Symptoms and General Pathology

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Respiratory Tract (Lung and Bronchial) Diseases

Inflammation

Lung Neoplasms

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Anti-Inflammatory Agents

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Analgesics

Platelet Aggregation Inhibitors

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Aspirin

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

Cyclooxygenase Inhibitors

Enzyme Inhibitors

Smoking cessation through the administration of Cytisine (in standard and prolonged administration) + reduction of inflammatory status through the administration of Acetylsalicylic acid, diet modification and physical activity increase + standard treatment for early lung cancer detection (ultra low dose CT) + spirometry with CO test + anthropometic data collection + blood test

Smoking cessation through the administration of Cytisine (in standard and prolonged administration) + standard treatment for early lung cancer detection (ultra low dose CT) + spirometry with CO test + anthropometic data collection + blood test

reduction of inflammatory status through the administration of Acetylsalicylic acid, diet modification and physical activity increase + standard treatment for early lung cancer detection (ultra low dose CT) + spirometry with CO test + anthropometic data collection + blood test

standard treatment for early lung cancer detection (ultra low dose CT) + spirometry with CO test + anthropometic data collection + blood test

Cytisine administration will be randomized 1:1 in standard (40 days)and prolonged treatment (84 days).

Subjects will be educated on how to take the product and informed about possible adverse effects.

Cytisine

The treatment will consist of Acetylsalicylic acid at 100mg once a day

Acetylsalicylic acid

It will be proposed:

1. an optimal diet with the aim of favoring control of weight, abdominal fat and adequate nutritional status without increasing the levels of IGF-I and inflammatory factors or glycemic peaks, with periodic verification of the results
2. a regular and sustainable physical activity program with periodic verification of the results.

Diet Modification and Physical Activity Increase

standard treatment for early lung cancer detection with ultra low dose CT

early lung cancer detection

spirometry with CO test

anthropometic data collection

blood test to assess the metabolic and inflammatory profile

blood test

Ugo Pastorino, MD

This prospective randomized pilot trial will evaluate a multiple intervention program of prevention in lifelong smokers aiming at reduction of chronic inflammation status through treatment with low-dose acetylsalicylic acid (ASA), smoking cessation with cytisine, targeted modification of diet and physical activity, in addition to early diagnosis with annual ultra low-dose spiral computed tomography (LDCT).

The most recent population-based studies carried out in Europe and the US on hundreds of thousands of individuals have unequivocally identified three principal causes of mortality, morbidity and chronic disability: tobacco smoke, inadequate diet, and reduced physical activity. These risk factors are in large part reversible, because in heavy smokers, even after 60 years of age, cessation is associated with a clear reduction in all-cause mortality. The finding that lifestyle and eating habits are associated with the development of cancer has been confirmed in many studies: smoking, a sedentary lifestyle, excess red meat, processed foods and sugars are associated with increased risk, while an active lifestyle, non-exposure to smoke (both active and passive), consumption of whole grains, legumes and vegetables are associated with protection or a reduced incidence in at-risk subjects.

What is clear, and confirmed by many studies, is that cancer occurs more often in overweight individuals, and that cancer patients who are overweight have more difficulty treating their disease. Elevated plasma levels of C-reactive protein (CRP), even when still within normal limits, are the reflection of a chronic state of inflammation and are associated with poor prognosis in several tobacco-related diseases. CRP measurement is besides a simple test to predict the risk of heart attack and stroke as well as mortality from all causes and from cardiovascular disease. In a systematic review on adult solid tumors, elevated CRP levels were associated with higher mortality and recurrence rates, and this observation was confirmed in early-stage lung cancer by a recent meta-analysis. In patients with chronic obstructive pulmonary disease (COPD), high CRP is a strong and independent predictor of future morbidity and mortality, and an increase in CRP concurrent with a reduction of the forced expiratory volume in 1 second (FEV1) shows an even stronger effect on patient's outcome.

