Zaigham Saghir

CT screening for lung cancer brings forward early disease. The randomised Danish Lung Cancer Screening Trial: status after five annual screening rounds with low-dose CT

Background The effects of low-dose CT screening on disease stage shift, mortality and overdiagnosis are unclear. Lung cancer findings and mortality rates are reported at the end of screening in the Danish Lung Cancer Screening Trial. Methods 4104 men and women, healthy heavy smokers/former smokers were randomised to five annual low-dose CT screenings or no screening. Two experienced chest radiologists read all CT scans and registered the location, size and morphology of nodules. Nodules between 5 and 15 mm without benign characteristics were rescanned after 3 months. Growing nodules (>25% volume increase and/or volume doubling time<400 days) and nodules >15 mm were referred for diagnostic workup. In the control group, lung cancers were diagnosed and treated outside the study by the usual clinical practice. Results Participation rates were high in both groups (screening: 95.5%; control: 93.0%; p<0.001). Lung cancer detection rate was 0.83% at baseline and mean annual detection rate was 0.67% at incidence rounds (p=0.535). More lung cancers were diagnosed in the screening group (69 vs 24, p<0.001), and more were low stage (48 vs 21 stage I–IIB non-small cell lung cancer (NSCLC) and limited stage small cell lung cancer (SCLC), p=0.002), whereas frequencies of high-stage lung cancer were the same (21 vs 16 stage IIIA–IV NSCLC and extensive stage SCLC, p=0.509). At the end of screening, 61 patients died in the screening group and 42 in the control group (p=0.059). 15 and 11 died of lung cancer, respectively (p=0.428). Conclusion CT screening for lung cancer brings forward early disease, and at this point no stage shift or reduction in mortality was observed. More lung cancers were diagnosed in the screening group, indicating some degree of overdiagnosis and need for longer follow-up.

Results of the Randomized Danish Lung Cancer Screening Trial with Focus on High-Risk Profiling

RATIONALE As of April 2015, participants in the Danish Lung Cancer Screening Trial had been followed for at least 5 years since their last screening. OBJECTIVES Mortality, causes of death, and lung cancer findings are reported to explore the effect of computed tomography (CT) screening. METHODS A total of 4,104 participants aged 50-70 years at the time of inclusion and with a minimum 20 pack-years of smoking were randomized to have five annual low-dose CT scans (study group) or no screening (control group). MEASUREMENTS AND MAIN RESULTS Follow-up information regarding date and cause of death, lung cancer diagnosis, cancer stage, and histology was obtained from national registries. No differences between the two groups in lung cancer mortality (hazard ratio, 1.03; 95% confidence interval, 0.66-1.6; P = 0.888) or all-cause mortality (hazard ratio, 1.02; 95% confidence interval, 0.82-1.27; P = 0.867) were observed. More cancers were found in the screening group than in the no-screening group (100 vs. 53, respectively; P < 0.001), particularly adenocarcinomas (58 vs. 18, respectively; P < 0.001). More early-stage cancers (stages I and II, 54 vs. 10, respectively; P < 0.001) and stage IIIa cancers (15 vs. 3, respectively; P = 0.009) were found in the screening group than in the control group. Stage IV cancers were nonsignificantly more frequent in the control group than in the screening group (32 vs. 23, respectively; P = 0.278). For the highest-stage cancers (T4N3M1, 21 vs. 8, respectively; P = 0.025), this difference was statistically significant, indicating an absolute stage shift. Older participants, those with chronic obstructive pulmonary disease, and those with more than 35 pack-years of smoking had a significantly increased risk of death due to lung cancer, with nonsignificantly fewer deaths in the screening group. CONCLUSIONS No statistically significant effects of CT screening on lung cancer mortality were found, but the results of post hoc high-risk subgroup analyses showed nonsignificant trends that seem to be in good agreement with the results of the National Lung Screening Trial. Clinical trial registered with www.clinicaltrials.gov (NCT00496977).

Smoking habits in the randomised Danish Lung Cancer Screening Trial with low-dose CT: final results after a 5-year screening programme

Background We present the final results of the effect of lung cancer screening with low-dose CT on the smoking habits of participants in a 5-year screening trial. Methods The Danish Lung Cancer Screening Trial (DLCST) was a 5-year screening trial that enrolled 4104 subjects; 2052 were randomised to annual low-dose CT (CT group) and 2052 received no intervention (control group). Participants were current and ex-smokers (≥4 weeks abstinence from smoking) with a tobacco consumption of ≥20 pack years. Smoking habits were determined annually. Missing values for smoking status at the final screening round were handled using two different models. Results There were no statistically significant differences in annual smoking status between the CT group and control group. Overall the ex-smoker rates (CT + control group) significantly increased from 24% (baseline) to 37% at year 5 of screening (p<0.001). The annual point prevalence quit rate increased from 11% to 24% during the five screening rounds; the ex-smokers’ relapse rate remained stable, around 11%, across the same period. Conclusions Screening with low-dose CT had no extra effect on smoking status compared with the control group, but overall the screening programme probably promoted smoking cessation. Clinical Trial Registration: The DLCST is registered in Clinical Trials.gov Protocol Registration System (identification no. NCT00496977).

Optimal graph based segmentation using flow lines with application to airway wall segmentation

This paper introduces a novel optimal graph construction method that is applicable to multi-dimensional, multi-surface segmentation problems. Such problems are often solved by refining an initial coarse surface within the space given by graph columns. Conventional columns are not well suited for surfaces with high curvature or complex shapes but the proposed columns, based on properly generated flow lines, which are non-intersecting, guarantee solutions that do not self-intersect and are better able to handle such surfaces. The method is applied to segment human airway walls in computed tomography images. Comparison with manual annotations on 649 cross-sectional images from 15 different subjects shows significantly smaller contour distances and larger area of overlap than are obtained with recently published graph based methods. Airway abnormality measurements obtained with the method on 480 scan pairs from a lung cancer screening trial are reproducible and correlate significantly with lung function.

