American Journal of Respiratory and Critical Care Medicine

Rationale: Screening for lung cancer with low-dose spiral computed tomography (LDCT) has been shown to reduce lung cancer mortality by 20% compared with screening with chest X-ray (CXR) in the National Lung Screening Trial, but uncertainty remains concerning the efficacy of LDCT screening in a community setting.

Objectives: To explore the effect of LDCT screening on lung cancer mortality compared with no screening. Secondary endpoints included incidence, stage, and resectability rates.

Methods: Male smokers of 20+ pack-years, aged 60 to 74 years, underwent a baseline CXR and sputum cytology examination and received five screening rounds with LDCT or a yearly clinical review only in a randomized fashion.

Measurements and Main Results: A total of 1,264 subjects were enrolled in the LDCT arm and 1,186 in the control arm. Their median age was 64.0 years (interquartile range, 5), and median smoking exposure was 45.0 pack-years. The median follow-up was 8.35 years. One hundred four patients (8.23%) were diagnosed with lung cancer in the screening arm (66 by CT), 47 of whom (3.71%) had stage I disease; 72 control patients (6.07%) were diagnosed with lung cancer, with 16 (1.35%) being stage I cases. Lung cancer mortality was 543 per 100,000 person-years (95% confidence interval, 413–700) in the LDCT arm versus 544 per 100,000 person-years (95% CI, 410–709) in the control arm (hazard ratio, 0.993; 95% confidence interval, 0.688–1.433).

Conclusions: Because of its limited statistical power, the results of the DANTE (Detection And screening of early lung cancer with Novel imaging TEchnology) trial do not allow us to make a definitive statement about the efficacy of LDCT screening. However, they underline the importance of obtaining additional data from randomized trials with intervention-free reference arms before the implementation of population screening.

Scientific Knowledge on the Subject

Screening for lung cancer with low-dose spiral CT (LDCT) has been shown to reduce lung cancer mortality by 20% compared with screening with chest radiography in the National Lung Screening Trial, but uncertainty remains concerning the efficacy and cost-effectiveness of CT screening in a community setting.

What This Study Adds to the Field

In this randomized trial of LDCT screening versus annual clinical review, stage I lung cancer was detected in 47 out of 1,264 participants (3.72%) in the LDCT arm and in 16 out of 1,186 (1.35%) in the control arm. A 31% lung cancer excess rate in the LDCT arm was observed, but no stage shift was evident. Lung cancer and all-cause mortality did not differ significantly between the two arms. The results of the DANTE (Detection And screening of early lung cancer with Novel imaging TEchnology) trial underline the importance of obtaining additional data from randomized trials with intervention-free reference arms before recommending population screening with LDCT.

Localized, surgically curable stage I–II lung cancers represent only approximately 16% of clinically detected cases (1), a statistic that has remained stagnant for decades. For this reason, screening of high-risk subjects to detect lung tumors before progression to advanced disease was proposed early in the second half of the last century as a potential strategy to curtail lung cancer mortality (2).

However, the randomized trials that followed in the 1970s (35) did not demonstrate a reduction in lung cancer mortality with chest X-ray (CXR) screening compared with conventional care despite a significant increase (up to ∼50%) in stage I detection rates. Although several aspects of those studies were eventually criticized (6, 7), the subsequent large Prostate, Lung, Colorectal, and Ovarian cancer screening trial in 2011 also reported that no reduction in lung cancer mortality could be obtained with CXR screening (8). The insufficient sensitivity of CXR was the most credited explanation for such failures.

In 1999, the ELCAP (Early Lung Cancer Action Program) study showed low-dose spiral computed tomography (LDCT) to be far more sensitive than CXR for small lung nodules, with 80% of the cancers detected by LDCT being stage I (9). Indeed, 5-year survival rates of 80 to 90% have been reported in a number of uncontrolled trials for patients whose lung cancers were detected by a screening LDCT (1013). Despite the enthusiasm for such results, it was also acknowledged that more data were needed from randomized controlled trials to avoid a biased and misleading interpretation of available evidence (14). In 2001, we therefore started the DANTE study (Detection and Screening of Early Lung Cancer with Novel Imaging Technology and Molecular Assays), a randomized trial of LDCT versus clinical review at annual intervals for five rounds to explore the effect of screening with low-dose spiral CT on lung cancer mortality.

Financial considerations precluded a large trial capable of addressing the question as a stand-alone study, but we were confident that more similar trials would follow and that pooling our data with other research groups would eventually become possible.

In 2003, the large National Lung Screening Trial (NLST), which included 53,000 high-risk patients, was initiated in the United States, and in 2011 the NLST investigators reported a 20% reduction of lung cancer–specific mortality with three annual rounds of LDCT screening compared with three rounds of CXR screening (15). Several major organizations have subsequently recommended screening with LDCT for high-risk subjects under certain conditions (16, 17). However, many significant issues remained, in particular regarding the most appropriate target population (18, 19), false positives (20, 21), optimal nodule workup (2224), potential harm (25), the costs of large-scale implementation (26), and the impact on lung cancer mortality achievable in a community setting (27). The European CT screening trials collaborative group therefore recommended in 2013 that all ongoing randomized studies of LDCT screening versus usual care be continued until their natural conclusion and analyzed thoroughly (28). Here, we present and discuss the final, long-term results of the DANTE study.

The trial methodology has been reported previously and is briefly described below (29, 30).

The research was coordinated by the Humanitas Research Hospital, Milan, Italy. The study was advertised through family doctors, the media, the internet, and in-hospital boards and leaflets.

Subject recruitment began in March 2001 and ended in February 2006. The Humanitas-Gavazzeni Hospital in Bergamo and the Humanitas Oncology Center in Catania contributed to enrollment during the last year. Eligible subjects included 60- to 74-year-old male smokers or former smokers of at least 20 pack-years who had quit less than 10 years before recruitment. Subjects with severe comorbid conditions carrying a life expectancy of less than 5 years, those deemed unable to comply with the follow-up protocol for any reason, and those with a history of previous malignancy within 10 years before recruitment were ineligible.

Applicants were interviewed on the phone to assess their age, sex, and whether they were current or former smokers. Applicants were randomized if appropriate, and an appointment was made at a weekly outpatient clinic for subsequent formal enrolment. At that time, prospective participants were briefed on the study purpose and procedures and were required to give written informed consent and to fill out a detailed questionnaire on their smoking exposure, occupational and medical history, and present health condition. A structured medical interview and physical examination were conducted to verify their baseline health status, reassess eligibility in depth, and confirm enrolment.

