LUNG CANCER

Lung cancer is the malignant transformation and expansion of lung tissue, and is responsible for 1.3 million deaths worldwide annually.[1] It is the most common cause of cancer-related death in men, and the second most common in women.[2][3]

Current research indicates that the factor with the greatest impact on risk of lung cancer is long-term exposure to inhaled carcinogens, especially tobacco smoke.[4] While some people who have never smoked do still get lung cancer, this appears to be due to a combination of genetic factors[5] and exposure to secondhand smoke.[6][7] Radon gas[8] and air pollution may also contribute to the development of lung cancer.[9][10][11]

Treatment and prognosis depend upon the histological type of cancer, the stage (degree of spread), and the patient's performance status. Treatments include surgery, chemotherapy, and radiotherapy.[12]
Signs and symptoms
Symptoms that suggest lung cancer include:[12]

dyspnea (shortness of breath)
hemoptysis (coughing up blood)
chronic coughing or change in regular coughing pattern
wheezing
chest pain or pain in the abdomen
cachexia (weight loss), fatigue and loss of appetite
dysphonia (hoarse voice)
clubbing of the fingernails (uncommon)
difficulty swallowing
If the cancer grows in the airway, it may obstruct airflow, causing breathing difficulties. This can lead to accumulation of secretions behind the blockage, predisposing the patient to pneumonia.

Many lung cancers have a rich blood supply. The surface of the cancer may be fragile, leading to bleeding from the cancer into the airway. This blood may subsequently be coughed up.

Depending on the type of tumor, so-called paraneoplastic phenomena may initially attract attention to the disease. In lung cancer, this may be Lambert-Eaton myasthenic syndrome (muscle weakness due to auto-antibodies), hypercalcemia and SIADH. Tumors in the top (apex) of the lung, known as Pancoast tumors, may invade the local part of the sympathetic nervous system, leading to changed sweating patterns and eye muscle problems (a combination known as Horner's syndrome), as well as muscle weakness in the hands due to invasion of the brachial plexus.

In many patients, the cancer has already spread beyond the original site by the time they have symptoms and seek medical attention. Common sites of metastasis include the bone, such as the spine (causing back pain and occasionally spinal cord compression), the liver and the brain.

About 10% of people with lung cancer do not have symptoms of it at the time of diagnosis; these cancers are usually found on routine chest x-rays.[12]

Unfortunately, many of the symptoms of lung cancer (bone pain, fever, weight loss ) are nonspecific and in the elderly may be attributed to comorbid illness. [13]


Causes
Exposure to carcinogens in tobacco smoke causes cumulative changes to the tissue lining the bronchi of the lungs (the bronchial mucous membrane) and more tissue gets damaged until a tumour develops.

There are four major causes of lung cancer (and cancer in general):

Carcinogens such as those in tobacco smoke
Radiation exposure
Genetic susceptibility
Viral infection

The role of smoking

The incidence of lung cancer is highly correlated with smoking. Source:NIH.Smoking, particularly of cigarettes, is by far the main contributor to lung cancer, which at least in theory makes it one of the easiest diseases to prevent. In the United States, smoking is estimated to account for 87% of lung cancer cases (90% in men and 79% in women), and in the UK for 90%. Cigarette smoke contains 19 known carcinogens[4] including radioisotopes from the radon decay sequence, nitrosamine, and benzopyrene. Additionally, nicotine appears to depress the immune response to malignant growths in exposed tissue. The length of time a person continues to smoke as well as the amount smoked increases the person's chances of developing lung cancer. If a person stops smoking, these chances steadily decrease as damage to the lungs is repaired and contaminant particles are gradually vacated. More recent work has shown that, across the developed world, almost 90% of lung cancer deaths are caused by smoking.[14] In addition, there is evidence that lung cancer in never-smokers has a better prognosis than in smokers,[15] and that patients who smoke at the time of diagnosis have shorter survival than those who have quit.[16] Passive smoking—the inhalation of smoke from another's smoking— is claimed to be a cause of lung cancer in non-smokers. Studies from the USA (1986,[17][18] 1992,[19] 1997,[20] 2001,[21] 2003[22]), Europe (1998[23]), the UK (1998[24][25]), and Australia (1997[26]) have consistently shown a significant increase in relative risk among those exposed to passive smoke.

In 1993, the United States Environmental Protection Agency (EPA) claimed that about 3,000 lung cancer-related deaths a year were caused by passive smoking. However, since this report was based on a study that was alleged to be heavily biased and was ruled by a federal judge to be "unscientific", the EPA report was declared null and void by a federal judge in 1998[27][28].




