Giulia Picozzi

Design, recruitment and baseline results of the ITALUNG trial for lung cancer screening with low-dose CT

BACKGROUND Results of randomized clinical trials (RCTs) are needed to assess the efficacy of lung cancer screening with low-dose chest computed tomography (CT) in reducing lung cancer mortality. We report design and results of enrolment and baseline screening test in the ITALUNG trial, a RCT. METHODS Invitation letters were sent to subjects of 55-69 years of age clients of 269 general practitioners. Smokers or former smokers of at least 20 pack/years were eligible and after written consent were randomized in an active arm undergoing a low-dose CT annually for 4 years and in a control arm receiving no screening. Management of positive screening test was carried out using follow-up low-dose CT, fluorodeoxyglucose positron emission tomography, fine needle aspiration cytology and fiber optic bronchoscopy. RESULTS A sample of 3206 eligible subjects was achieved by sending 71,232 letters (enrolment efficacy = 4.5%). Subjects in control (n = 1593) and active (n = 1613) arm were balanced for age, gender and smoking history. Two-hundred and seven (12.8%) subjects did not undergo CT after randomization. The baseline screening test was positive in 426 (30.3%) of 1406 subjects. Twenty-one lung cancers (prevalence = 1.5%) were found in 20 subjects: 18 non-small cell lung cancer (NSCLC), 2 small cell lung cancer (SCLC) and a case of typical carcinoid. Ten NSCLC (47.6%) were in Stage I. Sixteen fine needle aspirations were performed in 15 lung cancers, with a positive result in 12 (75%) cases. One biopsy only (6.3%) was performed on a benign lesion. Seventeen lung cancers (81%) were treated with surgical resection in 16 subjects. One subject underwent surgery for a benign lesion (5.5% of all surgical resections). CONCLUSIONS Recruitment by mail of high risk subjects for a lung cancer screening RCT is feasible but not efficient. Results of the baseline screening test in the active arm of the ITALUNG trial are substantially in line with those of RCT and observational studies.

3-D Segmentation Algorithm of Small Lung Nodules in Spiral CT Images

Computed tomography (CT) is the most sensitive imaging technique for detecting lung nodules, and is now being evaluated as a screening tool for lung cancer in several large samples studies all over the world. In this report, we describe a semiautomatic method for 3-D segmentation of lung nodules in CT images for subsequent volume assessment. The distinguishing features of our algorithm are the following. 1) The user interaction process. It allows the introduction of the knowledge of the expert in a simple and reproducible manner. 2) The adoption of the geodesic distance in a multithreshold image representation. It allows the definition of a fusion--segregation process based on both gray-level similarity and objects shape. The algorithm was validated on low-dose CT scans of small nodule phantoms (mean diameter 5.3-11 mm) and in vivo lung nodules (mean diameter 5--9.8 mm) detected in the Italung-CT screening program for lung cancer. A further test on small lung nodules of Lung Image Database Consortium (LIDC) first data set was also performed. We observed a RMS error less than 6.6% in phantoms, and the correct outlining of the nodule contour was obtained in 82/95 lung nodules of Italung-CT and in 10/12 lung nodules of LIDC first data set. The achieved results support the use of the proposed algorithm for volume measurements of lung nodules examined with low-dose CT scanning technique.

Four-year results of low-dose CT screening and nodule management in the ITALUNG trial.

Introduction: Recruitment and nodule management are critical issues of lung cancer screening with low-dose computed tomography (LDCT). We report subjects’ compliance and results of LDCT screening and management protocol in the active arm of the ITALUNG trial. Methods: Three thousand two hundred six smokers or former smokers invited by mail were randomized to receive four annual LDCT (n = 1613) or usual care (n = 1593). Management protocol included follow-up LDCT, 2-[18F]fluoro-2-deoxy-D glucose positron emission tomography (FDG-PET), and CT-guided fine-needle aspiration biopsy (FNAB). Results: One thousand four hundred six subjects (87%) underwent baseline LDCT, and 1263 (79%) completed four screening rounds. LDCT was positive in 30.3% of the subjects at baseline and 15.8% subsequently. Twenty-one lung tumors in 20 subjects (1.5% detection) were found at baseline, and 20 lung tumors in 18 subjects (0.5% detection) in subsequent screening rounds. Ten of 18 prevalent (55%) and 13 of 17 incident (76%) non–small-cell cancers were in stage I. Interval growth enabled diagnosis of lung cancer in 16 subjects (42%), but at least one follow-up LDCT was obtained in 741 subjects (52.7%) over the screening period. FDG-PET obtained in 6.5% of subjects had 84% sensitivity and 90% specificity for malignant lesions. FNAB obtained in 2.4% of subjects showed 90% sensitivity and 88% specificity. Positivity of both FDG-PET and FNAB invariably predicted malignancy. Surgery for benign lesions was performed on four subjects (10% of procedures) but followed protocol violations on three subjects. Conclusions: High-risk subjects recruited by mail who entered LDCT screening showed a high and stable compliance. Efficacy of screening is, however, weakened by low detection rate and specificity. Adhesion to management protocol might lessen surgery for benign lesions.

