Lung cancer is a type of cancer that begins in the lungs and is the leading cause of cancer death in industrialised countries. Lung cancer incidence has been steadily and continuously increasing. The incidence of lung cancer increases with age. The average age of patients at diagnosis of lung cancer is 60; more than one third of the new cases are in people over the age of 70.

STAFF

At the IEO lung cancer is treated by a multidisciplinary team consisting of specialists in:

• Thoracic Cancer Surgery
• Thoracic Oncology
• New Drugs and Early Drug Development for Innovative Therapies
• Department of Pathology and Laboratory Medicine
• Department of Medical Imaging and Radiation Sciences

Among the main risks of the onset of lung cancer are air pollution and exposure to toxic agents from industrial sources, but especially cigarette smoking

Some studies are bringing to light a cause that until recently was much underrated and that is the presence of radon inside homes or workplaces. These studies show that radon is the leading cause of lung cancer after cigarette smoking, with an incidence ranging from 10% to 20% of cases of lung cancer in Western countries and about 3,000 deaths a year in Italy. Radon's carcinogenic potential is 25 times greater in smokers.

The next causes in sequence for lung cancer are smog and air pollution produced by the combustion of petroleum products, processes involving the use of special metals (nickel, chromium) and radioactive substances. Many substances of occupational origin are recognised as lung carcinogens, even if they are less relevant than tobacco. People at risk of lung cancer are tar, railway and refinery workers, drivers of trucks and buses, city police officers. The chemicals tend to remain in the lungs for a long time due to their stability and difficulty of elimination. Among inorganic compounds, asbestos is in first place. Among other minerals mentioned, although with less frequency, are arsenic, chromium, nickel and cadmium.

The relationship between lung cancer and smoking is now demonstrated by large case series and it has been estimated that heavy smokers (more than 40 cigarettes/day) have a 60 times higher risk of developing the lung cancer than non-smokers. The same risk of developing lung cancer decreases with the number of years from smoking cessation. While it may take 3-4 years to undo the cardiovascular risk associated with smoking, bringing the risk of lung cancer nearly equal to that of a non-smoker would take 10-15 years and the risk becomes equal if you quit smoking before the age of 35. Non-smokers are still however at risk from passive cigarette smoking.

In the presence of a suspected lung cancer, it is necessary to go through an appropriate diagnostic process that provides a careful diagnosis of the lung cancer based on cytology and/or histology (typing) as well as a careful assessment of the disease’s extent (staging).

Lung cancers are divided into benign and malignant. Malignant lung cancers are divided into two main groups, small cell carcinomas (small-cell lung cancer-SCLC), which are about 15-20%, and non-small cell carcinomas (non-small-cell lung cancer-NSCLC) that are about 70%. NSCLC are further divided into three histological types, adenocarcinomas (50%), squamous cell or epidermoid (30%) and large cell cancers (10%).

Histological classification of lung cancers.

Benign

a)Papilloma

b)Adenoma

Malignant invasive

• Small cell lung cancer (SCLC) (20%)
• Non-small cell lung cancer (NSCLC) (70%)

Squamous cell or epidermoid

• Adenocarcinoma (acinar, papillary, bronchi-alveolar carcinoma)
• Large cell carcinoma
• Mixed

Other (10%)

• Adeno-squamous carcinoma
• Elements with pleomorphic carcinoma, sarcomatoid
• Carcinoid tumour
• Undifferentiated tumours

The lung squamous cell carcinoma

Epidermoid or squamous cell carcinoma develops from the bronchi and tends to grow within the bronchial tree, closing it, as well as outside and toward the lung tissue. In about 25% of metastasized lung cancer, this lung cancer can metastasize at the level of the adrenal glands and liver and more frequently to the hilar lymph nodes, mediastinum, pleura and the contra-lateral lung. However in 20-25% of cases lung metastases occur in the peripheral site evolving from the glands of the lung parenchyma. This site is usually that of adenocarcinomas, but it can also be the venue of lung metastases arising from primary cancers of other organs (pancreas, kidney, breast and large intestine), whose diagnosis can be made through the patient's clinical history and histology examination. Metastasized lung cancer is with high frequency (70-80%) to the mediastinal lymph nodes, the adrenal glands, liver, bones and brain.

Small cell lung cancer

Small cell lung cancer (SCLC) at the time of diagnosis is often scattered and tends to metastasize to regional lymph nodes, bone marrow, liver, adrenal gland and brain. Currently the incidence of small cell lung cancer is gradually declining (15%) in Europe.