All enrolled subjects had a baseline CXR and 3-day sputum cytology testing regardless of their allocation, but only subjects in the LDCT arm also received a baseline CT scan of the thorax on the same day.

Four subsequent yearly LDCT screening rounds were planned in the LDCT arm in addition to a more concise version of the baseline medical interview and a physical examination focused on reassessing smoking habits, recent medical history, and new signs and symptoms since the last assessment.

Control subjects underwent the same yearly clinical review only. The physician in charge could order a CXR as a first-line test in the case of respiratory complaints and/or abnormal findings. All participants were reinvited to attend annually by phone. After the last round, active follow-up through phone interviews was continued until 2012. Life status data and death certificates were requested for the entire study population from local health registries. The follow-up cut-off date was May 15, 2013.

Death certificates were cross-checked with hospital records and/or with written reports provided by the attending physicians or by the family doctor. A panel blinded to patients’ assignment reviewed the clinical cases whenever several competing causes of death were possible.

Statistical Methods

Subjects were randomized by a 1:1 scheme in blocks of four and stratified by center according to a computer-generated list supplied by the data center each week before enrolment sessions. Endpoints of the study included lung cancer mortality and all-cause mortality. Secondary endpoints included lung cancer incidence, stage at detection, and resectability rates.

A sample size of 2,400 subjects was calculated assuming a 50% mortality reduction in the LDCT arm. Sensitivity, specificity, and predictive values of the screening protocol were calculated on a per-patient basis (31). Proportions between groups were compared using the χ2 test or the Fisher’s exact test if needed; means were compared using the t test unless stated otherwise. Confidence intervals (CIs) for means and proportions were calculated by the Gaussian approximation method. Survival functions were estimated using the Kaplan-Meier method and compared using Cox regression analysis. Related hazard ratios were provided, with CIs calculated by the Wald method.

Additional details on the trial methodology are provided in the online supplement.

An outline of patient recruitment and outcomes is presented in Figure 1. Revision of the database for this final report led to the discovery of 20 duplicate registrations and two test records, so the actual number of evaluable subjects was 1,264 in the LDCT arm versus 1,186 in the control arm. As per the inclusion criteria, all subjects were male.

Age, smoking, and professional exposures were consistent between the two groups. Respiratory comorbidity was slightly more prevalent among subjects in the LDCT arm (35 vs. 31% P = 0.0321), but all other comorbid conditions were evenly distributed. By the end of the study, 1,184 (93%) subjects in the screening arm received all five CT scans (Table 1).

Table 1. Patient Characteristics

Patients enrolled, n (%)1,264 (51.59)1,186 (48.41)2,450 (100)
Current smokers, n (%)714 (56.48)681 (57.41)1,395 (56.93)
Age, yr   
 Mean (95% CI)64.6 (64.3–64.8)64.6 (64.4–64.9)64.6 (64.4–64.8)
 Median (IQR)64.0 (5)64.0 (5)64.0 (5)
 Mean (95% CI)47.3 (45.7–49.0)47.2 (45.5–49.0)47.3 (46.1–48.5)
 Median (IQR)45.0 (28.5)45.0 (32.5)45.0 (30.0)
Occupational exposure, n (%)*391 (31.33)402 (34.13)793 (32.69)
Comorbidities, n (%)   
 Respiratory446 (35.28)370 (31.20)816 (33.31)
 Hypertension456 (36.08)447 (37.69)903 (36.86)
 Cardiac159 (12.58)165 (13.91)324 (13.22)
 Peripheral vascular130 (10.28)107 (9.02)237 (9.67)
 Diabetes105 (8.31)99 (8.35)204 (8.33)
 Other452 (35.76)426 (35.92)878 (35.84)
Compliance, n (%)   
 Had ≥3 CT scans1,223 (96.76)  
 Had 5 CT scans1,184 (93.67)  
 Median follow-up, yr8.358.358.35

Definition of abbreviations: CI = confidence interval; CT = computed tomography; IQR = interquartile range; LDCT = low-dose spiral computed tomography.

Percentages are calculated based on group totals.

*Chemical industry, insulation, construction industry, metallurgy, agriculture, and mining.

P = 0.0321.

During the active phase, at least one abnormality was observed by LDCT in 471 out of 1,264 (37%) subjects in the screening arm (Table 2 and see Table E1 in the online supplement), and 355 (28%) underwent further testing, receiving in total 562 additional CT scans. Four patients in the LDCT arm underwent further investigation due to abnormal pulmonary cytology at baseline; one of these patients was diagnosed with a radiologically occult superficial squamous lung cancer.

Table 2. Abnormal Findings and Downstream Investigation Procedures

 LDCTControlAllP Value
Study subjects, n (%)1,264 (51.59)1,186 (49.41)2,450 (100) 
Reasons for further investigation, n (%)*    
 Baseline CXR (only)38 (3.20)  
 Baseline sputum4 (0.31)8 (0.34)12 (0.49) 
 Baseline LDCT169 (13.37)   
 Annual LDCT after baseline186 (14.71)   
 Annual clinical review4 (0.31)144 (12.14)  
 Symptoms31 (2.45)61 (5.14)92 (3.76) 
 Other reasons165 (13.05)192 (16.19)357 (14.57) 
 FDG-PET scan96 (7.59)17 (1.43)113 (4.61)<0.0001
Invasive procedures, n (%)    
 Any invasive procedure144 (11.39)64 (5.39)208 (8.49)<0.0001
 After screening test112 (9.65)17 (1.43)129 (5.27) 
 Surgery for lung cancer90 (7.12)31 (2.62)121 (4.94)<0.0001
 Lung cancer confirmed73 (5.78)26 (2.20)99 (4.04)<0.0001
 Number of procedures§9634130 (5.31) 
 Surgery for a benign lesion17 (1.34)5 (0.42)22 (0.9)0.0176
 Surgery for other conditions7 (0.55)2 (0.17)9 (0.37) 

Definition of abbreviations: CXR = chest X-ray; FDG-PET= 18F-fluorodeoxyglucose positron emission tomography; LDCT = low-dose spiral computed tomography.

Data were collected during the active observation period (no data available after January 2012). Data refer to single patients; percentages refer to column totals.

*Includes additional computed tomography (CT) earlier than 12-month follow-up, contrast-enhanced CT, FDG-PET, or biopsy.

Invasive procedures performed for staging purposes are not presented.

Includes bronchoscopy, percutaneous biopsy, video-assisted thoracoscopy (VATS), mediastinoscopy, or thoracotomy.

