Early Lung Cancer Detection in High Risk Individuals
Condition: Lung Cancer
MeSH terms: Lung Neoplasms
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Low dose CT
Intervention type(s): Radiation
Intervention description(s): annual CT vs biennial CT
Other intervention name(s): LDCT
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: low-dose computed tomography; lung; randomized controlled trial; neoplasms; screening; smoking