Staging of lung cancer

The stage classification of lung cancer follows the TNM system (where the symbol T refers to the primary tumour, N refers to the lymph nodes involved and M refers to the presence of distant metastases).

T1 ≤ 3 cm

T1a ≤ 2 cm

T1b> 2 cm, ≤ 3 cm

T2 main bronchus ≤ 2cm from the hull, invasion of the visceral pleura, partial atelectasis

T2a> 3cm, 5cm ≤

T2B> 5 cm, 7 cm ≤

T3> 7 cm; chest wall, diaphragm, pericardium, mediastinal pleura, main bronchus <2 cm from the hull, complete atelectasis; one or more separate nodules in the same lobe

T4 mediastinum, heart, great vessels, hull, trachea, esophagus, vertebral bodies, one or more separate nodules in one different homo-lateral lobe

N1 homo-lateral peri-bronchial, homo-lateral hilar

N2 Homo-lateral mediastinum; subcarinal homo-lateral

N3 mediastinum and contra-lateral hilar, scalenic or supraclavicular

M1 Distant metastasis

M1a one or more nodules separated in a contra-lateral lobe; pleural nodules or malignant pleural or pericardial effusion

M1b Distant metastasis

The only true primary prevention (risk factor reduction) is to quit smoking and reduce environmental exposure to known carcinogens. Here are some important steps to take :

• support prevention programmes in schools that can be repeated over the course of the study period;
• carefully observe smoking bans in public places;
• protect yourself in high-risk workplaces because some environments can be a source of exposure to chemical or physical carcinogens, that may increase the incidence of lung cancer. In this regard, occupational exposure to asbestos involves a fivefold increase of the risk of lung cancer, and this risk becomes 50 times higher for those who are also smokers.

Secondary prevention (early detection of diseases already in progress) includes early diagnosis and treatment of pre-neoplastic lesions, or population screening, which in the case of lung cancer has unfortunately not shown great efficacy. Various studies for population screening have been carried out using chest X-ray, CT and sputum cytology. The results showed an increase in the percentage of lung cancer that is still resectable in the patients screened, but we do not know if this would reduce mortality in the whole population. The latest studies with spiral CT would seem to indicate an improvement of early diagnosis with an impact on survival, but the results of large randomised trials in progress are still pending. Other biological and genetic methods that seem promising are under investigation but they still need large-scale prospective studies. Tertiary prevention is the therapeutic treatment of lung cancer.

The symptoms of lung cancer strictly depend on the anatomical location of the disease, the level of aggressiveness and the type of growth. Sometimes the diagnosis of lung cancer is random.

The following lung cancer symptoms may cause the physician to suspect lung cancer:

• persistent cough
• dyspnea
• chest pain
• haemoptysis (coughing producing blood)
• dysphonia (voice alteration).

It is not easy for the doctor or the patient to attribute the symptoms to lung cancer, because they are mostly symptoms of other diseases that are quite common in smokers. That’s why the risk of delayed diagnosis is tangible in subjects with chronic bronchitis or emphysema.

Lung metastases are usually diagnosed randomly during follow-up visits after treatment of the primary cancer. It is rare for a lung metastasis to have symptoms. In this case the most frequent symptoms of lung cancer are cough, weight loss, and haemoptysis (emission of blood with cough).

Study for the early diagnosis of lung cancer

In 2000, the European Institute of Oncology (IEO) undertook a scientific study called C.O.SMO.S. (Continuous Observation of Smoking Subjects) enrolling 1,000 smoking volunteers in the year 2000. In 2004, the study was expanded by involving 500 more smoking volunteers.
The study demonstrated the efficacy of computer tomography at low-dose radiation (CT) in the diagnosis of the majority of lung cancers at a curable stage. The COSMOS study has shown the possibility of associating spiral CT with a specific blood test that detects the presence of molecules (Micro RNA - tumour markers) indicating the presence of lung cancer. This line of research is active at IEO, it is part of the COSMOS 2 project and will lead to results in a few years’ time. The latest studies with spiral CT would seem to indicate an improvement of early diagnosis of lung cancer with an impact on survival, but the results of large randomised trials in progress are still pending.

The first rule to prevent lung cancer is therefore not to smoke or not to be exposed to cigarette smoke, but the Mediterranean diet appears to be associated with a lower risk of lung cancer among heavy smokers.

