Italian Lung Cancer Screening Trial (ITALUNG)
Condition: Lung Cancer
MeSH terms: Lung Neoplasms
Study type: Interventional

Summary: 
      ITALUNG is a RCT for the evaluation of the efficacy of lung cancer screening with low-dose
      Computer Tomography (LDCT) , carried out in three screening centers in Florence, Pisa and
      Pistoia districts of the Tuscany region of Italy.

      3106 high risk subjects (age 55-69, smokers or ex-smokers) were recruited and randomized to
      the Active arm (Baseline + 3 annually repeated LDCT screening) or to the Passive arm,
      followed up in usual care (no screening reccomended ) All subjects were invited, if smokers,
      to consider smoking cessation practice. Follow-up for cause specific mortality and overall
      mortality and for lung cancer incidence was performed (actually at 9.3 years since
      randomization) . Blood and sputum samples were stored from the Active arm in a Biobank, with
      1304 subjects enrolled in the Italung Biomarker study.
    

Detailed description: 
      ITALUNG is a RCT for the evaluation lo the efficacy of lung cancer screening with low-dose CT
      carried out in three screening centers in Florence, Pisa and Pistoia districts of the Tuscany
      region of Italy. The study was completely funded by the Regional Health Public Authority and
      approved by the Local Ethic Committee of each participating institution.

      The study involves 269 general practitioners (GPs) operating in the 3 districts, one
      screening centre for each district, where CT scans and clinical management are performed, and
      the Institute for Cancer Prevention Research (CSPO) of Florence as a coordinating centre.

      Methods The base for subject recruitment was the list of subjects in the 55-69 years range
      resident in one of the 3 districts where the screening centres are located and registered
      with one of the GPs who has accepted to participate in the study. These subjects received a
      letter signed by their GP and by the local screening centre in which the aims and
      characteristics of the study were explained and a standardized multiple choices questionnaire
      about age, gender, smoking history, and general health information were enclosed. The
      candidates were asked to sign their consent of being randomized and to send the letter back
      to the coordinating centre by mail, free of charge, or to give the questionnaire back to
      his/her GP. Only subjects registered with participating GPs who gave the letter back with the
      consent to the randomization were enrolled in the trial.

      The consent to be enrolled and randomized was contained in the initial mailing as the consent
      to be followed up by the GP. All respondents signed the consent before knowing their
      eligibility and randomization status.

      Eligible for the study were subjects aged between 55 and 69 years at the time of enrolment
      with a smoking history of at least 20 packs-year since the last 10 years (former smokers who
      quitted since more than 10 years were excluded). Other exclusion criteria were a history of
      previous cancer other than non-melanoma skin cancer and general conditions precluding
      thoracic surgery. Eligible subjects only were centrally randomised by a software procedure in
      an active arm receiving annual low-dose CT for 4 years and a control arm receiving usual care
      but no screening. Subjects randomized in the control arm then received a letter communicating
      their allocation in the no screening arm of the study and an invitation for a free access to
      a smoking cessation program.

      Subjects randomized into the active arm were contacted by phone call to have an appointment
      for an interview in which a pneumologist after providing further information about CT scan
      and positive findings management collected the consent for CT examination and scheduled the
      CT screening test. An additional written consent for enrolment in a biomarkers collateral
      research project was also requested. A free-access invitation to a smoking cessation program
      was provided to all the subjects enrolled in the study.

      All randomised subjects will be followed up by cancer registry of the Tuscany Region
      (http://www.ispo.it/) for incidence and mortality. Furthermore each enrolled subject or
      his/her GP will be interviewed by telephone after 4 years since randomisation to assess
      health conditions and smoking habits.

      We considered subjects who withdrew from the screening process at whatever time after
      randomisation as drop-outs.The CT screening tests were performed using five spiral CT
      scanners including one with single row of detectors (SD) and four with multi-rows of
      detectors (MD). Low-dose acquisition techniques followed the international recommendations
      including 120-140 kilovolt peak (kVp), 20-43 milliampere (mA) and bone reconstruction filter.
      Slice collimation was 3 mm with 1.5 mm reconstruction interval with the SD scanner and 1-1.25
      with 1-1.25 mm reconstruction interval with the MD scanners. Each CT scan was read
      independently by two radiologists on a work-station with a consensus reached in case of
      disagreement. Three radiologists performed all the first reading, while 15 additional
      radiologists performed the second reading. All 18 radiologists had a minimum of 4 years
      experience in chest CT. Within the next 3 weeks the result of the baseline screening test was
      mailed home if negative, whereas subjects with positive test received a phone call by the
      local screening centre and were invited to meet the pneumologist for further assessment.The
      main criterion for test evaluation was the nodule size, measured manually with electronic
      callipers on the workstation. CT scans was considered as negative when no focal abnormalities
      were found and also when solid non-calcified nodules (NCN) < 5 mm in mean diameter or pure
      non-solid nodules with a mean diameters < 10 mm were observed. In case of negative baseline
      screening test the subject was scheduled for the annual repeat screening test.The test was
      considered as positive when it demonstrated at least one NCN ≥ 5 mm or a non-solid nodule ≥
      10 mm or the presence of a part-solid nodule. Management of positive screening test was
      carried out at each screening centre according to a shared protocol basically similar to that
      of the International-Early Lung Cancer Action Program (ELCAP) Study using follow-up low-dose
      CT, fluorodeoxyglucose positron emission tomography (FDG-PET), and fine needle aspiration
      (FNA) biopsy. In particular, solid NCN with a mean diameter ≥ 8 and non- solid NCN > 10 mm
      were scheduled for FDG-PET examination. In PET positive nodules a FNA was recommended,
      whereas a 3-month follow-up was performed in PET negative cases. A 3-month follow- up was
      also requested for nodules with negative or indeterminate FNA. All cases showing no nodule
      growth at the follow-up examination were invited to annual repeat CT scan. Solid or
      part-solid NCN with mean diameter between 5 and 7 mm received a follow-up low-dose CT scan
      after three months. In case of significant growth, defined as an increase of at least 1 mm in
      mean diameter in a solid nodule or increase of the solid component in a part-solid nodule,
      nodules were considered potentially malignant. For peripheral nodules two options were then
      available: FDG-PET or CT-guided FNA. In case of deep nodules FDG-PET or fiberoptic
      BronchoScopy (FBS) was performed on a case-by-case basis. FBS was also occasion- ally
      performed in case of airways abnormalities. If the screening test revealed focal
      abnormalities consistent with inflammatory disease, antibiotic therapy and a 1-month
      follow-up CT were recommended. In case of complete resolution, the subject was sent to annual
      repeat screening, whereas further 2-month follow-up CT was performed in case of partial or
      lack of resolution. All subjects with FNA evidence of malignancy underwent a staging CT
      including full-dose chest, upper abdomen and head examination with intravenous iodinated
      contrast administration. Surgery was recommended for nodules with findings consistent with
      malignancy at FNA and also in two subjects with a PET positive and FNA indeterminate solid
      nodule.All the surgically removed lesions were evaluated according to the World Health
      Organization Criteria]. Blood and sputum samples were stored from the Active arm in a
      Biobank, with 1304 subjects enrolled in the Italung Biomarker study.
    

Intervention name(s): Low Dose Computed Tomography
Intervention type(s): Device
Intervention description(s): Assessment protocol were adopted from the ELCAP study (modified) for Non Calcific Nodule with a diameter of less- equal than 5 mm at baseline and 3mm at repeated.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Screening
Keywords: screening