computed tomography (CT) scans as per protocol. Referral to multidisciplinary team clinics was determined by nodule size criteria. MAIN OUTCOME MEASURES 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. RESULTS 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. CONCLUSIONS 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. FUTURE WORK 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. TRIAL REGISTRATION Current Controlled Trials ISRCTN78513845. FUNDING 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.

Computed tomography measurement of lung volume in preoperative assessment for living donor lung transplantation: volume calculation using 3D surface rendering in the determination of size compatibility.

Abstract:  The objective of this study was to describe the use of CT volume quantification assessment of candidates for LLDLT. Six pediatric candidates for LDLLT and their donors were investigated with helical chest CT, as part of the preoperative assessment. The CT images were analyzed as per routine and additional post‐processing with CT volume quantification (CT densitovolumetry) was performed to assess volume matching between the lower lobes of the donors and respective lungs of the receptors. CT images were segmented by density and region of interest, using post‐processing software. Size matching was also assessed using the FVC formula. Compatible volumes were found in three cases. The other three cases were considered incompatible. All three recipients with compatible sizes survived the procedure and are alive and well. One patient with incompatible size was submitted to the procedure and died because of complications attributed to the incompatible volumes. One patient with incompatible size has subsequently grown and new measurements are to be taken to check the current volumes. Different donors are being sought for the remaining patient whose lung volumes were considered too big for the prospective transplant donor lobes. Under FVC formula criteria, all cases were considered compatible. CT volume quantification is an easy to perform, non‐invasive technique that uses CT images for the preassessment of candidates for LDLLT, to compare the volume of the lower lobes from the donors with volume of each lung in the prospective recipients. Size matching based on CT densitovolumetry and FVC may differ.

Proteus syndrome: high-resolution CT and CT pulmonary densitovolumetry findings.

Cystic transformation of the lungs in Proteus syndrome is considered an important manifestation of this disease. We describe a case of an 11-year-old girl with a diagnosis of Proteus syndrome with lung involvement. Low-dose multidetector computed tomography (CT) revealed extensive diffuse cystic lung disease with left lung predominance, affecting mostly the lower lung zones. The cystic lesions had various sizes and variable wall thickness. Postprocessing using CT histogram densitometric volumetry software (CT densitovolumetry), using the threshold -950 Houndsfield units (HU) for quantifying emphysema, revealed that 31% of her total lung volume was composed of areas with CT attenuation values below -950 HU.

Comparing the performance of trained radiographers against experienced radiologists in the UK lung cancer screening (UKLS) trial

OBJECTIVE To compare the performance of radiographers against that of radiologists for CT lung nodule detection in the UK Lung Cancer Screening (UKLS) pilot trial. METHODS Four radiographers, trained in CT nodule detection, and three radiologists were prospectively evaluated. 290 CTs performed for the UKLS were independently read by 2 radiologists and 2 radiographers. The reference standard comprised all radiologist-identified positive nodules after arbitration of discrepancies. For each radiographer and radiologist, relative sensitivity and average false positives (FPs) per case were compared for all cases read, as well as for subsets of cases read by each radiographer-radiologist combination (10 combinations). RESULTS 599 nodules in 209/290 (72.1%) CT studies comprised the reference standard. The relative mean (±standard deviation) sensitivity of the four radiographers was 71.6 ± 8.5% compared with 83.3 ± 8.1% for the three radiologists. Radiographers were less sensitive and detected more FPs per case than radiologists in 7/10 and 8/10 radiographer-radiologist combinations, respectively (ranges of difference 11.2-33.8% and 0.4-2.6; p < 0.05). In 3/10 and 2/10 combinations, there was no difference in sensitivity and FPs per case between radiographers and radiologists. For nodules ≥100 mm(3) in volume or ≥5 mm in maximum diameter, radiographers were relatively less sensitive than radiologists in only 5/10 radiographer-radiologist combinations (range of difference 16.1-30.6%; p < 0.05) and not significantly different in the remaining 5/10 combinations. CONCLUSION Although overall radiographer performance was lower than that of experienced radiologists in this study, some radiographer performances were comparable with that of radiologists. ADVANCES IN KNOWLEDGE Overall, radiographers were less sensitive than radiologists reading the same CTs and also displayed higher average FP detections per case when compared with a reference standard derived from radiologist readings. However, some radiographers compared favourably with radiologists, especially when considering larger potentially clinically relevant nodules. Thus, while probably not sensitive enough to function as first readers, radiographers may still be able to fulfil the role of an assistant reader-that is, as a first or concurrent reader, who presents detected nodules for verification to a reading radiologist.