§Including repeat surgery for metachronous lung cancers.

LDCT: three mediastinoscopies, seven VATS wedge resections, and six open wedge resections. Control: two VATS biopsies, two VATS wedge resections, and one open wedge resection.

LDCT arm: one open biopsy, one extrapleural pneumonectomy for mesothelioma, two esophagectomies for cancer, one esophageal leiomyoma VATS resection, two VATS thymectomies, and one lobectomy for aspergilloma. Control: one open lung biopsy for hilar lymphoma and one VATS thymectomy.

In the same period, 38 control subjects (3%) underwent further evaluation after a baseline screening CXR, eight underwent further evaluation for abnormal sputum cytology, and 144 (12%) received a CXR after a planned clinical review. CXR obtained for such a reason prompted further investigation by a chest CT in seven control subjects, none of whom had lung cancer.

Significantly more invasive procedures of any type and more surgical procedures for potential cancer lesions were recorded in the spiral CT arm of the study (Tables 2 and E2).

The overall rate of surgical procedures that did not reveal any cancer was 17 out of 96 (17.7%) in 90 patients (18.9% of those who underwent surgery for possible lung cancer in the screening arm).

Three patients with lung cancer in the LDCT arm died postoperatively (3.3% surgical mortality): two died after lobectomy (from sudden cardiac death and suture-line failure), and one died after pneumonectomy (ARDS). One patient (3.2%) in the control arm died after pneumonectomy due to suture-line failure and ARDS. There were no deaths associated with surgical procedures for benign lesions in either arm.

Detection modality, stage, histology, and resectability rates for all lung cancer patients observed in the DANTE trial are summarized in Tables 3 and E3.

Table 3. Lung Cancer Detection Modality, Stage, and Histology

 LDCTControlAllP Value
Study subjects, n (%)1,264 (51.59)1,186 (49.41)2,450 (100) 
Total patients with LC, n (%)104 (8.23)72 (6.07)176 (7.18)0.0418
Mode of detection, n (%)    
 Baseline CXR or sputum only1*10  
 Baseline CT29 (2.29) 29 
 Follow-up CT37 (2.92)239 (1.59) 
 Symptoms/other37 (2.92)62 (5.24)99 (4.04)0.0040
 Complete resection57 (4.51)21 (1.77)78 (3.18)0.0001
Stage of primary, n (%)    
 IA31 (2.45)6 (0.50)37 (1.51)<0.0001
 IB16 (1.26)10 (0.84)26 (1.06)
 II7512 (0.49) 
 IIIA9615 (0.61) 
 IIIB8614 (0.57) 
 IV26 (2.06)33 (2.78)59 (2.41)0.2915
Histology of primary, n (%)    
 Adenocarcinoma44 (3.48)19 (1.60)63 (2.57)0.0032
  Lepidic-predominant17 (1.34)1 (0.08)18 (0.73)0.0002
  Other subtypes271845 (1.84)0.2930
 Squamous251742 (1.71)0.3510
 Non–small cell, NOS7815 (0.61) 
 Other7613 (0.53) 
 Small cell9 (0.71)6 (0.51)15 (0.61) 
 Missing§12 (0.95)16 (1.35)28 (1.14) 

Definition of abbreviations: CT = computed tomography; CXR = chest X-ray; LC = lung cancer; LDCT = low-dose spiral computed tomography; NOS = not otherwise specified.

Data refer to single patients. Percentages refer to column totals. Invasive procedures performed for staging purposes are not presented. Patients for whom the data are missing (five patients with LDCT and four control subjects) and one patient in each group with a contralateral radiologically occult tumor that was not resected are counted as incomplete resections.

*Radiologically occult; detected by baseline sputum examination.

One patient inappropriately enrolled despite having already had stage IV lung cancer diagnosed elsewhere.

Two control patients were diagnosed by CT due to breach of protocol.

§Diagnosis established clinically or obtained by a death certificate.

As of May 15, 2013, 104 patients in the LDCT group (8.23%) had developed 118 lung cancers, including four patients with two synchronous primary tumors and eight patients with metachronous second primaries. Overall, 66 of 104 patients (63%) were diagnosed with lung cancer by a screening CT, and one patient was diagnosed with lung cancer by sputum cytology. Thirteen patients were diagnosed with lung cancer due to symptoms between two screening rounds, two patients who did not comply with the screening protocol were diagnosed for other reasons within 5 years of recruitment, and two patients were diagnosed for other reasons within 1 year from the final screening round. Finally, 20 patients were diagnosed more than 1 year after their final negative CT scan. By intention-to-treat analysis, the sensitivity of the screening protocol for primary lung cancer detection during the active phase was therefore 0.7952 (95% CI, 0.7716–0.8169), and its negative predictive value was 0.9813 (95% CI, 0.9718–0.9878) (Table E4).

Forty-two (63.6%) cases of CT-detected lung cancer were stage I disease, as opposed to only four (10.5%) of those detected for any other reason. By comparison, 72 patients in the control group (5.98%) were diagnosed with 75 lung cancers by the end of the study, including one patient with a radiologically occult synchronous squamous cancer and one patient who developed two subsequent metachronous cancers (both were successfully resected). Ten out of 72 (14%) patients were diagnosed with lung cancer by CXR and/or sputum at baseline, three (4%) were detected clinically during a scheduled annual review, and 59 (84%) were detected due to symptoms or other reasons, including two patients who received a CT scan inappropriately (one due to an error in allocation and one who received a CT scan at another institution).

In the screening arm, significantly fewer patients were detected with lung cancer for any reason other than a screening LDCT compared with lung cancer patients in the control arm detected for any reason other than a baseline chest radiograph; additionally, significantly more patients with lung cancer were amenable to complete surgical resection in the LDCT group than in the control group (Tables 3 and E3).

A significantly higher number and proportion of patients with stage IA–IB primary lung cancer was observed the spiral CT arm than in the control arm (47 vs. 16; P = 0.0002), whereas patients with stage II–IV lung cancer accounted for 50 cases in each arm. The distribution of all histological types was similar in the two study arms, with the exception of lepidic–predominant adenocarcinomas (Table 3).

In 19 patients with LDCT, definitive diagnosis and treatment were delayed 12 to 91 months after the lesion(s) became detectable by CT for the following reasons: small size (n = 3), ground-glass nodules (n = 6), multiple indeterminate lesions (n = 2), missed or misinterpreted in the previous CT scan (n = 5), and patient noncompliance with our recommendations (n = 3).