Percentage of lung cancer deaths attributable to smoking in the developed world 35-69 years 70 years+ All ages
Men 93.9% 90.3% 92.5%
Women 68.8% 68.9% 68.8%
Both 88.7% 84.3% 86.6%

The extensive attempts made by Philip Morris to delay the release of the 1997 IARC study, to affect the wording of its conclusions, to neutralise its negative results for their business, and to counteract its impact on public and policymakers' opinion have been documented by Ong & Glantz in The Lancet journal.[29] Their work was based on 32 million pages of documents made public as part of the settlement of the 1998 legal case of State of Minnesota and Blue Cross/Blue Shield of Minnesota vs Philip Morris Inc, et al. and available at Philip Morris' own website.[30]

Recent investigation of sidestream smoke suggests it is more dangerous than direct smoke inhalation.[31]


Asbestos
Asbestos can cause a variety of lung diseases. It increases the risk of developing lung cancer. There is a synergistic effect between tobacco smoking and asbestos in the formation of lung cancer.[32]

Asbestos can also cause cancer of the pleura, called mesothelioma (which is distinct from lung cancer).


Radon gas
Radon is a colorless and odourless gas generated by the breakdown of radioactive radium, which in turn is the decay product of uranium, found in the earth's crust. The radiation decay products ionize genetic material, causing mutations that sometimes turn cancerous. Radon exposure is the second major cause of lung cancer after smoking.[8]

Radon gas levels vary by locality and the composition of the underlying soil and rocks. For example, in areas such as Cornwall in the UK (which has granite as substrata), radon gas is a major problem, and buildings have to be force-ventilated with fans to lower radon gas concentrations. The United States Environmental Protection Agency (EPA) estimates that one in 15 homes in the USA has radon levels above the recommended guideline of 4 picoCuries per liter (pCi/L).[33] Iowa has the highest average radon concentration in the United States; studies performed there have demonstrated a 50% increased lung cancer risk with prolonged radon exposure above the EPA's action level of 4 pCi/L.[34][35]


Genetics and viruses
Oncogenes are genes that are believed make people more susceptible to cancer. Proto-oncogenes are believed to turn into oncogenes when exposed to particular carcinogens.[36] Viruses are known to cause lung cancer in animals[37][38] and recent evidence suggests similar potential in humans.[39][40]


Diagnosis

Chest x-ray showing lung cancer in the left lung.Performing a chest x-ray is the first step if a patient reports symptoms that may be suggestive of lung cancer. This may reveal an obvious mass, widening of the mediastinum (suggestive of spread to lymph nodes there), atelectasis (collapse), consolidation (infection) and pleural effusion. If there are no X-ray findings but the suspicion is high (e.g. a heavy smoker with blood-stained sputum), bronchoscopy and/or a CT scan may provide the necessary information. In any case, bronchoscopy or CT-guided biopsy is often necessary to identify the tumor type.[12]


CT scan showing lung cancer in the left lung.The differential diagnosis for patients who present with abnormalities on chest x-ray includes lung cancer, as well as other nonmalignant diseases. These include infectious causes such as tuberculosis or pneumonia, or inflammatory conditions such as sarcoidosis. These diseases can result in mediastinal lymphadenopathy or lung nodules, and sometimes mimic lung cancers.[13]


Types
There are two main types of lung cancer categorized by the size and appearance of the malignant cells seen by a histopathologist under a microscope: non-small cell (80%) and small-cell (roughly 20%) lung cancer.[12] This classification although based on simple pathomorphological criteria has very important implications for clinical management and prognosis of the disease.


Non-small cell lung cancer
The non-small cell lung cancers are grouped together because their prognosis and management are roughly identical. When it cannot be subtyped, it is frequently coded to 8046/3. The subtypes are:

Squamous cell carcinoma, accounting for 29% of lung cancers,[12] also starts in the larger bronchi but grows slower. This means that the size of these tumours varies on diagnosis.
Adenocarcinoma is the most common subtype of NSCLC, accounting for 32% of lung cancers.[12] It is a form which starts near the gas-exchanging surface of the lung. Most cases of adenocarcinoma are associated with smoking. However, among people who have never smoked ("never-smokers"), adenocarcinoma is the most common form of lung cancer.[41] A subtype of adenocarcinoma, the bronchioloalveolar carcinoma, is more common in female never-smokers, and may have different responses to treatment.[42]
Large cell carcinoma is a fast-growing form, accounting for 9% of lung cancers,[12] that grows near the surface of the lung.

Small cell lung cancer

Small cell lung carcinoma (microscopic view of a core needle biopsy)SCLC (also called "oat cell carcinoma") is the less common form of lung cancer. It tends to start in the larger breathing tubes and grows rapidly becoming quite large. The oncogene most commonly involved is L-myc. The "oat" cell contains dense neurosecretory granules which give this an endocrine/paraneoplastic syndrome association. It is initially more sensitive to chemotherapy, but ultimately carries a worse prognosis and is often metastatic at presentation. This type of lung cancer is strongly associated with smoking.