High levels of CRP are associated with poor prognosis in cancers of the upper aerodigestive tract, rhinopharynx, lung and urinary tract. From a dietary point of view, consumption of saturated fats has been directly associated with an increase in inflammatory status as measured by high levels of CRP, just like consumption of meat, while an inverse correlation with consumption of vegetables has been observed. For example, low levels of inflammatory factors have been found in individuals adhering to a Mediterranean diet. Another recurrent finding, at least for cancer, is the importance of daily physical activity, such as brisk walking for 30 minutes. Moreover, regular physical activity is associated with better prognosis and increased survival in patients with a cancer diagnosis.

The number of heavy smokers that will participate in early-diagnosis programs using spiral CT will undoubtedly increase in the future as a result of awareness campaigns, and the participating volunteers represent an excellent opportunity to evaluate the efficacy of targeted primary prevention programs.

The present program will combine several interventions according to the randomization arm, proposed in combination or in single treatment, including treatment with cytisine, reduction of chronic inflammation by treatment with low-dose aspirin (ASA), targeted modification of diet and physical activity, in addition to early diagnosis with annual ultra low-dose spiral computed tomography (LDCT).

At baseline each volunteer will undergo:

* questionnaires on population evaluation (e.g. socio-demographic, smoking habits, physical activity, etc)
* blood sampling for the assessment of the inflammatory and metabolic profile
* evaluation of respiratory function and measurement of carbon monoxide (CO)
* thorax ultra low-dose computed tomography (LDCT) without contrast
* anthropometric evaluation (e.g. weight, height, BMI, etc)

To reduce levels of chronic inflammation will be used:

* treatment with low-dose acetylsalicylic acid (ASA)
* dietary / nutritional intervention in order to promote an optimal diet, based on characteristic of the Mediterranean Diet, for weight maintenance, visceral fat control and an adequate nutritional status
* physical activity intervention, through the reduction of sedentary behaviour and the implementation of a moderate intensity activity of about 30 min a day

In the Smoking cessation will be used Cytisine. It is a molecule known since the early 60s for the treatment of smoking. In recent clinical trials it revealed efficacy in smoking cessation. In 2014, the NHS (National Health Service) produced a document evaluating the cost-effectiveness of drug treatment of smoking, concluding that cytisine has the most favorable profile among the drugs taken into consideration

The imaging will be performed by volumetric acquisition with a computed tomography scanner equipped with advanced technology hardware and software, including: high performance X-ray tube with low potential, high sensitivity detectors combined with dedicated reconstruction algorithms for optimisation of the signal to noise ratio within an ultra low radiation dose. The protocol for ultra-low dose computed tomography will be specifically set for lung cancer screening with semiautomated image analysis and nodule quantification, according to the international standard for image quality (Quantitative Imaging Biomarker Alliance). In particular, the ultra-low dose computed tomography protocol will be developed for the lowest radiation exposure and tested by dedicated phantom for quantitative analysis of imaging metrics.

In the control group subjects will receive an information booklet containing advice on an optimal lifestyle with particular reference to smoking, diet and physical activity according to the best international guidelines.

Screening and Multiple Intervention on Lung Epidemics

Multifactorial Intervention of Primary Prevention in High Risk Subjects: a Randomized Trial

Reduction in the percentage of subjects with CRP\>=2 mg/L

Dietary intakes are collected by a self reported food frequencies questionnaire and data are expressed as the average daily/weekly consumption of foods and food groups.

Servings size is defined as "natural unit" (e.g. 1 glass of soft drinks, 1 teaspoon of sugar) or as an average serving (e.g. 80 g of pasta or rice, 30 g of dried fruits).

The frequency of serving size is reported as continuous measure. Data will be collected as continuous measures and will be analyzed by performing statistical models to investigate a potential relationship among changes in dietary habits and anthropometric parameters (BMI, waist circumference..), socio-demographic characteristics (gender, smoking status, physical activity), biochemical parameters (CRP blood levels), drugs assumption and the risk of chronic diseases, such as lung cancer.

Increase in the physical activity measured by the validate short form IPAQ questionnaire (International Physical Activity Questionnaire) The items in the short IPAQ form were structured to provide separate scores on walking, moderate-intensity and vigorous-intensity activity. Computation of the total score requires summation of the duration (in minutes) and frequency (days) of each activity.