People who consume a diet rich in fruits and vegetables, with olive oil as the principal source of fat, moderate consumption of wine and a low consumption of red meat tend to get sick less. The Mediterranean diet has long been recognised as being responsible for a better state of general health, longer survival and a reduced risk of cancer attributable to the content of fatty acids and antioxidants (polyphenolic compounds, carotenoids, tocopherols), found mainly in fruits, vegetables and olive oil. This positive effect is probably not due to individual nutrients, but the arrangement of all components interacting with each other and playing a positive effect in our body.

High consumption of red meat and processed meat have been associated with an increased probability of getting cancer. There is an increased risk among people who have high consumption of beef and offal, but not for high consumption of pork and poultry meat. The exact mechanism is not clear, it may be related to fat content but also to the presence of carcinogenic substances (N-nitroso compounds, heterocyclic amines and polycyclic aromatic hydrocarbons) and iron which can act as a pro-oxidant causing cell damage.

To prevent lung cancer, it is helpful to follow a healthy and balanced diet that includes regular consumption of fruit and vegetables rich in carotenoids such as tomatoes, carrots, sweet and spicy peppers, pumpkin, apricots, aromatic herbs. Taking large doses of vitamins in the form of potentially harmful supplements should be avoided. It is also helpful to be active by doing regular physical activity.

Diagnostic and therapeutic procedures for lung cancer and for diseases of the respiratory system

Interventional Pneumology

Interventional Pneumology is a new branch of pneumology that uses minimally invasive techniques for diagnosis and treatment of patients suffering from respiratory problems and for the diagnosis of lung cancer. IEO offers an interventional pulmonology outpatient clinic for patients who require a preliminary evaluation before procedures are performed. The IEO interventional pneumology programme started in 2010 and is able to provide a diagnostic and therapeutic service at the forefront of pulmonary medicine. The IEO interventional pneumology service annually performs more than 700 operational bronchoscopy procedures for the diagnosis and treatment of lung cancer patients. The interventional pulmonologists work in the Thoracic Surgery Division and collaborate with many specialists (radiation oncologists, medical oncologists and other surgical specialties) for the diagnosis and treatment of lung cancers.

EBUS-TBNA (trans-bronchial ultrasound)

EBUS (Endo-bronchial Ultrasound) is a minimally invasive new bronchoscopy technologythat allows the respiratory specialist to visualise the central structures of the mediastinum and peripheral lung parenchyma, otherwise not accessible with traditional bronchoscopy, using an ultrasound probe.

EBUS is used in many cases of lung cancer for evaluation of the mediastinal lymph nodes (mediastinal staging), diagnosis of peripheral lung nodules, mediastinal lymph nodes enlarged and affected by other diseases, for the diagnosis of benign pulmonary and mediastinal diseases, thymomas, tuberculosis and sarcoidosis.

The procedure does not require general anaesthesia (not requiring intubation) and runs under sedation by the anaesthetist, ensuring patient comfort and safety.

EBUS significantly increases the diagnostic accuracy of transbronchial biopsies under fluoroscopic guidance and transbronchial needle aspiration.

EBUS-TBNA bronchoscopies are performed in collaboration with a pathologist in the endoscopy room who can provide immediate evaluation of the sample material (ROSE: Rapid on-site cytologic Evaluation). EBUS-TBNA is an excellent method for obtaining new biopsies in cancer patients for the detection of cancerous genetic mutations that may lead to targeted therapies with biologics.

Rigid bronchoscopy

Rigid bronchoscopy is performed with a rigid bronchoscope under general anaesthesia. It allows the major airways (trachea and main bronchi) obstructed by intra-luminal lung cancer to be recanalised, thereby restoring patency. The lesions are removed mechanically or by laser therapy. In patients with intra-luminal lesions that cannot be completely recanalised and in those with distortion of the trachea-bronchial tree due to extrinsic compression, prostheses (endo-bronchial stents) can also be positioned for palliative purposes.

Pleural medical inspection

Pleuroscopy is a minimally invasive technique that allows exploration of the pleural cavity through a thoracic access performed under local anaesthesia and sedation. This procedure has diagnostic and therapeutic purposes in diseases of the pleura (malignant and benign).

Various studies for lung cancer screening have been carried out using chest X-ray, CT and sputum cytology. The results showed an increase in the percentage of lung cancer that was still resectable in the patients screened, but we do not know if this would affect the reduction of mortality in the whole population.

Chest Computed Tomography (TC)

Chest Computed Tomography (CT) scans provide definition of the extent of the lung cancer, detection of enlarged lymph nodes in the hilar-mediastinal areas, infiltration of the chest wall, pleural effusion and other pulmonary nodules.

CT scan of the brain and the abdomen

The CT scan of the brain and the abdomen completes staging, highlighting the presence of liver adrenal and brain metastases from lung cancer.

