Lung cancer


Lung cancer
Lung cancer
Classification and external resources

Cross section of a human lung. The white area in the upper lobe is cancer; the black areas are discoloration due to smoking.
ICD-10 C33-C34
ICD-9 162
DiseasesDB 7616
MedlinePlus 007194
eMedicine med/1333 med/1336 emerg/335 radio/807 radio/405 radio/406
MeSH D002283

Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary lung cancers, are carcinomas that derive from epithelial cells. Worldwide, lung cancer is the most common cause of cancer-related death in men and women, and is responsible for 1.3 million deaths annually, as of 2004.[1] The most common symptoms are shortness of breath, coughing (including coughing up blood), and weight loss.[2]

The main types of lung cancer are small-cell lung cancer (SCLC), also called oat cell cancer, and non-small-cell lung cancer (NSCLC). The most common cause of lung cancer is long-term exposure to tobacco smoke.[3] Nonsmokers account for 15% of lung cancer cases,[4] and these cases are often attributed to a combination of genetic factors,[5][6] radon gas,[7] asbestos,[8] and air pollution[9][10][11] including secondhand smoke.[12][13]

Lung cancer may be seen on chest radiograph and computed tomography (CT scan). The diagnosis is confirmed with a biopsy. This is usually performed by bronchoscopy or CT-guided biopsy. Treatment and prognosis depend on the histological type of cancer, the stage (degree of spread), and the patient's general wellbeing, measured by performance status. Common treatments include surgery, chemotherapy, and radiotherapy. NSCLC is sometimes treated with surgery, whereas SCLC usually responds better to chemotherapy and radiation therapy. This is partly because SCLC often spreads quite early, and these treatments are generally better at getting to cancer cells that have spread to other parts of the body.[14]

Survival depends on stage, overall health, and other factors, but overall 14% of people diagnosed with lung cancer survive five years after the diagnosis.[2]

Contents

Signs and symptoms

Symptoms that may suggest lung cancer include:[15]

If the cancer grows in the airway, it may obstruct airflow, causing breathing difficulties. The obstruction can lead to accumulation of secretions behind the blockage, and predispose 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.[16] In lung cancer, these phenomena may include Lambert-Eaton myasthenic syndrome (muscle weakness due to auto-antibodies), hypercalcemia, or syndrome of inappropriate antidiuretic hormone (SIADH). Tumors in the top (apex) of the lung, known as Pancoast tumors,[17] 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.

Many of the symptoms of lung cancer (bone pain, fever, and weight loss) are nonspecific; in the elderly, these may be attributed to comorbid illness.[14] 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 brain, bone, adrenal glands, contralateral (opposite) lung, liver, pericardium, and kidneys.[18] About 10% of people with lung cancer do not have symptoms at diagnosis; these cancers are incidentally found on routine chest radiograph.[2]

Causes

The main causes of any cancer include carcinogens (such as those in tobacco smoke), ionizing radiation, and viral infection. This exposure causes cumulative changes to the DNA in the tissue lining the bronchi of the lungs (the bronchial epithelium). As more tissue becomes damaged, eventually a cancer develops.[14]

Smoking

NIH Graph showing how a general increase in sales of tobacco products in the USA in the first 4 decades of the 20th century (cigarettes per person per year) led to a corresponding rapid increase in the incidence of lung cancer during the 1930s, 40s and 50s (lung cancer deaths per 100000 male population per year).

Smoking, particularly of cigarettes, is by far the main contributor to lung cancer.[19] Cigarette smoke contains over 60 known carcinogens,[20] including radioisotopes from the radon decay sequence, nitrosamine, and benzopyrene. Additionally, nicotine appears to depress the immune response to malignant growths in exposed tissue.[21] Across the developed world, 91% of lung cancer deaths in men during the year 2000 were attributed to smoking (71% for women).[22] In the United States, smoking is estimated to account for 87% of lung cancer cases (90% in men and 85% in women).[23] Among male smokers, the lifetime risk of developing lung cancer is 17.2%; among female smokers, the risk is 11.6%. This risk is significantly lower in nonsmokers: 1.3% in men and 1.4% in women.[24]