Other types
Carcinoid
Adenoid cystic carcinoma
Cylindroma
Mucoepidermoid carcinoma

Metastatic cancers
The lung is a common place for metastasis from tumors in other parts of the body. These cancers, however, are identified by the site of origin, i.e., a breast cancer metastasis to the lung is still known as breast cancer. The adrenal glands, liver, brain, and bone are the most common sites of metastasis from primary lung cancer itself.


Lung cancer staging
Lung cancer staging is an assessment of the degree of spread of the cancer from its original source. It is an important contributor to the prognosis and potential treatment of lung cancer.

Non-small cell lung cancer is staged from IA ("one A", best prognosis) to IV ("four", worst prognosis).

See non-small cell lung cancer staging.[43]

Small cell lung cancer is classified as limited stage if it is confined to one half of the chest and within the scope of a single radiotherapy field. Otherwise it extensive stage.[44]


Treatment
Treatment for lung cancer depends on the cancer's specific cell type, how far it has spread, and the patient's performance status. Common treatments include surgery, chemotherapy, and radiation therapy. The 5-year overall survival rate is 14%.[12]


Surgery
If investigations confirm lung cancer, CT scan and often positron emission tomography (PET) are used to determine whether the disease is localised and amenable to surgery or whether it has spread to the point where it cannot be cured surgically.

Blood tests and spirometry (lung function testing) are also necessary to assess whether the patient is well enough to be operated on. If spirometry reveals a very poor respiratory reserve, as may occur in chronic smokers, surgery may be contraindicated.

Surgery itself has an overall operative death rate of 5%, depending on the patient's lung function and other risk factors.[45] Surgery is usually only an option in non-small cell lung cancer limited to one lung, up to stage IIIA. This is assessed with medical imaging (computed tomography, positron emission tomography). A sufficient pre-operative respiratory reserve must be present to allow adequate lung function after the tissue is removed.

Procedures include wedge excision (removal of part of a lobe), lobectomy (one lobe), bilobectomy (two lobes) or pneumonectomy (whole lung). In patients with adequate respiratory reserve, lobectomy is the preferred option, as this minimizes the chance of local recurrence. If the patient does not have enough functional lung for this, wedge excision may be performed.[46] Radioactive iodine brachytherapy at the margins of wedge excision may reduce recurrence to that of lobectomy.[47]


Chemotherapy
Small cell lung cancer is treated primarily with chemotherapy, as surgery has no demonstrable influence on survival. Primary chemotherapy is also given in metastatic non-small cell lung cancer.

The combination regimen depends on the tumour type:

NSCLC: cisplatin or carboplatin, in combination with gemcitabine, paclitaxel, docetaxel, etoposide or vinorelbine.[48]
SCLC: cisplatin and etoposide are most commonly used.[49] Combinations with carboplatin, gemcitabine, paclitaxel, vinorelbine, topotecan and irinotecan are also used.[50][51]

Adjuvant chemotherapy
Adjuvant chemotherapy refers to the use of chemotherapy after surgery to improve the outcome. During surgery, samples are taken from the lymph nodes. If these samples contain cancer, then the patient has stage II or III disease. In this situation, adjuvant chemotherapy may improve survival by up to 15%.[52][53]

Standard practice is to offer platinum-based chemotherapy (e.g. cisplatin and vinorelbine).[54]

Adjuvant chemotherapy for patients with stage IB cancer is controversial as clinical trials have not clearly demonstrated a survival benefit.[55][56]

Trials of preoperative chemotherapy (neoadjuvant chemotherapy) in resectable non-small cell lung cancer have been inconclusive.[57]


Targeted therapy
In recent years, various molecular targeted therapies have been developed for the treatment of advanced lung cancer. Gefitinib (Iressa) is one such drug, which targets the tyrosine kinase domain of the epidermal growth factor receptor (EGF-R) which is expressed in many cases of non-small cell lung cancer. However despite an exciting start it was not shown to increase survival, although females, Asians, non-smokers and those with the bronchioloalveolar carcinoma cell type appear to be deriving most benefit from gefitinib.[42]

Erlotinib (Tarceva), another tyrosine kinase inhibitor, has been shown to increase survival in lung cancer patients and has recently been approved by the FDA for second-line treatment of advanced non-small cell lung cancer. [Similar to gefitinib, it appeared to work best in females, Asians, non-smokers and those with the bronchioloalveolar carcinoma cell type.]