As retrospectively determined, 14 such patients were likely to have stage I disease at the outset, five of whom eventually progressed while being observed. Three such patients died of lung cancer; in one patient the lesion had been misinterpreted as benign, in one patient it had been missed, and one patient refused further investigation until accelerated progression occurred 8 years later. Including the above patients, 27 out of 66 patients (41%) detected by a screening CT and 32 out of 38 (84%) cases detected for any other reason died of lung cancer in the LDCT arm.

Active follow-up was terminated in February 2012, and vital status information as of May 15, 2013 was obtained through health registries for the whole study population, reaching a median follow-up of 8.35 years.

Death certificates could be cross-verified in 279 out of 356 cases (78%): 105 out of 114 (91%) lung cancer deaths, 90 out of 113 (80%) nonpulmonary cancer deaths, and 84 out of 127 (76%) noncancer deaths. In the remaining cases, the cause of death was known through death certificates alone or remained unknown in two subjects (Table 4).

Table 4. Lung Cancer–Specific and All-Cause Mortality Rates (per 100,000 Person-Years)

Study subjects, n (%)1,264 (51.59)1,186 (49.41)2,450 (100)
FU, person-years10,87510,10420,979
Cause of death, n (%)   
 Cancer of the lung59 (4.66)55 (4.64)114 (4.65)
 Cancer of other organs5459 
 Nonneoplastic disease6562 
Total deaths180 (14.24)176 (14.84)356 (14.53)
Lung cancer mortality (95% CI)543 (413–700)544 (410–709)543 (448–653)
All-cause mortality (95% CI)1,655 (1,422–1,916)1,742 (1,494–2,019)1,697 (1,525–1,883)

Definition of abbreviations: CI = confidence interval; FU = follow-up; LDCT = low-dose spiral computed tomography.

*One patient died of disseminated cancer of unknown origin, and one patient died of unknown causes in a foreign country.

In the LDCT arm, the lung cancer–specific mortality rate was 543 per 100,000 person-years (95% CI, 413–700) versus 544 per 100,000 person-years (95% CI, 410–709) in the control arm (hazard ratio [HR], 0.993; 95% CI, 0.688–1.433), and all-cause mortality rate was 1,655 per 100,000 person-years (95% CI, 1,422–1,916) versus 1,742 per 100,000 person-years (95% CI, 1,494–2,019) in the control arm (HR, 0.947; 95% CI, 0.769–1.165) (Figures 2 and 3).

In 2001, the DANTE trial began enrolling patients in a randomized fashion with the aim of exploring whether LDCT screening could reduce lung cancer mortality compared with no screening. Several other groups in Europe eventually started their own randomized LDCT screening trials, all sharing the same methodology of comparing LDCT screening with no screening (3237). DANTE, the first and smallest of these trials, holds several distinctive features: it had a unique control regimen, only male subjects were eligible, and a lower age limit of 60 years was chosen to maximize the efficiency of screening.

The two arms of the trial appear well balanced except for a slightly higher prevalence of clinically detected respiratory comorbidity among subjects in the LDCT arm. In the LDCT arm of the DANTE trial, recalls, false positives, and stage I disease detection rate are comparable with those in the other European randomized trials (28) and with the LDCT arm of the NLST (15); however, the proportion of subjects diagnosed with lung cancer is the highest among all trials performed so far (Table 5).

Table 5. Detection Rates and Mortality Data in Selected Lung Cancer Screening Trials

    Lung Cancers*LDCT DetectedStage IDied, Lung Cancer
Study (Reference[s])GroupNAge (yr)n%n%n%FUn%
NELSON (22, 49)LDCT7,91550–752112.672002.531481.87
ITALung (34, 50)LDCT1,40655–69402.84382.7231.64
 Usual1,593 00    
DLCST (32, 47)LDCT2,05250–75703.41693.36472.294.81150.73
 Usual2,052 241.17  50.244.81110.54
MILD (37)LDCT11,190≥50342.86292.44181.514.4121.01
 LDCT21,186 252.11201.69141.18 60.51
 Usual1,723 201.16   4.470.41
 Clinical1,186 726.07100.84161.358.35554.64
NLST (15)LDCT26,30955–741,0604.036492.474001.526.53561.35
 CXR26,035 9413.612791.071310.56.54431.70
PLCO (8)§CXR77,44555–741,6962.193070.44620.611.91,2131.57
 Usual77,456 1,6202.093740.4811.91,2301.59
MLP (3, 6)CXR4,618≥452064.46901.95681.4771222.64
 Usual4,593 1603.48310.6771152.50

Definition of abbreviations: CXR = chest X-ray; DANTE = Detection And screening of early lung cancer with Novel imaging TEchnology; DLCST = Danish Lung Cancer Screening Trial; FU = follow-up; LDCT = low-dose spiral computed tomography; MILD = Multicentric Italian Lung Detection trial; MLP = Mayo Lung Project; NELSON = Dutch-Belgian Randomized Lung Cancer Screening Trial (Dutch acronym); NLST = National Lung Screening Trial; PLCO = Prostate, Lung, Colorectal, Ovary cancer screening trial.

Data reported on a per-patient basis. Percentages refer to entire study populations.

*Nonscreen-detected cases include interval cases and cases detected for any reason more than 1 yr after the last screening round. Interval cases are defined as non–screening-detected cases occurring within 1 yr of the previous or last negative screening computed tomography.

Median follow-up in years.

In the MILD trial, LDCT1 and LDCT2 indicate annual and biennial screening.

§PLCO and MLP data are included as a reference term for the control arm of the NLST.

A higher rate of surgical procedures (7%) and of surgical biopsies for benign lesions (1.34%) also occurred in the DANTE trial, although only six patients (0.47%) had a thoracotomy for such a reason. Early during the trial, video-assisted thoracoscopic biopsies for undetermined nodules were indeed more commonly performed; however, selection factors may in part account for such results in the DANTE cohort, where the median age of participants was 64 years. More false-positive findings, together with an increased lung cancer detection rate, were also reported for the Medicare-eligible (65-yr-old and above) subset of NLST participants (38).

In the DANTE study, patients with both early and advanced disease were increasingly detected in the LDCT arm after a drop after the baseline screen (see Figure E1 in the online supplement), and in the end no stage shift could be observed. Lung cancer–specific and all-cause mortality were unfortunately similar in the screening and in the control arm (Figures 2 and 3).