Women who smoke (former smokers and current smokers) and take hormone therapy are at a much higher risk of dying of lung cancer. In a study by Chlebowski et al. published in 2009, the women taking hormones were about 60% more likely to die of lung cancer than the women taking a placebo. Not surprisingly, the risk was highest for current smokers, followed by past smokers, and lowest for those who have never smoked. Among the women who smoked (former or current smokers), 3.4% of those taking hormone therapy died of lung cancer compared to 2.3% for women taking the placebo.[25]

The time a person smokes (as well as rate of smoking) increases the person's chance of developing lung cancer. If a person stops smoking, this chance steadily decreases as damage to the lungs is repaired and contaminant particles are gradually removed.[26] In addition, there is evidence that lung cancer in never-smokers has a better prognosis than in smokers,[27] and that patients who smoke at the time of diagnosis have shorter survival times than those who have quit.[28]

Passive smoking—the inhalation of smoke from another's smoking—is a cause of lung cancer in nonsmokers. A passive smoker can be classified as someone living or working with a smoker. Studies from the U.S.,[29] Europe,[30] the UK,[31] and Australia[32] have consistently shown a significant increase in relative risk among those exposed to passive smoke. Recent investigation of sidestream smoke suggests that it is more dangerous than direct smoke inhalation.[33]

10–15% of lung cancer patients have never smoked.[34] That means between 20,000 to 30,000 never-smokers are diagnosed with lung cancer in the United States each year. Because of the five-year survival rate, each year in the U.S. more never-smokers die of lung cancer than do patients of leukemia, ovarian cancer, or AIDS.[35]

Radon gas

Radon is a colorless and odorless 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 in the general population, after smoking[7] with the risk increasing 8–16% for every 100 Bq/ increase in the radon concentration.[36] 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 U.S. has radon levels above the recommended guideline of 4 picocuries per liter (pCi/L) (148 Bq/m³).[37] 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.[38][39]

Asbestos

Ferruginous bodies the histopathologic finding associated with asbestosis.

Asbestos can cause a variety of lung diseases, including lung cancer. There is a synergistic effect between tobacco smoking and asbestos in the formation of lung cancer.[8] In the UK, asbestos accounts for 2–3% of male lung cancer deaths.[40] Asbestos can also cause cancer of the pleura, called mesothelioma (which is different from lung cancer).

Viruses

Viruses are known to cause lung cancer in animals,[41][42] and recent evidence suggests similar potential in humans. Implicated viruses include human papillomavirus,[43] JC virus,[44] simian virus 40 (SV40), BK virus, and cytomegalovirus.[45] These viruses may affect the cell cycle and inhibit apoptosis, allowing uncontrolled cell division.

Particulate matter

Studies of the American Cancer Society cohort directly link the exposure to particulate matter with lung cancer. For example, if the concentration of particles in the air increases by only 1%, the risk of developing a lung cancer increases by 14%.[46][47] Further, it has been established that particle size matters, as ultrafine particles penetrate further into the lungs.[48]

Pathogenesis

Similar to many other cancers, lung cancer is initiated by activation of oncogenes or inactivation of tumor suppressor genes.[49] Oncogenes are genes that are believed to make people more susceptible to cancer. Proto-oncogenes are believed to turn into oncogenes when exposed to particular carcinogens.[50] Mutations in the K-ras proto-oncogene are responsible for 10–30% of lung adenocarcinomas.[51][52] The epidermal growth factor receptor (EGFR) regulates cell proliferation, apoptosis, angiogenesis, and tumor invasion.[51] Mutations and amplification of EGFR are common in non-small-cell lung cancer and provide the basis for treatment with EGFR-inhibitors. Her2/neu is affected less frequently.[51] Chromosomal damage can lead to loss of heterozygosity. This can cause inactivation of tumor suppressor genes. Damage to chromosomes 3p, 5q, 13q, and 17p are particularly common in small-cell lung carcinoma. The p53 tumor suppressor gene, located on chromosome 17p, is affected in 60-75% of cases.[53] Other genes that are often mutated or amplified are c-MET, NKX2-1, LKB1, PIK3CA, and BRAF.[51]

Several genetic polymorphisms are associated with lung cancer. These include polymorphisms in genes coding for interleukin-1,[54] cytochrome P450,[55] apoptosis promoters such as caspase-8,[56] and DNA repair molecules such as XRCC1.[57] People with these polymorphisms are more likely to develop lung cancer after exposure to carcinogens.