A number of targeted agents are at the early stages of clinical research, such as cyclo-oxygenase-2 (COX-2) inhibitors, the apoptosis promoter exisulind,[58] proteasome inhibitors, bexarotene (Targretin) and vaccines.[59]

Treatment of lung cancer is evolving.[60][61][62]


Radiotherapy
Radiotherapy is often given together with chemotherapy, and may be used with curative intent in patients who are not eligible for surgery. A radiation dose of 40 or more Gy in many fractions is commonly used with curative intent in non-small cell lung cancer; typically in North America, the dose prescribed is 60 or 66 Gy in 30 to 33 fractions given once daily, 5 days a week, for 6 to 6½ weeks. For small cell lung cancer cases that are potentially curable, in addition to chemotherapy, chest radiation is often recommended. For these small cell lung cancer cases, chest radiation doses of 40 Gy or more in many fractions are commonly given; typically in North America, the dose prescribed is 45 to 50 Gy and can be given in either once daily treatments for 5 weeks or twice daily treatments for 3 weeks.[63]

For both non-small cell lung cancer and small cell lung cancer patients, radiation of disease in the chest to smaller doses (typically 20 Gy in 5 fractions) may be used for symptom control.


Interventional radiology
Radiofrequency ablation is increasing in popularity for this condition as it is nontoxic and causes very little pain. It seems especially effective when combined with chemotherapy as it catches the cells deeper inside a tumor—the ones difficult to get with chemotherapy due to reduced blood supply to the center of the tumor. It is done by inserting a small heat probe into the tumor to kill the tumor cells.[64]


Prognosis
For non-small cell lung cancer, prognosis is poor. Following complete surgical resection of stage IA disease, five-year survival is 67%. With stage IB disease, five-year survival is 57%.[65] The 5-year survival rate of patients with stage IV NSCLC is about 1%.[66]

See non-small cell lung cancer staging.

For small cell lung carcinoma, prognosis is also poor. The overall five-year survival for patients with SCLC is about 5%.[12] Patients with extensive-stage SCLC have an average five-year survival rate of less than 1%. The median survival time for limited-stage disease is 20 months, with a five-year survival rate of 20%.[66]

See Manchester score.


Epidemiology

Lung cancer distribution in the United States.The population segment most likely to develop lung cancer is the over-fifties who also have a history of smoking. Lung cancer is the second most commonly occurring form of cancer in most western countries, and it is the leading cancer-related cause of death for men and women. In the US, 175,000 new cases are expected in 2006:[67] 90,700 in men and 80,000 in women. Although the rate of men dying from lung cancer is declining in western countries, it is actually increasing for women due to the increased takeup of smoking by this group. Among lifetime non-smokers, men who have never smoked have higher age-standardized lung cancer death rates than women. Of the 80,000 women who are diagnosed with lung cancer in 2006, approximately 70,000 are expected to die from it.[68]

Lung cancer was extremely rare prior to the advent of cigarette smoking. In 1878, malignant lung tumors made up only 1% of all cancers seen at autopsy; this had risen to 10-15% by the early 1900s.[69] Case reports in the medical literature numbered only 374 worldwide in 1912.[70] The British Doctors Study, published in the 1950s, first offered solid epidemiological evidence on the link between lung cancer and smoking.

Not all cases of lung cancer are due to smoking, but the role of passive smoking is increasingly being recognized as a risk factor for lung cancer, leading to policy interventions to decrease undesired exposure of non-smokers to others' tobacco smoke. Emissions from automobiles, factories and power plants also pose potential risks.[9][11][71]

Eastern Europe has the highest lung cancer mortality among men, while northern Europe and the USA have the highest mortality among women. Lung cancer incidence is less common in developing countries.[72]


Prevention

Primary prevention
Prevention is the most cost-effective means of fighting lung cancer on the national and global scales. While in most countries industrial and domestic carcinogens have been identified and banned, tobacco smoking is still widespread. Eliminating tobacco smoking is a primary goal in the prevention of lung cancer, and smoking cessation is an important preventative tool in this process.[73]

Policy interventions to decrease passive smoking (e.g. in restaurants and workplaces) have become more common in various Western countries, with California taking a lead in banning smoking in public establishments in 1998, Ireland playing a similar role in Europe in 2004, followed by Italy and Norway in 2005 and Scotland as well as several others in 2006 New Zealand has also recently banned smoking in public places. (See Smoking ban and list of smoking bans).

Only the Asian state of Bhutan has a complete smoking ban (since 2005). In many countries pressure groups are campaigning for similar bans. Arguments cited against such bans are criminalisation of smoking, increased risk of smuggling and the risk that such a ban cannot be enforced.


Screening
Main article: lung cancer screening
Screening refers to the use of medical tests to detect disease in asymptomatic people. Possible screening tests for lung cancer include chest x-ray or computed tomography (CT) of the chest.

So far, screening programs for lung cancer have not demonstrated any clear benefit. However randomized controlled studies are underway in this area to see if decreased long-term mortality can be directly observed from CT screening.[74]