Healthcare costs in the Danish randomised controlled lung cancer CT-screening trial: a registry study.

OBJECTIVES Low dose computerised tomography (CT) screening for lung cancer can reduce lung-cancer-specific mortality. The objective of this study was to analyse healthcare costs and healthcare utilisation of participants in the Danish lung cancer CT-screening trial (DLCST). MATERIALS AND METHODS This registry study was nested in a randomised controlled trial (DLCST). 4104 participants, current or former heavy smokers, aged 50-70 years were randomised to five annual low dose CT scans or usual care during 2004-2010. Total healthcare costs and healthcare utilisation data for both the primary and the secondary healthcare sector were retrieved from public registries from randomisation - September 2011 and compared between (1) the CT-screening group and the control group and, (2) the control group and each of the true-positive, false-positive and true-negative groups. RESULTS The median annual costs per participant were significantly higher in the CT-screening group (Euros [EUR] 1342, interquartile range [IQR] 750-2980) compared with the control group (EUR 1190, IQR 590-2692) (p<0.0001). When the cost of the CT-screening programme was excluded, there was no longer a statistically significant difference between the CT-screening group (EUR 1155, IQR 567-2798) and the control group (p=0.52). Analyses according to the diagnostic groups showed that annual costs were 10.57 (95% CI 7.09-15.75) times higher for the true-positive and 1.67 (95% CI 1.20-2.32) times higher for the false-positive group compared with the control group. CONCLUSION Low dose lung cancer CT screening increases healthcare costs compared with no screening; this difference was attributable to the costs of the CT-screening programme. Overall healthcare costs were higher for the true-positive and false-positive groups than for the control group, also when excluding the cost of the CT-screening programme. This increase was outweighed by the larger true-negative group showing no significant differences in costs compared with the control group.

Bronchoscopy as a supplement to computed tomography in patients with haemoptysis may be unnecessary.

Background Haemoptysis is a common symptom and can be an early sign of lung cancer. Careful investigation of patients with haemoptysis may lead to early diagnosis. The strategy for investigation of these patients, however, is still being debated. Objectives We studied whether the combination of computed tomography (CT) and bronchoscopy had a higher sensitivity for malignant and non-malignant causes of haemoptysis than CT alone. Methods The study was a retrospective, non-randomised, two-centre study and included patients who were referred from primary care for the investigation of haemoptysis. Results A total of 326 patients were included in the study (mean age 60.5 [SD 15.3] years, 63.3% male). The most common aetiologies of haemoptysis were cryptogenic (52.5%), pneumonia (16.3%), emphysema (8.0%), bronchiectasis (5.8%) and lung cancer (4.0%). In patients diagnosed with lung cancer, bronchoscopy, CT and the combination of bronchoscopy and CT had a sensitivity of 0.61, 0.92 (p<0.05) and 0.97 (p=0.58), respectively. In patients with non-malignant causes of haemoptysis, most aetiologies were diagnosed by CT and comprised mainly pneumonia, emphysema and bronchiectasis. Bronchoscopy did not reveal these conditions and the sensitivity to these conditions was not increased by combining CT and bronchoscopy. Conclusions CT can stand alone as a diagnostic workup for patients with haemoptysis referred to an outpatient clinic. Bronchoscopy does not identify any malignant aetiologies not already diagnosed by CT. Combining the two test modalities does not result in a significant increase in sensitivity for malignant or non-malignant causes of haemoptysis.

Interstitial lung abnormalities are associated with increased mortality in smokers

OBJECTIVE The aim of this study was to investigate whether smokers with incidental findings of interstitial lung abnormalities have an increased mortality during long-term follow-up, and review the contributing causes of death. METHODS Baseline CT scans of 1990 participants from the Danish Lung Cancer Screening Trial were qualitatively assessed for predefined interstitial lung abnormalities of any severity. Inclusion criteria for this lung cancer screening trial included current or former smoking, > 20 pack-years, and age 50-70 years. Patients were followed up for up to 12 years. RESULTS We found interstitial lung abnormalities in 332 participants (16.7%). Interstitial lung abnormalities were associated with increased all-cause mortality in the full cohort (HR: 2.0, 95% CI: 1.4-2.7, P < 0.001) and in lung cancer-free participants (HR: 1.6, 95% CI: 1.1-2.4, P = 0.007). The findings were associated with death from lung cancer (HR: 3.2, 95% CI: 1.7-6.2, P < 0.001) and non-pulmonary malignancies (HR: 2.1, 95% CI: 1.1-4.0, P = 0.02). Participants with fibrotic and non-fibrotic interstitial lung abnormalities had similar survival. CONCLUSION Interstitial lung abnormalities were common in this lung cancer screening population of relatively healthy smokers and were associated with mortality regardless of the interstitial morphological phenotype. The increased mortality was partly due to an association with lung cancer and non-pulmonary malignancies.

Implementation of lung cancer CT screening in the Nordic countries

Abstract Introduction: We review the current knowledge of CT screening for lung cancer and present an expert-based, joint protocol for the proper implementation of screening in the Nordic countries. Materials and methods: Experts representing all the Nordic countries performed literature review and concensus for a joint protocol for lung cancer screening. Results and discussion: Areas of concern and caution are presented and discussed. We suggest to perform CT screening pilot studies in the Nordic countries in order to gain experience and develop specific and safe protocols for the implementation of such a program.