Positron Emission Tomography (PET)

A lung positron emission tomography (PET) scan is an important imaging modality in lung cancer patients. It uses a radioactive substance (called a tracer) to look for disease in the lungs such as lung cancer and distant metastases.

The fine needle aspiration/trans-thoracic biopsy

CT or bronchoscopy-guided fine needle aspiration/transthoracic biopsy are the examinations of choice for typing the lung cancer. In addition, transbronchial ultrasonography (EBUS) can be performed using bronchoscopy, allowing evaluation of the mediastinal lymph nodes, which is essential for the appropriate choice of therapeutic procedure for lung cancer.

Micro-RNAs and molecular diagnosis

Various studies show that lung cancer cells and the cells defending the body from the tumour itself release specific gene fragments (miRNA, microRNA), circulating long before the more advanced imaging tool today available (low-dose CAT) is able to detect the nodule. Via a simple blood test, fundamental information can be obtained for an in-depth diagnosis and for orientating the treatment of lung cancer, which in most cases, if discovered promptly, is a curable disease.

Serum miRNA can accurately identify patients with non-small cell lung cancer at an early stage in asymptomatic subjects. They can distinguish between benign and malignant lesions. They are abundant and stable in serum and have a simple clinic application. MicroRNA can represent a cheaper, simpler and immediately applicable screening platform for lung cancer than spiral CT.

As part of screening programmes in accordance with international guidelines (IASLC, American Cancer Society, NCCN), positive cases of lung cancer (doubtful or suspected nodules) are evaluated through a multidisciplinary approach by a team of specialists consisting of radiologists, thoracic surgeons and pulmonologists.

Patients diagnosed with a pulmonary nodule suspected to be lung cancer are contacted by phone by the thoracic surgeon for a first communication of the results of CT scans and an outpatient interview is fixed to discuss the possible diagnostic and therapeutic interventions under the national healthcare system regime, preceded by appropriate outpatient examinations for staging and functional cardio-respiratory assessment.

In the absence of preoperative diagnosis the lung cancer is surgically removed under general anaesthesia through a minimally invasive video-assisted technique, and an intraoperative examination is performed by microscope in order to obtain histological diagnosis. In the case of lung cancer, standard surgery of lobectomy or conservative pneumonectomy (segment resection) is performed with removal of lymph nodes via a minimally invasive robotic technique or preferably through muscle conserving lateral thoracic resection. An atypical conserving resection is performed in cases of insufficient cardio-respiratory reserve, when the nodule location and size allow it.The minimally invasive surgery (robot-assisted in centres where robotic technology is available) allows a conservative operation to be offered in the majority of patients with early-stage lung cancer.

Therapy of non-small cell lung cancer

Surgical therapy is the therapy of choice for patients with non-small cell lung cancer metastases (NSCLC) in the initial stages of the disease.

In the initial stages I and II complete resection of the lung cancer is in general possible. The removal of the mediastinal lymph nodes is required for accurate surgical and pathological staging (removal of a series of lymph glands located in the space between the two lungs called the mediastinum together with the pulmonary lobe). Patients undergoing lung cancer surgery with curative aims must undergo some pulmonary function tests prior to treatment (spirometry, blood gas analysis, pulmonary scintigraphy) as well as cardiac and anaesthesia-related assessments in order to exclude from surgery those cases that could not sustain the intervention.

The types of surgery commonly performed are:

• pneumonectomy
• bilobectomy
• lobectomy
• segmental resection.

The term "sleeve resection" means a segmental resection of one main bronchus with reconstruction of tracheo-bronchial continuity. In cases where cardiopulmonary diseases contraindicate lobectomy and in patients with small peripheral lesions (T1, N0) an atypical segmental resection ("wedge resection") can be carried out. The intervention of choice is lobectomy accompanied by removal of mediastinal lymph nodes.

The post-operative mortality of these interventions has sharply declined in recent years, settling at around 6% for pneumonectomy, 3% for lobectomy and less than 1% for minor resections.

For stage IIIA, the presence of lung metastases in the mediastinal lymph nodes (N2) is a contraindication to performing an initial surgery, although technically feasible. The international standard suggests a treatment of chemotherapy alone for these cases, or chemo/radiotherapy preceding the surgery with neo-adjuvant purposes in some other cases.

Stage IIIB and Stage IV are considered inoperable.

The use of adjuvant chemotherapy after surgery in patients undergoing surgery for stages I-II-IIIA, to increase the chances of the lung cancer not reappearing, is worth noting. This method should be reserved for non-elderly patients, without co-morbidities, with very good respiratory function and without complications after surgery.

