Incidence of lung cancer

Lung cancer is the leading cause of cancer death in industrialised countries. In the US it is the leading cause of death in men and has now surpassed breast cancer in women, occupying the top position in terms of mortality. Its incidence has been steadily and continuously increasing. In Italy, the number of new cases per year is around 35-40,000 per 100,000 inhabitants, with a mortality rate of 81,000/100,000 in men and 12,000/100,000 in women. The incidence increases with age. The average age of patients at diagnosis is 60; more than one third of the new cases are in people over the age of 70. 

Main causes of lung cancers

Among the main causes of the onset of lung cancer are air pollution and exposure to toxic agents from industrial sources, but especially cigarette smoking. In Italy today almost 25% of the active population smokes (over 12 million people).

Some studies are bringing to light a cause that until recently was very 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 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 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 disease than non-smokers. The same risk 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 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.

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 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. 

How to prevent lung cancer

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 be followed:

1. support prevention programmes in schools that can be repeated over the course of the study period;
2. carefully observe smoking bans in public places;
3. 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 cancer disease.

The most common symptoms in 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 is random.

The following 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 a 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.

Diagnostic process for the treatment of lung cancer (X-ray, tomography,biobsy)

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

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 was still resectable in the patients screened, but we do not know if this would affect the reduction of 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.

Micro-RNAs and molecular diagnosis

In oncology, prevention is increasingly being confirmed as the best course. Ten years ago, DNA decoding offered real hope to really achieving a significant reduction not only in cancer deaths, but also in the physical and psychological burden of the disease. The screening programme can be joined by all heavy smokers or former heavy smokers (who quit less than 15 years ago), and smokers more than 50 years old who have smoked at least one packet of cigarettes per day for the last 20 years. 

Scientists learned how to apply genetic knowledge to diagnosis in order to catch the disease before it manifests in its initial forms. Molecular diagnosis was therefore created and is emerging as a revolution in DNA-related cancer research, comparable to cancer therapy itself. The strategy is clear. The cancer is the final outcome of a broad and silent process originally caused by the mutation of a gene. Traces of this mutated gene should then be found in the body before the process is complete and the disease presents. Fragments of abnormal genes have been sought in biological fluids and in some cases they have already been found, discovering valuable warning signs for early 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.

The treatment of lung cancers detected by screening

As part of screening programmes in accordance with international guidelines (IASLC, American Cancer Society, NCCN), positive cases (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 pulmonary nodule 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 cancer.

Surgical therapy of lung cancer

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

In the initial stages I and II complete resection of the tumour 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 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.

For stage IIIA, the presence of 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.

Stages IIIB-IV are considered inoperable.

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. 

The use of adjuvant chemotherapy after surgery in patients undergoing surgery for stages I-II-IIIA, to increase the chances of the disease 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 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, 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.

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

Surgical therapy of small cell lung cancer

Small cell lung cancer (SCLC) is considered a systemic disease (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, 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 SCLC (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 tumours (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. 

The robot is the ideal tool for conservative surgery because it enhances the ability of the surgeon and amplifies the senses (vision, range of motion). A multicentre study aims to compare quality of life and morbidity and postoperative pain results in patients undergoing Robotic thoracic surgery and standard thoracic surgery with traditional video thoracoscopy. The study will be conducted in a collaboration between the Thoracic Surgery Division at IEO and some prominent American robotic technology centres.

• Breath test in patients with lung cancer S683/112
• Open-label, randomised, prospective, multicentre, parallel-group study comparing the efficacy and safety of TachoSil and standard surgical treatment in patients undergoing pulmonary lobebectomy due to malignant lung cancer and requiring treatment through air dispersion "Tachosil International Study” S282/605
• Prospective, randomised, phase III trial: a comparison between surgery and surgery plus preoperative chemotherapy with cisplatin-gemcitabine in non-small cell lung cancer in early stage (T2N0, T1-2N0-1, T3N0 and T3N1) "CHEST Study” S29/499
• Randomised, phase III study comparing pulmonary sub-lobar resection   versus lobectomy for the treatment of non-small cell lung cancer in stage IA S638/311
• Early diagnosis of lung cancer in high-risk subjects with low-dose CT and molecular markers (Cosmos 2) S669/511
• Validation of spiral CT for early diagnosis of lung cancer - extension of the pilot study S039/100
• Validation of spiral CT for early diagnosis of lung cancer S039/699

Given the close relationship between cigarette smoking and lung cancer, the primary method of prevention is to avoid the habit of active and passive smoking completely. Even if food intake is less important in determining the onset of lung cancer, a healthy diet may play a role in the likelihood of becoming ill. According to the World Cancer Research Fund, the weight of the diet is minimal compared to smoke. One element to consider is that high doses of beta-carotene in the form of supplements is a certain cause of lung cancer in heavy smokers. Fruit and food naturally containing carotenoids may play a protective role, the role of other dietary factors is less certain.

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 disease among heavy smokers.

These are the results of the COSMOS project, initiated by our Institute in 2004. The study involved 5,200 smokers in a screening programme for early diagnosis with low-dose spiral CT. The dietary survey involved 4,336 participants, all current or former smokers (at least one pack a day for 20 years) and free of signs of disease at the time of recruitment. Comparing their eating habits has shown that 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. In our sample we found 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 like 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.