METs are multiples of the resting metabolic rate and a MET-minute is computed by multiplying the MET score of an activity by the minutes performed:

* Walking MET-minutes/week = 3.3 \* walking minutes \* walking days
* Moderate MET-minutes/week = 4.0 \* moderate-intensity activity minutes \* moderate days
* Vigorous MET-minutes/week = 8.0 \* vigorous-intensity activity minutes \* vigorous-intensity days
* Total physical activity MET-minutes/week = sum of Walking + Moderate + Vigorous MET-minutes/week scores

Weight and height will be combined to report BMI in kg/m\^2. Reduction in BMI

Reduction in waist circumference expressed in centimeters

Enhancement in blood glucose, total cholesterol, LDL, HDL and triglycerides

Reduction in lung cancer specific and overall mortality

Istituto Di Ricerche Farmacologiche Mario Negri

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Head of Thoracic Surgery Division

Infections

Rare Diseases

Neoplasm Metastasis

Lung Diseases

Lung Diseases, Obstructive

Pulmonary Disease, Chronic Obstructive

Communicable Diseases

Respiratory Tract Infections

Respiratory Tract Neoplasms

Thoracic Neoplasms

Respiratory Tract Diseases

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Acute Graft Versus Host Disease

Volunteers with a negative baseline LDCT will repeat LDCT after the first screening with an annual interval (according to guidelines)

Volunteers with a negative baseline LDCT will repeat LDCT after the first screening with an interval of two years.

standard treatment for early lung cancer detection with LDCT at one or two years interval

blood analysis for microRNA and other biomarkers detection

Chiara Bovolenta, PhD

This prospective randomized multicentered clinical study aims at implementing early diagnosis of lung cancer in high-risk heavy smokers in the Italian population. The main goal of the study is to develop a nationwide lung cancer prevention screening with high quality standard, similar to that of other screening programs i.e. breast, colon and cervix ongoing in Italy.

The Italian Pulmonary Screening Network (RISP) includes 18 centers, which will promote primary prevention by offering a smoking cessation program (i.e. counselling and anti-smoking cytisine-based therapy) and secondary prevention by screening volunteers with chest Low Dose Computed Tomography (LDCT). The primary objective of the study is to demonstrate the non-inferiority of a risk-based screening strategy (less intensive, every 2 years) compared to the standard annual screening, in terms of stage I/II lung cancer incidence.

Furthermore, the study aims to provide evidence whether blood biomarkers screening intervals can improve the efficiency of lung cancer screening by requiring less CT examinations while retaining the ability to diagnose lung cancer at curative state.

Tobacco smoking is the most relevant cause of avoidable death in all high-income countries, including the European Union and Italy. Smoking increases the risk of dying from emphysema by 10 times, doubles that of having a stroke, and increases two to four times that of being affected by a heart attack. In addition, the carcinogenic substances contained in tobacco smoke are responsible for about 90% of lung cancers, but also for most cancers of the oral cavity, larynx and bladder. Therefore, the main causes of death attributable to tobacco smoke are cancers, cardiovascular and respiratory diseases. Lung cancer is a serious and far-reaching health problem with reduced survival after 5 years. Seventy per cent of lung cancers are at an advanced clinical stage and difficult to treat when the first symptoms occur, and a certain diagnosis is made. Lung cancer mainly affects people over the age of 50, with a peak incidence around 70-75 years. Over a third of deaths attributed to smoking are between 35 and 69 years of age. For long time it was not possible to have a certain diagnosis by diagnostic tests. Only at the end of the '90s, it became clear that computed tomography allows lung cancer to be detected at an early stage (stage I), before symptoms occur.

Large-scale randomized clinical trials (RCTs) have shown that early detection of lung cancer by CT can reduce lung cancer mortality between 20% and 39%, according to the duration of the intervention. In particular, LDCT screening has been shown to significantly reduce lung cancer mortality by 8-26% for men and 26-61% in women. International lung cancer screening guidelines, currently adopted in the United States, recommend repeating LDCT at annual intervals. However, annual chest LDCT screening has heavy economic impact and can induce radiation-related damage.

