The MILD project is a randomized lung cancer screening trial whose primary aim is to evaluate the impact on mortality of early lung cancer detection through LDCT (low-dose computed tomography) in 2 groups: a control group undergoing a program of primary prevention with pulmonary function test evaluation and a group undergoing a periodic spiral CT associated with primary prevention and pulmonary function test evaluation. This last one is also randomized in two arms: yearly low-dose CT vs CT every 2 years.

MILD trial comprehensive design combines for the first time primary prevention (smoking cessation) with early detection, and molecular risk profile through assessing the value of blood and tissue biomarkers.

The preliminary results of the pilot study on early lung cancer detection by spiral CT and PET launched in Milan in 2000 and published in the Lancet in 2003 showed a positive outcome, confirming the essential safety of spiral CT and a high proportion (95%) of complete resections and stage I disease (77%). However, the results at six years revealed a different picture, with an increasing number of advanced lung cancers being detected from the third to the fifth year, and no evidence of significant mortality reduction for lung cancer by annual CT monitoring of our cohort of heavy smokers. These data were confirmed by a meta-analysis conducted by two senior epidemiologists of Memorial Sloan-Kettering Cancer Center, Peter Bach and Colin Begg, of the three concurrent single arms studies: IEO/INT, Mayo Clinic and Lee Moffitt Cancer Center trials. Such a meta-analysis demonstrated that annual CT increases by 3-4 fold the number of detected lung cancers but does not reduce the incidence of advanced and potentially lethal disease. These data strengthen the validity of the plan to continue clinical research on early lung cancer detection by a randomized controlled study in 2005. In fact there is an overwhelming consensus in the International scientific community that uncontrolled observational studies will not be able to provide further knowledge in this field. Only large randomised controlled clinical trial will hopefully provide convincing evidence on the magnitude of the benefit achievable by early detection programmes with spiral CT in heavy smokers.

In 2005, with the support of AIRC (Italian Association for Cancer Research) and the Ministry of Health, the investigators launched the new INT (National Institute of Tumors) randomized controlled study, named Multicentric Italian Lung Detection trial (MILD), combining smoking cessation with early diagnosis and biologic assessment of individual risk of lung cancer.

The initial goal at INT was to recruit 10,000 subjects from 10 different Italian centres by the end of 2008. This task has proven unfeasible for a number of reasons, including the lack of available institutions with sufficient experience and logistic facilities to run large long-term trials, and the strong campaign in the media in favor of early detection programmes, which has made the randomisation in a control arm unacceptable for a large proportion of volunteers. As a matter of fact, despite the formal collaboration of Istituto Superiore di Sanità (ISS Rome), signed in February 2006, and the acceptance of the protocol by the Ethics Committee of many Italian centres, only two other Institutions have started active accrual by July 2007.

As a consequence, the INT has decided to increase its target for the MILD trial to 4000 subjects, with the aim of joining the other two Italian randomized studies (DANTE and ITALUNG) to provide a strong Italian meta-analysis of at least 10,000 subjects, that might in the future be compared with the two large on-going randomised trials, the NCI trial in the United States and the Nelson trial in northern Europe (Netherlands, Belgium, Denmark), providing concurrent data on the southern European population.

MILD study recruits subjects randomized in 2 groups: a control group undergoes to a program of primary prevention with pulmonary function test evaluation and a group to periodic spiral CT associated with primary prevention and pulmonary function test evaluation. The last one is randomized in two arms: yearly low-dose CT vs CT every 2 years. MILD trial comprehensive design combines for the first time primary prevention with early detection and molecular risk profiling representing an innovative research against lung cancer.

The investigators recruited volunteers through a newspaper and television campaign, that provided information about the study design and eligibility criteria. The participants were asked to sign written informed consent to randomization in one of the two groups. Upon arrival, subjects were given a questionnaire to be completed and returned before leaving the centre. It includes a brief personal and family medical history, smoking details and information about attempts and assistance to stop smoking. A blood sample is collected from each subject at baseline and every two years follow-up. A basic spirometry is performed on each occasion.