Risk-benefit analysis of X-ray exposure associated with lung cancer screening in the Italung-CT trial.

OBJECTIVE Prior analyses of X-ray exposures in lung cancer screening with CT considered the basic acquisition technique in single-detector scanners and the effects of a lifetime screening regimen, whereas the potential benefit in terms of lives saved was not addressed. MATERIALS AND METHODS We determined the total-body effective dose of different acquisition techniques for one single-detector and one MDCT scanner and made projections about the cumulative radiation exposure to smokers undergoing four annual CT examinations on the same scanners in the Italung-CT Trial. Combining these data with estimates of radiation-induced fatal cancer and of the benefit of screening, we calculated the risk-benefit ratio for participants in the trial, ex-smokers, and never-smokers. RESULTS The cumulative effective doses per 1,000 subjects were 3.3 Sv using an MDCT scanner and 5.8 or 7.1 Sv using a single-detector scanner. Potential fatal cancers associated with radiation exposure were 0.11 per 1,000 subjects for MDCT scanners and 0.20 or 0.24 for single-detector scanners, which is about 10-100 times lower than the number of expected lives saved by screening assuming a 20-30% lung cancer-specific mortality reduction in current smokers. They were, however, of similar magnitude to the lives saved by screening in never-smokers and former smokers assuming a 10% efficacy of screening. CONCLUSION MDCT is associated with lower radiation doses than single-detector CT technology. The risk of radiation dose in the Italung-CT Trial is compensated for by the expected benefit. CT screening for lung cancer should not be offered to never-smokers, whereas its recommendation in former smokers is debatable.

Automated Segmentation Refinement of Small Lung Nodules in CT Scans by Local Shape Analysis

One of the most important problems in the segmentation of lung nodules in CT imaging arises from possible attachments occurring between nodules and other lung structures, such as vessels or pleura. In this report, we address the problem of vessels attachments by proposing an automated correction method applied to an initial rough segmentation of the lung nodule. The method is based on a local shape analysis of the initial segmentation making use of 3-D geodesic distance map representations. The correction method has the advantage that it locally refines the nodule segmentation along recognized vessel attachments only, without modifying the nodule boundary elsewhere. The method was tested using a simple initial rough segmentation, obtained by a fixed image thresholding. The validation of the complete segmentation algorithm was carried out on small lung nodules, identified in the ITALUNG screening trial and on small nodules of the lung image database consortium (LIDC) dataset. In fully automated mode, 217/256 (84.8%) lung nodules of ITALUNG and 139/157 (88.5%) individual marks of lung nodules of LIDC were correctly outlined and an excellent reproducibility was also observed. By using an additional interactive mode, based on a controlled manual interaction, 233/256 (91.0%) lung nodules of ITALUNG and 144/157 (91.7%) individual marks of lung nodules of LIDC were overall correctly segmented. The proposed correction method could also be usefully applied to any existent nodule segmentation algorithm for improving the segmentation quality of juxta-vascular nodules.

Dose exposure in the ITALUNG trial of lung cancer screening with low-dose CT

Few data are available on the effective dose received by participants in lung cancer screening programmes with low-dose CT (LDCT). We report the collective effective dose delivered to 1406 current or former smokers enrolled in the ITALUNG trial who completed 4 annual LDCT examinations and related further investigations including follow-up LDCT, 2-[(18)F]flu-2-deoxy-d-glucose positron emission tomography (FDG-PET) or CT-guided fine needle aspiration biopsy (FNAB). Using the air CT dose index and Monte Carlo simulations on an anthropomorphic phantom, the whole-body effective dose associated with LDCT was determined for the eight CT scanners used in the trial. A value of 7 mSv was assigned to FDG-PET while the measured mean effective dose of CT-guided FNAB was 1.5 mSv. The mean collective effective dose in the 1406 subjects ranged between 8.75 and 9.36 Sv and the mean effective dose to the single subject over 4 years was between 6.2 and 6.8 mSv (range 1.7-21.5 mSv) according to the cranial-caudal length of the LDCT volume. 77.4% of the dose was owing to annual LDCT and 22.6% to further investigations. Considering the nominal risk coefficients for stochastic effects after exposure to low-dose radiation according to the National Radiological Protection Board, International Commission on Radiological Protection (ICRP) 60, ICRP103 and Biological Effects of Ionizing Radiation VII, the mean number of radiation-induced cancers ranged between 0.12 and 0.33 per 1000 subjects. The individual effective dose to participants in a 4-year lung cancer screening programme with annual LDCT is very low and about one-third of the effective dose that is associated with natural background radiation and diagnostic radiology in the same time period.

Lung cancer screening update.