A recent study suggested that the MDM2 309G allele is a low-penetrant risk factor for developing lung cancer in Asians.[58]

Diagnosis

Chest radiograph showing a cancerous tumor in the left lung.

Performing a chest radiograph is the first step if a patient reports symptoms that may suggest lung cancer. This may reveal an obvious mass, widening of the mediastinum (suggestive of spread to lymph nodes there), atelectasis (collapse), consolidation (pneumonia), or pleural effusion. If there are no radiographic findings but the suspicion is high (such as a heavy smoker with blood-stained sputum), bronchoscopy and/or a CT scan may provide the necessary information. Bronchoscopy or CT-guided biopsy is often used to identify the tumor type.[2]

Abnormal findings in cells ("atypia") in sputum are associated with an increased risk of lung cancer. Sputum cytologic examination combined with other screening examinations may have a role in the early detection of lung cancer.[59]

CT scan showing a cancerous tumor in the left lung.

The differential diagnosis for patients who present with abnormalities on chest radiograph includes lung cancer as well as 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.[14] Lung cancer can also be an incidental finding: a solitary pulmonary nodule (also called a coin lesion) on a chest radiograph or CT scan taken for an unrelated reason. The definitive diagnosis of lung cancer and its classification (described above) is based on examination of the suspicious tissue under the microscope by a pathologist.

Classification

Lung cancers are classified according to histological type. This classification has important implications for clinical management and prognosis of the disease. The vast majority of lung cancers are carcinomas—malignancies that arise from epithelial cells. The two most prevalent histological types of lung carcinoma, categorized by the size and appearance of the malignant cells seen by a histopathologist under a microscope, are non-small-cell and small-cell lung carcinoma.[60] The non-small-cell type is the most prevalent by far (see accompanying table).

Frequency of histological types of lung cancer[60]
Histological type Frequency (%)
Non-small-cell lung carcinoma 80.4
Small-cell lung carcinoma 16.8
Carcinoid[61] 0.8
Sarcoma[62] 0.1
Unspecified lung cancer 1.9

Cancer found outside of the lung may be determined to have arisen within the lung, as lung cancers that metastasize, i.e. spread, often retain a cell marker profile that allow a pathologist to say, with a good deal of certainty, that the tumor arose from the lung, i.e. is a primary lung cancer. Primary lung cancers of adenocarcinoma histology typically have nuclear immunostaining with TTF-1.[63][64]

Non-small-cell lung carcinoma

Micrograph of squamous carcinoma, a type of non-small-cell carcinoma. FNA specimen. Pap stain.

The non-small-cell lung carcinomas (NSCLC) are grouped together because their prognosis and management are similar. There are three main sub-types: squamous cell lung carcinoma, adenocarcinoma, and large-cell lung carcinoma.

Sub-types of non-small-cell lung cancer in
smokers and never-smokers
[65]
Histological sub-type Frequency of non-small-cell lung cancers (%)
Smokers Never-smokers
Squamous cell lung carcinoma 42 33
Adenocarcinoma Adenocarcinoma (not otherwise specified) 39 35
Bronchioloalveolar carcinoma 4 10
Carcinoid 7 16
Other 8 6
Pie chart of the incidence of lung cancer types in the Nurses' Health Study, sorted by histological subtypes, in turn sorted into how many are non-smokers versus smokers[66]

Accounting for 25% of lung cancers,[67] squamous cell lung carcinoma usually starts near a central bronchus. A hollow cavity and associated necrosis are commonly found at the center of the tumor. Well-differentiated squamous cell lung cancers often grow more slowly than other cancer types.[14]

Adenocarcinoma accounts for 40% of non-small-cell lung cancers.[67] It usually originates in peripheral lung tissue. 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.[68] A subtype of adenocarcinoma, the bronchioloalveolar carcinoma, is more common in female never-smokers, and may have different responses to treatment.[69]

Small-cell lung carcinoma

Small-cell lung carcinoma (microscopic view of a core needle biopsy).