Thirty-two more lung cancer patients were diagnosed in the screening arm compared with the control arm, representing a lung cancer excess rate of 30.76% in the face of an unchanged mortality rate, indicating some degree of overdiagnosis.

There may be several reasons why the positive results of the NLST trial could not be replicated in the DANTE study. Sample size was a known limitation at the outset, but rather than yet another (even large) observational trial, we opted for a small, randomized study, choosing a large effect size as an endpoint based on optimistic assumptions. DANTE is therefore an inconclusive study. Second, a borderline interaction between sex- and lung-cancer–specific mortality, with greater benefit expected for female patients, has been reported (39) in a recent post hoc analysis of the NLST data. In our study, only male patients were enrolled, as in all earlier screening trials of CXR screening versus standard care, which was our only comparison when we started the DANTE trial. Our eligibility criteria might therefore have reduced the ability of this study to detect a small mortality advantage in favor of LDCT screening. Third, a baseline CXR and sputum examination and a yearly clinical review were offered to all to attract potential participants. It was anticipated that this control regimen would further limit the power of the study, and we acknowledged that it would not fully reflect what is likely to occur in the community setting. Nevertheless, it was also believed that media pressure in favor of LDCT screening and competition with neighbor institutions would otherwise make recruitment into our randomized study very difficult and that the impact of this regimen in the control arm would be modest, as our data show (Tables 2 and 3).

Our disappointing results might also be due to the low sensitivity of the screening protocol. Multidetector scanners and workstations became available after 2003 and were only used for follow-up CT scans. In addition, a 3-mm reconstruction interval, 5-mm slice thickness, and two-dimensional evaluations were used for nodule assessment, whereas in most major trials, 0.7- to 2.5-mm reconstruction intervals and 1- to 3-mm slice thickness were adopted, and in several cases, volumetric software was used (15, 24, 27, 32, 33, 35, 40, 41). Indeed, the proportion of cancers that escaped detection by LDCT during the active phase of the study is higher than in all other trials (Table 5). Nevertheless, 47 out of 1,264 screened subjects (3.72%) were also diagnosed with stage I lung cancer by CT in the DANTE LDCT arm; therefore, stage I disease was also proportionally intercepted in the screened population much more frequently than in all other randomized trials (Table 5) and in major observational studies (10, 11, 13, 23, 42), suggesting that our high “miss rate” may not be due to low sensitivity alone.

Issues related to the evaluation of nodules might have contributed to decreasing the effectiveness of intervention in the LDCT arm because definitive diagnosis or treatment were delayed in 19 patients, and 5 (9.6%) out of 52 patients with stage I disease (five of whom were retrospectively identified) progressed while being observed. However, false negatives (i.e., lung cancer nodules that were either misinterpreted as benign or missed and eventually progressed beyond stage I) have occurred with similar or greater frequency (8–17%) in other major screening trials as well (4244). Such data are not yet available for the NLST trial.

Surgical mortality in the DANTE trial was 3.3%, whereas it was only 1% in the NLST. Because advanced age, male sex, and comorbidity negatively affect postoperative mortality in lung cancer surgery (45), case selection may have contributed to our less favorable results, which, however, are close to the 3.4% surgical mortality in the U.S. National Cancer Database (46).

Besides the NLST, three more randomized trials of lung cancer screening with LDCT have so far produced mortality data: the Danish Lung Cancer Screening Trial (47), the Multicentric Italian Lung Cancer Detection (MILD) trial (37), and DANTE. Although these studies are far smaller than the NLST, they all compared LDCT screening with conventional care or, as in DANTE, with something closely approximating it. In all three studies, a significant excess rate (30–66%) of lung cancer detection by CT was observed (in the NLST, it was only 11%), and unfortunately none of them was able to demonstrate a stage shift or any mortality advantage with CT screening.

The results of DANTE also suggest that aggressive cancers (that escape detection by LDCT) may appear with increasing frequency as the screened population gradually grows older and that the relative proportions of indolent, moderately progressive (suitable for early detection), or highly aggressive cancers in a given population may largely account for the results of LDCT screening rather than test sensitivity for small nodules. Even though the NLST was an outstanding trial, based on which the Centers for Medicare and Medicaid Services has finally approved financial coverage for LDCT screening in the United States (48), there is still some concern, at least in Europe (28), as to what extent it will eventually be possible to replicate those positive results in a community setting.

Given the limited statistical power of the DANTE trial, our data do not allow making a definitive statement about whether or not LDCT screening is effective in reducing lung cancer mortality. Yet such results suggest that additional information should be obtained from all randomized trials of LDCT screening for lung cancer that use intervention-free reference arms, in particular the NELSON study (44), and thoroughly evaluated before population screening can be recommended in Europe. Pooled analyses of European studies will include 37,000 subjects and will hopefully be able to provide the answers of paramount importance that are still needed concerning lung cancer screening with LDCT.

The authors thank Dr. Emanuela Morenghi for kind advice and suggestions; Dr. Nanda Horeweg and Dr. Prof. Harry De Koning for providing NELSON data not available in previous publications; Anika Giannattasio, Natascia Cazzarò, and the staff of the Medical Director Office of the Humanitas Hospital for support in retrieving vital status data; and Isabella Quarto, Vito De Giorgi, Tiziana Di Caprio, Giampaolo Muraro, Danilo Rossetti, and Adriano Nasti for administrative and technical support. The authors also thank thank the following persons for their assistance in retrieving health records and registry data: Tiziana Codazzi, Elena Bertocchi, and Anna Maghini, Lombardy Cancer Registry, Milan; Dr. Giovanna Tagliabue, Lombardy Cancer Registry, Istituto Nazionale Tumori, Milan; Dr. Ugo Pastorino, Istituto Nazionale Tumori, Milan; Dr. Cesare Fratti, Epidemiology Service, Pavia; Dr. Mariangela Autelitano and Dr. Luigi Bisanti, Central Epidemiology Service, Milan; Dr. Antonio G. Russo and Rosalba Distefano, Epidemiology Service, Milan Area 1; Dr. Maurizio Montanelli and Maurizio Bonaccolto, Epidemiology Service, Milan Area 2; Dr. Luca Cavalieri d'Oro, Epidemiology Service, Monza; Dr. Giuseppe Sampietro, Epidemiology Service, Bergamo; Dr. Alessandro Gatti, Dr. Cinzia Gasparotti, and Dr. Michele Magoni, Spedali Civili Brescia; Dr. Domenico Bonarrigo, Epidemiology Service, Varese; Dr. Annamaria Belloni and Dr. Eva Rossetti, Epidemiology Service, Lodi; Dr. Roberta Baldi and Dr. Elisa Raggio, Epidemiology Service, La Spezia; Dr. Elisabetta Borciani, Epidemiology Service, Piacenza; Dr. Lucio Bomben, Epidemiology Service, Pordenone; Dr. Sabrina Bizzoco, Epidemiology Service, Cremona; Dr. Simonetta Santus and Dr. Giorgio Steri, Epidemiology Service, Cagliari; Dr. Francesca Picciotti, Epidemiology Service, San Benedetto del Tronto (AP); Dr. Angelo Di Leo and Dr. Simone Anderini, Massa Carrara Hospital; Dr. Massimiliano Casati, Vimercate Hospital; Dr. Barbara Conti, Treviglio Hospital; Dr. Camillo Gerosa, San Carlo Hospital, Milan; Dr. Giuseppe Beltramo, Centro Diagnostico Italiano, Milano; Dr. Alberto Mainini, Dr. John Lovisolo, and Dr. Claudio Verusio, Busto Arsizio Hospital; Dr. Giulio Orlandoni, San Matteo Hospital, Pavia; Dr. Fabrizio Parente, General Hospital, Lecco; Dr. Alessandro Gronchi, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan; Dr. Enzo Gregoli, Vimodrone; and Dr. Giambattista Botticini, Spedali Civili, Brescia. Finally, the authors thank Ilaria Malvezzi and Ezio Canetoli of the Italian Association for the Fight against Cancer (Lega Italiana per la Lotta contro i Tumori)–Milan Section for administrative work and promotional support in favor of the DANTE trial project.