Purpose of review Lung cancer is a health problem of global proportions. Despite intensive research over many years, the prognosis is still very poor. For the surgery to be effective, tumours need to be recognized early. Computed tomography (CT) is significantly more sensitive than chest radiograph for identifying small, asymptomatic lung cancers. Although low-dose CT screening observational trials have demonstrated that survival for all tumour types and sizes detected were extremely high, there is no clear evidence that low-dose CT screening reduces deaths from lung cancer. Only the results of ongoing randomized controlled trials can reveal a real benefit of screening in terms of mortality reduction. Recent findings We summarize the protocols and the preliminary results of the lung cancer screening randomized controlled trial and the problems linked to the detection of suspected early cancer. Summary Today, we cannot already prove the ultimate mortality benefit of lung cancer screening with low-dose CT nor we can confirm that this approach is not harmful. We are waiting the final analysis of randomized controlled trials for lung cancer mortality. Even if is widely accepted that pooling data of randomized controlled trials could be of help to get powerful results in terms of mortality reduction in shorter follow-up time, this opportunity is still under evaluation.

Molecular profile in body fluids in subjects enrolled in a randomised trial for lung cancer screening: Perspectives of integrated strategies for early diagnosis

The aim of this study was to evaluate the diagnostic value of a grid of molecular genetic markers detectable in sputum and plasma samples of individuals enrolled in a lung cancer screening program with low-dose CT. Subjects enrolled in the baseline screening round of the ITALUNG (randomised) screening trial were invited to provide biological specimens for molecular analysis (1356 subjects out of 1406). We included 98 subjects in this analysis. There was a highly statistically significant difference between proportion of subjects with a negative baseline CT screening test who were positive to allelic imbalance, and those with a non-calcified nodule (NCN greater than or equal to 5mm), the reason of recall for all suspects at CT Scan (chi(2): 22.9; P<0.0001). Allelic imbalance showed good performance for screening of NCN > or = 5 mm. In subjects recalled for NCN > or = 5 mm, LOH, K-ras mutations and high levels of free plasma DNA (>5ng/ml plasma) might be important to support clinical decision making for further follow-up and repeated screening. This study, embedded in an early diagnosis randomised trial, suggests that a multi-screening approach integrating imaging technique and a biomolecular marker panel is worth of further investigation.

Operator-dependent Reproducibility of Size Measurements of Small Phantoms and Lung Nodules Examined With Low-dose Thin-section Computed Tomography

Objective:We sought to assess the reproducibility of size measurements of small lung nodules examined with low-dose thin-section computed tomography (LDTSCT). Materials and Methods:Three radiologists measured volume with a semiautomatic tool and diameters manually of 20 (equivalent diameter range, 5.3–11 mm) phantom nodules and 37 (mean diameter range, 5–8.5 mm) lung nodules in subjects undergoing LDTSCT. Results:In phantoms, the worst 95% limits of agreement (95% LA) for volume were −3.0% and 3.0% within operator and −3.1% and 2.8% between operators. The coefficient of repeatability (CR) for diameter ranged between 0.51 and 0.67 mm within operator and the 95% LA were from −0.71 to 0.71 mm between operators. In nodules, the worst intraoperator 95% LA for volume were −14.4% and 17.6% within operator and −13.1% and 14.2% between operators. The CR for diameter ranged between 0.48 and 0.73 mm within operator and the 95% LA were from −1.16 to 1.16 mm between operators. Conclusion:Operator-dependent variability of size measurements of small nodules examined with LDTSCT is not negligible and should be considered in lung cancer-screening studies.

Multimodal lung cancer screening using the ITALUNG biomarker panel and low dose computed tomography. Results of the ITALUNG biomarker study

Asymptomatic high‐risk subjects, randomized in the intervention arm of the ITALUNG trial (1,406 screened for lung cancer), were enrolled for the ITALUNG biomarker study (n = 1,356), in which samples of blood and sputum were analyzed for plasma DNA quantification (cut off 5 ng/ml), loss of heterozygosity and microsatellite instability. The ITALUNG biomarker panel (IBP) was considered positive if at least one of the two biomarkers included in the panel was positive. Subjects with and without lung cancer diagnosis at the end of the screening cycle with LDCT (n = 517) were evaluated. Out of 18 baseline screen detected lung cancer cases, 17 were IBP positive (94%). Repeat screen‐detected lung cancer cases were 18 and 12 of them positive at baseline IBP test (66%). Interval cancer cases (2‐years) and biomarker tests after a suspect Non Calcific Nodule follow‐up were investigated. The single test versus multimodal screening measures of accuracy were compared in a simulation within the screened ITALUNG intervention arm, considering screen‐detected and interval cancer cases. Sensitivity was 90% at baseline screening. Specificity was 71 and 61% for LDCT and IBP as baseline single test, and improved at 89% with multimodal, combined screening. The positive predictive value was 4.3% for LDCT at baseline and 10.6% for multimodal screening. Multimodal screening could improve the screening efficiency at baseline and strategies for future implementation are discussed. If IBP was used as primary screening test, the LDCT burden might decrease of about 60%.