Normal variance in emphysema index measurements in 64 multidetector-row computed tomography

The purpose of this study was to identify the normal variance of emphysema index (EI) measured in examinations acquired with 64 multidetector‐row computed tomography (64‐MDCT). A longitudinal, noninterventional study was performed retrieving all patients in our institution who are currently registered in our lung nodule protocol. All patients with clinical, functional, or significant radiological changes were excluded. We assumed that EI should remain unchanged within a short period of time. We reviewed 475 MDCTs in order to select 50 clinically stable patients who had two sequential chest MDCTs performed within a time interval of less than three months, and who presented at least one lung free of abnormalities but emphysema. CT densitovolumetry was used to calculate EI with thresholds set at −950 Hounsfield units (HUs) (EI‐950) and −970 HUs (EI‐970); on both studies from each patient. We observed the variation of total lung volume (TLV), mean lung density (MDL), and EI for measurements at the baseline and at follow‐up scans. Differences observed between baseline and follow‐up measurements were: TLVμ=149ml; IC=μ+1.96(133); EI−950=0.02%; p95=0.89%; EI−970μ=0.04%; p95=0.23% and MLDμ=15HU; IC=μ+1.96(18). The correlations obtained were the following: TLV r=0.96, EI−950r=0.79, EI−970r=0.85. Accepting that emphysema would remain unchanged within three months on stable patients, differences of less than 0.89% for EI‐950 and of less than 0.23% for EI‐970 are within the variance of the method. PACS number: 87.50.ct

Two cases of rounded atelectasis presenting after coronary artery surgery

Rounded atelectasis developed in two patients after coronary artery bypass grafting. Although both lesions led to the suspicion of a primary pulmonary tumor on initial assessment, malignancy was excluded by biopsy and radiologic observation in the first patient and excision biopsy in the second.

Abstract 4602: Exome sequencing of UKLS lung cancer CT screened early stage cancers

INTRODUCTION Developments in both low-dose CT-screening within populations at high risk of lung cancer and sequencing analysis of lung tumours have improved the prospects for early detection and clinical management of lung cancer. Such approaches potentially could provide biological insight into the early stages of lung cancer development, which until now have been refractory to genomic analysis, since lung tumours are rarely identified at a presymptomatic timepoint. BRIEF DESCRIPTION OF PERTINENT EXPERIMENTAL PROCEDURES Individuals with at least a 5% risk of developing lung cancer within 5 years (according to the LLPv2 lung cancer risk score) were recruited to the UK Lung low dose CT Screening (UKLS) trial. Ten of the early stage NSCLC UKLS tumours were prepared for exome sequencing. Tumour DNA was extracted from FFPE material and DNA was also extracted from matched blood samples. Tumour and blood libraries were prepared using an Agilent SureSelect exome-capture kit and sequenced to 100x and 50x, depth respectively, on the Illumina HiSeq platform (Oxford Gene Technology, UK). Sequence data were aligned against the GRCh37 human reference and matched samples were subject to local realignment in pairs. Somatic variants were identified using a combination of EBCall, MuTect and VarScan2 and were post-filtered to remove false positive variants (alignment artifacts and FFPE-hypersensitive sites) by comparison between samples. TCGA (The Cancer Genome Atlas) lung adenocarcinoma and squamous cell carcinoma samples from smokers and former smokers (who had complete data for a minimal set of clinical and epidemiological variables) were compared to the UKLS samples described above. To ensure comparable genomic regions were studied, both the UKLS and TCGA somatic variants were restricted to protein-coding regions covered by the Agilent SureSelect array but disjoint from simple-repetitive regions. SUMMARY OF THE NEW, UNPUBLISHED DATA Despite detection at an early stage, somatic mutations were identified in all CT-detected tumours, including non-synonymous variants in known driver genes. Between 71 and 471 variants were detected within non-repetitive protein-coding regions, which is comparable to, if somewhat lower than, the number of variants in the same regions in the TCGA ever-smoker samples (p = 0.17; Kruskal-Wallis). The results suggest that the majority of somatic variants exist in lung tumours prior to the evolution of symptoms and are consistent with recent studies of lung cancer heterogeneity wherein the majority of mutations occur prior to subclonal branching. STATEMENT OF CONCLUSIONS Somatic variations in the host genome are readily detected in FFPE material from pre-symptomatic lung tumours. Mutational burden is comparable to lung adenocarcinoma and squamous carcinoma from mature symptomatic individuals providing further evidence for the long latency of lung tumour development. Citation Format: Russell Hyde, Michael Davies, Martin Ledson, John A. Holemans, Richard D. Page, John Gosney, David R. Baldwin, Anand Devaraj, David M. Hansell, Stephen W. Duffy, John K. Field. Exome sequencing of UKLS lung cancer CT screened early stage cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4602. doi:10.1158/1538-7445.AM2015-4602