Members of the Dante Study Group

Thoracic Surgery Department, Istituto Clinico Humanitas, Rozzano (Milano), Italy: Marco Alloisio, M.D., Martina Andresi, M.D., Edoardo Bottoni, M.D., Umberto Cariboni, M.D., Valentina Errico, M.D., Giorgio Ferraroli, M.D., Maurizio Infante, M.D., Francesco Inzirillo, M.D., Diego Ruzzante, M.D., Alberto Testori, M.D., and Emanuele Voulaz, M.D. Radiology Department, Istituto Clinico Humanitas, Rozzano (Milano), Italy: Luca Balzarini, M.D., Giorgio Brambilla, M.D., Sara Imparato, M.D., Fabio Lutman, M.D., Vittorio Pedicini, M.D., Dario Poretti, M.D., and Pasquala Ragucci Manuel Profili, M.D. Thoracic Surgery Department, Humanitas-Gavazzeni, Bergamo, Italy: Giuseppe Chiesa, M.D., Giovanni Guanella Alberto Meroni, M.D., Eliseo Passera, M.D., and Adriano Rizzi, M.D. Radiology Department, Humanitas-Gavazzeni, Bergamo, Italy: Enzo Angeli, M.D., Emanuela Torda, M.D., and Alessandro Zanello, M.D. Radiology Department, Humanitas–Catania Oncology Center, Italy: Aranzulla Giuseppe, M.D. Oncology Department, Humanitas–Catania Oncology Center (Centro Catanese di Oncologia), Catania, Italy: Michele Caruso, M.D., and Maurizio Chiarenza, M.D. Pathology Department, Istituto Clinico Humanitas, Rozzano (Milano), Italy: Ekaterina Barishnykova, D.Sc., Paolo Bianchi, M.D., Ph.D., Anna Destro, Ph.D., and Massimo Roncalli, M.D., Ph.D. Nuclear Medicine Department, Istituto Clinico Humanitas, Rozzano (Milano), Italy: Arturo Chiti, M.D., and Marcello Rodari, M.D. Medical Oncology Department, Istituto Clinico Humanitas, Rozzano (Milano), Italy: Raffaele Cavina, M.D., Giovanna Finocchiaro, M.D., Armando Santoro, M.D., and Luca Toschi, M.D. Radiation Oncology Department, Istituto Clinico Humanitas, Rozzano (Milano), Italy: Piera Navarria, M.D., and Marta Scorsetti, M.D. Pulmonology and Internal Medicine Department, Istituto Clinico Humanitas, Rozzano (Milano), Italy: Michele Ciccarelli, M.D., and Francesca Puggioni, M.D. Pulmonology and Internal Medicine Department, Ospedale C. Cantù, Abbiategrasso (Milano), Italy: Arnaldo Alessandrini, M.D. Clinical Research Department, Istituto Clinico Humanitas, Rozzano (Milano), Italy: Michele Tedeschi, M.D., and Emanuela Morenghi, M.D. Consultant Statistician: Silvio Cavuto, D.Sc.