Randomization:

• Control group protocol Control group undergo a program of primary prevention with pulmonary function test evaluation and blood collection. Each participant is contacted annually to collect relevant data on health status, hospital admission, and diagnosis or treatment of any concurrent disease, with particular emphasis on respiratory disorders and interval cancers. The study database is updated in real time with all such information.
• CT scan group protocol Baseline and annual single-slice spiral CT are performed without contrast material, with a low-dose protocol, and reconstruction with lung algorithm at every 1 and 5 mm. The CT scanner is a 16 slice. Effective radiation dose is equivalent to 1.54 mSv (milliSievert). Examinations are independently reported by two radiologists within 6 days, on a dedicated workstation and standard lung and mediastinum windows and maximum projection visual resolution reconstruction, for between-observer variability testing. A sophisticate algorithm for volumetric reconstruction and CAD (Computer-Aided Detection) software are used. Investigators deem calcified nodules or lesions with a maximum diameter of 5 mm (measured on lung window) non-suspicious and schedule repeat low-dose CT at next year, as per the protocol. Spiral thin-section CT limited to the area of interest and further examinations for growth assessment are completed within 3 months of baseline CT in every case of non-calcified lesion larger than 5 mm. Non-calcified lesions of 7 mm or larger, are tested with fluorine-18-labelled fluorodeoxyglucose PET(positron emission tomography) and calculation of standardised uptake value. For each patient, the metabolic activity of the lung nodule is assessed by standardised uptake values, measured with regions of interest manually drawn around the nodule on transaxial images.

Blood sample and plasma collection In both groups a sample of peripheral blood is collected during the first evaluation. Five aliquots of 1 millilitre of whole blood are frozen at -80°C.

The aim of biomarker and proteomic analysis and evaluation of individual genetic lung cancer risk is to assess whether this analysis can identify individuals at higher risk of cancer, improve the sensitivity and specificity of imaging techniques, such as low-dose CT scan and PET scan, or both. A team of research nurses, a data manager, and the study coordinator have maintained continuous contact with the enrolled volunteers to guarantee an appropriate follow-up. Each participant is recalled at least twice yearly to collect relevant data on health status, hospital admission, and diagnosis or treatment of any concurrent disease, with particular emphasis on respiratory disorders and interval cancers. The study database is updated in real time with all such information.

In both groups, pulmonary function tests is evaluated with a spirometer connected to a computer for the analysis of data. The following parameters are registered: forced vital capacity (FVC), forced expiratory volume (FEV), the amount of air you exhale may be measured at 1 second (FEV1), forced expiratory flow 25% to 75%, peak expiratory flow (PEF).

People who have even a brief counselling session with a health care professional are more likely to quit smoking. The ASK, ADVISE, ASSESS, ASSIST, and ARRANGE model was developed to help health care professionals with their patients who smoke. The physician asks the patient about their smoking status at every visit; advises the patient to stop smoking; assesses the patient's willingness to quit; assists the patient by setting a date to quit smoking, provides self-help materials, and recommends use of nicotine replacement therapy (such as the nicotine patch); and arranges for follow-up visits.

At present, blood sample aliquots have been collected and stored in the MILD tissue bank, as well as the cancer and healthy tissue samples from all surgically resected cases.

Also the strong commitment to biological research is been boosted by increasing the spectrum of MILD-related studies, covering proteomic and micro-arrays analysis, and launching a new research initiative aimed at evaluation of the role of COPD (Chronic obstructive pulmonary disease) in lung cancer development, with particular interest to the structural, morphologic and proteomic inflammatory damages related to lung cancer.

Inclusion Criteria:

• Current or former smokers, age ≥50 years or older with a minimum of 20 pack-years smoking history, no history of malignant disease, and adequate performance status (assessed on the basis of the patient's eligibility to undergo thoracic surgery).

Exclusion Criteria:

• History of malignant disease in the previous years and not adequate performance status (assessed on the basis of the patient's eligibility to undergo thoracic surgery).