Radiotherapy may be used for curative or palliative purposes. Candidate patients for curative treatment are those with localised non–small cell lung cancer (NSCLC stage I and II), unsuitable for surgery due to concomitant diseases. For these early stages, inoperable for medical reasons (co-morbidity), the use of stereotactic radiotherapy (or radio surgery) is under investigation, and it seems to provide better results than the traditional one. In stage III B cases of lung cancer, radiotherapy should be included with chemotherapy in a programme of combined therapy. Another possible indication for radiotherapy with curative purposes is represented by intrathoracic recurrence after surgery alone.

Lung metastases

Malignant lung cancers have the potential to infiltrate surrounding tissues and to disseminate through the body, giving rise to other neoplastic lesions (lung metastases) removed from the primary tumour. This process is called metastasis and secondary neoplastic lesions are called lung metastases (or secondary cancers or repetitive lesions).

Cancers that most frequently give lung metastases in the body are:

• colon cancer,
• renal cancer,
• melanoma,
• breast cancer,
• head and neck cancer

Lung metastases in different areas of the same lung or in the contralateral lung should be added to the above list. In all of these cases the original cancer disseminates to the lung via the blood vessels (haematogenous route).

Chest CT scans enable identification of the location and the number of lung metastases. The lung metastases can be treated surgically. However, it is necessary that the primary cancer is under control, that the time between the treatment of the primary cancer and the diagnosis of lung metastases is sufficiently long (> 36 months) and the patient is in good general condition. If these three conditions are realised surgery associated with various types of chemotherapy can give very good results. For patients who cannot undergo surgery, there is a wide range of non-surgical therapies such as chemotherapy, stereotactic radiotherapy and radiofrequency ablation lung metastases

Palliative radiotherapy aims to control the symptoms that can be determined by the primary lung cancer (haemoptysis, chest pain, Pancoast syndrome, mediastinal syndrome) or metastases (pain from bone metastases from lung cancer, brain metastases, intracranial localisation), thus improving the quality of life.

Therapy of small cell lung cancer

Small cell lung cancer (SCLC) is considered a systemic lung cancer (potentially widespread or diffusible) already at diagnosis although at limited stage. For this reason, surgical treatment (which is a local treatment) is not the therapy of choice for the treatment of small cell lung cancer, even in the technically operable forms.

Due to the high index of cell replication, small cell lung cancer is a particularly chemo-sensitive cancer and therefore chemotherapy plays a primary role and has become increasingly used over time. The small cell lung cancer (SCLC) is also highly radiosensitive. Radiotherapy is indicated for curative purposes in limited forms in combination with chemotherapy. Prophylactic cranial irradiation or PCI (in order to prevent the formation of metastases) is indicated in patients with small cell lung cancer (both limited and extended) as a response to chemo-radiotherapy on the basis of the high probability that the brain can become a site of disease.

Conservative surgery for lung cancer

IEO has designed and coordinates a randomised multicentre trial with the objective of demonstrating the equivalence between lobectomy with lymph node removal and segment resection (removal of one lobe segment) without removal of lymph nodes, performed through thoracoscopy or robotic surgery in cases of small lung cancers (stage 1, less than 2 cm, without affected lymph nodes as demonstrated by PET and CT).

It is hoped to show that the chances of recovery are the same for the two types of treatment while the quality of life benefits are obviously greater in the case of the removal of a single segment.

Lung bone and brain metastases

In general, bone is the third metastatic site after liver and lungs. Bone metastases occur in one out of three lung cancers and are usually of osteolytic aspect. Osteolytic bone metastases from lung cancer are responsible for long bone and vertebral fractures leading to restricted mobility, surgery and medullar compression that severely alter quality of life and have a huge medico-economic impact. In recent years, a multidisciplinary board has been developed to optimize bone metastases management for each patient in harmony with the oncology program. We have different strategies to treat the bone metastases from lung cancer: systemic treatments (Zoledronic acid and Denosumab), local treatments (radiofrequency ablation lung metastases and radiotherapy) and or a surgical approach.

Brain metastases from lung cancer are a common cause of morbidity and mortality in patients with non-small-cell lung cancer in ~25%–40% of patients.

Therapeutic options for brain metastases from lung cancer have been limited to local therapies such as whole-brain radiation therapy, stereotactic radiosurgery, surgery, or a combination of the above. Due to concerns about inadequate central nervous system penetration, chemotherapy is not typically a standard primary treatment for brain metastases from lung cancer.