1. National Cancer InstituteSEER stat fact sheets: lung and bronchus cancer. Bethesda, MD: National Cancer Institute; 2012.
2. Brett GZ. The value of lung cancer detection by six-monthly chest radiographs. Thorax 1968;23:414420.
3. Fontana RS, Sanderson DR, Woolner LB, Taylor WF, Miller WE, Muhm JR, Bernatz PE, Payne WS, Pairolero PC, Bergstralh EJ. Screening for lung cancer: a critique of the Mayo Lung Project. Cancer 1991;67(4 Suppl):11551164.
4. Marcus PM, Bergstralh EJ, Zweig MH, Harris A, Offord KP, Fontana RS. Extended lung cancer incidence follow-up in the Mayo Lung Project and overdiagnosis. J Natl Cancer Inst 2006;98:748756.
5. Kubík AK, Parkin DM, Zatloukal P. Czech study on lung cancer screening: post-trial follow-up of lung cancer deaths up to year 15 since enrollment. Cancer 2000;89(11 Suppl)23632368.
6. Flehinger BJ, Kimmel M, Polyak T, Melamed MR. Screening for lung cancer: the Mayo Lung Project revisited. Cancer 1993;72:15731580.
7. Strauss GM, Gleason RE, Sugarbaker DJ. Screening for lung cancer: another look; a different view. Chest 1997;111:754768.
8. Oken MM, Hocking WG, Kvale PA, Andriole GL, Buys SS, Church TR, Crawford ED, Fouad MN, Isaacs C, Reding DJ, et al.; PLCO Project Team. Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial. JAMA 2011;306:18651873.
9. Henschke CI, McCauley DI, Yankelevitz DF, Naidich DP, McGuinness G, Miettinen OS, Libby DM, Pasmantier MW, Koizumi J, Altorki NK, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999;354:99105.
10. Henschke CI, Yankelevitz DF, Libby DM, Pasmantier MW, Smith JP, Miettinen OS; International Early Lung Cancer Action Program Investigators. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006;355:17631771.
11. Wilson DO, Weissfeld JL, Fuhrman CR, Fisher SN, Balogh P, Landreneau RJ, Luketich JD, Siegfried JM. The Pittsburgh Lung Screening Study (PLuSS): outcomes within 3 years of a first computed tomography scan. Am J Respir Crit Care Med 2008;178:956961.
12. Sone S, Nakayama T, Honda T, Tsushima K, Li F, Haniuda M, Takahashi Y, Suzuki T, Yamanda T, Kondo R, et al. Long-term follow-up study of a population-based 1996-1998 mass screening programme for lung cancer using mobile low-dose spiral computed tomography. Lung Cancer 2007;58:329341.
13. Lindell RM, Hartman TE, Swensen SJ, Jett JR, Midthun DE, Tazelaar HD, Mandrekar JN. Five-year lung cancer screening experience: CT appearance, growth rate, location, and histologic features of 61 lung cancers. Radiology 2007;242:555562.
14. Patz EF Jr, Goodman PC, Bepler G. Screening for lung cancer. N Engl J Med 2000;343:16271633.
15. Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, Gareen IF, Gatsonis C, Marcus PM, Sicks JD; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395409.
16. Moyer VA; U.S. Preventive Services Task Force. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014;160:330338.
17. Vansteenkiste J, Crinò L, Dooms C, Douillard JY, Faivre-Finn C, Lim E, Rocco G, Senan S, Van Schil P, Veronesi G, et al.; Panel Members; Panel Members. 2nd ESMO Consensus Conference on Lung Cancer: early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up. Ann Oncol 2014;25:14621474.
18. Kovalchik SA, Tammemagi M, Berg CD, Caporaso NE, Riley TL, Korch M, Silvestri GA, Chaturvedi AK, Katki HA. Targeting of low-dose CT screening according to the risk of lung-cancer death. N Engl J Med 2013;369:245254.
19. de Koning HJ, Meza R, Plevritis SK, ten Haaf K, Munshi VN, Jeon J, Erdogan SA, Kong CY, Han SS, van Rosmalen J, et al. Benefits and harms of computed tomography lung cancer screening strategies: a comparative modeling study for the U.S. Preventive Services Task Force. Ann Intern Med 2014;160:311320.
20. Yip R, Henschke CI, Yankelevitz DF, Smith JP. CT screening for lung cancer: alternative definitions of positive test result based on the national lung screening trial and international early lung cancer action program databases. Radiology 2014;273:591596.
21. McWilliams A, Tammemagi MC, Mayo JR, Roberts H, Liu G, Soghrati K, Yasufuku K, Martel S, Laberge F, Gingras M, et al. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med 2013;369:910919.
22. Horeweg N, van der Aalst CM, Vliegenthart R, Zhao Y, Xie X, Scholten ET, Mali W, Thunnissen E, Weenink C, Groen HJ, et al. Volumetric computed tomography screening for lung cancer: three rounds of the NELSON trial. Eur Respir J 2013;42:16591667.
23. Menezes RJ, Roberts HC, Paul NS, McGregor M, Chung TB, Patsios D, Weisbrod G, Herman S, Pereira A, McGregor A, et al. Lung cancer screening using low-dose computed tomography in at-risk individuals: the Toronto experience. Lung Cancer 2010;67:177183.
24. Ashraf H, Dirksen A, Loft A, Bertelsen AK, Bach KS, Hansen H, Pedersen JH, Mortensen J. Combined use of positron emission tomography and volume doubling time in lung cancer screening with low-dose CT scanning. Thorax 2011;66:315319.
25. Menezes R, Roberts H. Lung cancer screening using low-dose computed tomography: keeping participants out of Harm’s way. J Thorac Oncol 2014;9:912913.
26. Black WC, Gareen IF, Soneji SS, Sicks JD, Keeler EB, Aberle DR, Naeim A, Church TR, Silvestri GA, Gorelick J, et al.; National Lung Screening Trial Research Team. Cost-effectiveness of ct screening in the national lung screening trial. N Engl J Med 2014;371:17931802.
27. Bach PB, Mirkin JN, Oliver TK, Azzoli CG, Berry DA, Brawley OW, Byers T, Colditz GA, Gould MK, Jett JR, et al. Benefits and harms of CT screening for lung cancer: a systematic review. JAMA 2012;307:24182429.
28. Field JK, van Klaveren R, Pedersen JH, Pastorino U, Paci E, Becker N, Infante M, Oudkerk M, de Koning HJ; European Randomized Screening Trial Group. European randomized lung cancer screening trials: post NLST. J Surg Oncol 2013;108:280286.
29. Infante M, Cavuto S, Lutman FR, Brambilla G, Chiesa G, Ceresoli G, Passera E, Angeli E, Chiarenza M, Aranzulla G, et al.; DANTE Study Group. A randomized study of lung cancer screening with spiral computed tomography: three-year results from the DANTE trial. Am J Respir Crit Care Med 2009;180:445453.
30. Infante M, Lutman FR, Cavuto S, Brambilla G, Chiesa G, Passera E, Angeli E, Chiarenza M, Aranzulla G, Cariboni U, et al.; DANTE Study Group. Lung cancer screening with spiral CT: baseline results of the randomized DANTE trial. Lung Cancer 2008;59:355363.
31. Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med 1998;17:857872.
32. Pedersen JH, Ashraf H, Dirksen A, Bach K, Hansen H, Toennesen P, Thorsen H, Brodersen J, Skov BG, Døssing M, et al. The Danish randomized lung cancer CT screening trial: overall design and results of the prevalence round. J Thorac Oncol 2009;4:608614.
33. Becker N, Motsch E, Gross ML, Eigentopf A, Heussel CP, Dienemann H, Schnabel PA, Pilz L, Eichinger M, Optazaite DE, et al. Randomized study on early detection of lung cancer with MSCT in Germany: study design and results of the first screening round. J Cancer Res Clin Oncol 2012;138:14751486.
34. Lopes Pegna A, Picozzi G, Mascalchi M, Maria Carozzi F, Carrozzi L, Comin C, Spinelli C, Falaschi F, Grazzini M, Innocenti F, et al.; ITALUNG Study Research Group. Design, recruitment and baseline results of the ITALUNG trial for lung cancer screening with low-dose CT. Lung Cancer 2009;64:3440.
35. Xu DM, Gietema H, de Koning H, Vernhout R, Nackaerts K, Prokop M, Weenink C, Lammers JW, Groen H, Oudkerk M, et al. Nodule management protocol of the NELSON randomised lung cancer screening trial. Lung Cancer 2006;54:177184.
36. Baldwin DR, Duffy SW, Wald NJ, Page R, Hansell DM, Field JK. UK Lung Screen (UKLS) nodule management protocol: modelling of a single screen randomised controlled trial of low-dose CT screening for lung cancer. Thorax 2011;66:308313.
37. Pastorino U, Rossi M, Rosato V, Marchianò A, Sverzellati N, Morosi C, Fabbri A, Galeone C, Negri E, Sozzi G, et al. Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial. Eur J Cancer Prev 2012;21:308315.
38. Pinsky PF, Gierada DS, Hocking W, Patz EF Jr, Kramer BS. National Lung Screening Trial findings by age: Medicare-eligible versus under-65 population. Ann Intern Med 2014;161:627633.
39. Pinsky PF, Church TR, Izmirlian G, Kramer BS. The National Lung Screening Trial: results stratified by demographics, smoking history, and lung cancer histology. Cancer 2013;119:39763983.
40. Veronesi G, Bellomi M, Mulshine JL, Pelosi G, Scanagatta P, Paganelli G, Maisonneuve P, Preda L, Leo F, Bertolotti R, et al. Lung cancer screening with low-dose computed tomography: a non-invasive diagnostic protocol for baseline lung nodules. Lung Cancer 2008;61:340349.
41. Henschke CI, Yankelevitz DF, Yip R, Reeves AP, Farooqi A, Xu D, Smith JP, Libby DM, Pasmantier MW, Miettinen OS; Writing Committee for the I-ELCAP Investigators. Lung cancers diagnosed at annual CT screening: volume doubling times. Radiology 2012;263:578583.
42. Veronesi G, Maisonneuve P, Spaggiari L, Rampinelli C, Pardolesi A, Bertolotti R, Filippi N, Bellomi M. Diagnostic performance of low-dose computed tomography screening for lung cancer over five years. J Thorac Oncol 2014;9:935939.
43. Xu DM, Yip R, Smith JP, Yankelevitz DF, Henschke CI; I-ELCAP Investigators. Retrospective review of lung cancers diagnosed in annual rounds of CT screening. AJR Am J Roentgenol 2014;203:965972.
44. Horeweg N, Scholten ET, de Jong PA, van der Aalst CM, Weenink C, Lammers JW, Nackaerts K, Vliegenthart R, ten Haaf K, Yousaf-Khan UA, et al. Detection of lung cancer through low-dose CT screening (NELSON): a prespecified analysis of screening test performance and interval cancers. Lancet Oncol 2014;15:13421350.
45. Kozower BD, Sheng S, O'Brien SM, Liptay MJ, Lau CL, Jones DR, Shahian DM, Wright CDSTS database risk models: predictors of mortality and major morbidity for lung cancer resection. Ann Thorac Surg 2010;90:875881; discussion 881–873.
46. Rosen JE, Hancock JG, Kim AW, Detterbeck FC, Boffa DJ. Predictors of mortality after surgical management of lung cancer in the National Cancer Database. Ann Thorac Surg 2014;98:19531960.
47. Saghir Z, Dirksen A, Ashraf H, Bach KS, Brodersen J, Clementsen PF, Døssing M, Hansen H, Kofoed KF, Larsen KR, et al. 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. Thorax 2012;67:296301.
48. Centers for Medicare and Medicaid Services. Decision memo for screening for lung cancer with low dose computed tomography [accessed 2015 Feb 9]. Available from:
49. van Klaveren RJ, Oudkerk M, Prokop M, Scholten ET, Nackaerts K, Vernhout R, van Iersel CA, van den Bergh KA, van ’t Westeinde S, van der Aalst C, et al. Management of lung nodules detected by volume CT scanning. N Engl J Med 2009;361:22212229.
50. Lopes Pegna A, Picozzi G, Falaschi F, Carrozzi L, Falchini M, Carozzi FM, Pistelli F, Comin C, Deliperi A, Grazzini M, et al.; ITALUNG Study Research Group. Four-year results of low-dose CT screening and nodule management in the ITALUNG trial. J Thorac Oncol 2013;8:866875.
Correspondence and requests for reprints should be addressed to Maurizio Infante, M.D., Thoracic Surgery Department, Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano (Milan), Italy. E-mail:

*A complete list of members may be found before the beginning of the References.

Supported by the Italian Association for the Fight against Cancer (Lega Italiana per la Lotta contro i Tumori)–Milan Section, the Cariplo Foundation, and the Italian Association for the Fight against Cancer (Lega Italiana per la Lotta contro i Tumori), Rome, Italy.

In loving memory of Prof. Gianni Ravasi.

Author Contributions: M.I. and S.C.: conception, design, and implementation of the study; collection, analysis, and interpretation of data; and drafting of the manuscript for important intellectual content. F.R.L. and G.B.: significant contribution to the implementation of the study, collection of data, and drafting of the manuscript for important intellectual content. E.P., M. Chiarenza, G.C., E.A., G.A., A.C., M.S., P.N., R.C., and E.B.: significant contribution to the implementation of the study, collection of data, evaluation of clinical cases, and critical review of the manuscript. M. Ciccarelli: significant contribution to the collection of data, evaluation of clinical cases, and critical review of the manuscript. M.R. and A.D.: significant contribution to the implementation of the study, collection of data, evaluation of the data, and critical review of the manuscript. E.V., V.E., and G. Ferraroli: significant contribution to the implementation of the study, collection of data, and critical review of the manuscript. G. Finocchiaro and L.T.: significant contribution to the collection of data and critical review of the manuscript. A.S.: significant contribution to the evaluation of the data and drafting of the manuscript for important intellectual content. M.A.: significant contribution to the implementation of the study, collection of data, evaluation of data, and critical review of the manuscript.

This article has an online supplement, which is accessible from this issue's table of contents at

Originally Published in Press as DOI: 10.1164/rccm.201408-1475OC on March 11, 2015

Author disclosures are available with the text of this article at

Comments Post a Comment

New User Registration

Not Yet Registered?
Benefits of Registration Include:
 •  A Unique User Profile that will allow you to manage your current subscriptions (including online access)
 •  The ability to create favorites lists down to the article level
 •  The ability to customize email alerts to receive specific notifications about the topics you care most about and special offers
American Journal of Respiratory and Critical Care Medicine

Click to see any corrections or updates and to confirm this is the authentic version of record