Recent studies have shown that the first LDCT screening exam provides information on individual risk thus allowing the personalization of the screening interval. In particular, there are indications that screening interval can be extended safely for low-risk individuals. For example, several studies show that individuals with a negative baseline exam have a substantially lower risk than those with a positive baseline exam. A randomized prospective assessment of risk-based screening intervals therefore has the potential to improve efficiency and reduce the economic-health impact of lung cancer screening. In fact, a personalized screening protocol has a less serious economic impact, both at the instrumental level and in terms of the commitment of the radiological staff.

In this context, the RISP network aims to promote a nationwide early diagnosis program with LDCT that reduces mortality from lung cancer, and at the same time, brings benefit in primary prevention of smoking-related diseases, such as chronic obstructive pulmonary diseases (COPD) and other cardiovascular diseases. RISP will start lung screening in a gradual and controlled way, through a network of reference centers with multidisciplinary clinical competence that provide adequate coverage of the territory, and meanwhile a level of quality fitting to the standards currently achieved in the screening of other cancers (breast, cervix, colon). A systematic screening program will also increase the percentage of lung cancer patients eligible for early-stage surgical resection from the current 25% (without screening) to 50-60%.

At baseline- each volunteer will undergo:

* a baseline questionnaire (e.g. socio-demographic, smoking habits, etc) with anti-smoking counseling program that includes cytisine-based anti-smoking therapy.
* blood sampling for the assessment of the inflammatory and metabolic profile (i.e. bio-markers) (optional)
* evaluation of respiratory function and measurement of carbon monoxide (CO)
* chest LDCT without contrast
* anthropometric evaluation (e.g. weight, height, BMI, etc)

Follow-up- each randomized volunteer will undergo:

* clinical examinations of LDCT
* blood sampling and CO after 12 months of follow-up or 24 months depending on the arm to which they belong.

Imaging will be performed by volumetric acquisition with a computed tomography scanner equipped with advanced technology hardware and software, including an AI-based second reading that will be validated by a radiologists panel.

All data will be entered into a password-protected database. The protection of the identity of the subjects will be guaranteed by assigning unique participation numbers specific to the study. In a separate database, accessible only by the principal investigator or assigned team members, the unique identification number can be linked to participants' names and addresses for the purposes of local and central administrative processes such as scheduling scans, sending invitation letters, sending screening results and questionnaires for topics, and collecting follow-up information. All volunteer samples and paper/electronic files will be destroyed 15 years after completion of the study.

Participants are assured that no personal data will be published in articles, reports or other study documentation.

Randomization will be carried out using real-time automated statistical software: eligible subjects will be randomly assigned to one of the two intervention arms (A, B) with a 1:1 ratio.

Lung Cancer Prevention Screening Programme in Italy

Early Diagnosis of Lung Cancer of the Italian Pulmonary Screening Network (RISP): Comparative Analysis for the Use of Low Dose Computed Tomography and Promotion of Primary Prevention Interventions in Subjects at High Risk for Lung Cancer

Change in lung cancer incidence: evaluate the impact on lung cancer incidence through LDCT at annual or biennial intervals.

Change in lung cancer specific and overall mortality: evaluate the impact on lung cancer mortality through LDCT at annual or biennial intervals.

MicroRNA expression profile, using TaqMan microfluidic cards: increased efficiency of lung cancer diagnosis by requiring less CT examinations while retaining the ability to diagnose lung cancer at curative state.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Screening and Multiple Intervention on Lung Epidemics	NCT03654105	Inflammation Smoking Cessati... Diet Modificati... Physical Activi... Lung Cancer	Cytisine Acetylsalicylic... Diet Modificati... early lung canc... spirometry with... anthropometic d... blood test	55 Years - 75 Years	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Lung Cancer Prevention Screening Programme in Italy	NCT05766046	Lung Cancer COPD (Chronic O... Cardiovascular ...	early lung canc... blood test	55 Years - 75 Years	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Spots Global Cancer Trial Database for early lung cancer detection