Small-cell lung carcinoma (SCLC) is less common. It was formerly referred to as "oat-cell" carcinoma.[70] Most cases arise in the larger airways (primary and secondary bronchi) and grow rapidly, becoming quite large.[71] The small cells contain dense neurosecretory granules (vesicles containing neuroendocrine hormones), which give this tumor an endocrine/paraneoplastic syndrome association.[72] While initially more sensitive to chemotherapy and radiation, it is often metastatic at presentation, and ultimately carries a worse prognosis. Small-cell lung cancers have long been dichotomously staged into limited and extensive stage disease. This type of lung cancer is strongly associated with smoking.[73]

Others

Lung cancers are highly heterogeneous malignancies, with tumors containing more than one subtype being very common.[74]

Currently, the most widely recognized and utilized lung cancer classification system is the 4th revision of the Histological Typing of Lung and Pleural Tumours, published in 2004 as a cooperative effort by the World Health Organization and the International Association for the Study of Lung Cancer. It recognizes numerous other distinct histopathological entities of non-small-cell lung carcinoma, organized into several additional subtypes, including sarcomatoid carcinoma, salivary gland tumors, carcinoid tumor, and adenosquamous carcinoma. The latter subtype includes tumors containing at least 10% each of adenocarcinoma and squamous cell carcinoma. When a tumor is found to contain a mixture of both small-cell carcinoma and non-small-cell carcinoma, it is classified as a variant of small-cell carcinoma and called a combined small-cell carcinoma. Combined small-cell carcinoma is the only currently recognized variant of small-cell carcinoma.

In infants and children, the most common primary lung cancers are pleuropulmonary blastoma and carcinoid tumor.[75]

Metastasis

Micrograph of a lung lymph node biopsy showing metastatic colorectal adenocarcinoma. Field stain.

The lung is a common place for metastasis of tumors from other parts of the body. Secondary cancers are classified by the site of origin; e.g., breast cancer that has spread to the lung is called breast cancer. Metastases often have a characteristic round appearance on chest radiograph.[76] Solitary round lung nodules are not infrequently of an uncertain etiology and may prompt a lung biopsy.

In children, the majority of lung cancers are secondary.[75]

Primary lung cancers themselves most commonly metastasize to the adrenal glands, liver, brain, and bone.[14]

Staging

Lung cancer staging is an assessment of the degree of spread of the cancer from its original source. In most studies, it is the most important factor affecting the prognosis and potential treatment of lung cancer.

Staging varies for the two major cell types of lung cancer (non-small cell lung carcinoma and small cell lung carcinoma). It is normally done prior to attempts at curative therapy, and usually consists of an extensive battery of tests, to include physical examination, laboratory tests, imaging studies, and/or biopsies and other invasive procedures (such as mediastinoscopy). Non-small cell lung carcinoma is usually staged from IA ("one A"; best prognosis) to IV ("four"; worst prognosis).[77] Small cell lung carcinoma has traditionally been classified as limited stage (confined to one half of the chest and within the scope of a single tolerable radiotherapy field) or extensive stage (more widespread disease).

For both NSCLC and SCLC, there are two general types of staging evaluations:

Clinical Staging: evaluated prior to definitive surgery, and typically based on the results of physical examination, imaging studies, and pertinent laboratory findings. Does not necessarily involve a pathologist.

Pathological Staging: usually evaluated either intra- or post-operatively, and based on the combined results of surgical and clinical findings.[71]

Prevention

Prevention is the most cost-effective means of fighting lung cancer. 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 preventive tool in this process.[78] Of utmost importance are prevention programs that target the young. In 1998 the Master Settlement Agreement entitled 46 states in the USA to an annual payout from the tobacco companies.[79] Between the settlement money and tobacco taxes, each state's public health department funds their prevention programs, although none of the states are living up to the Center for Disease Control's recommended amount by spending 15 percent of tobacco taxes and settlement revenues on these prevention efforts.[79]

Policy interventions to decrease passive smoking in public areas such as restaurants and workplaces have become more common in many Western countries, with California taking a lead in banning smoking in public establishments in 1998. Ireland played a similar role in Europe in 2004, followed by Italy and Norway in 2005, Scotland as well as several others in 2006, England in 2007, France in 2008 and Turkey in 2009. New Zealand has banned smoking in public places as of 2004. The state of Bhutan has had a complete smoking ban since 2005.[80] In many countries, pressure groups are campaigning for similar bans. In 2007, Chandigarh became the first city in India to become smoke-free. India introduced a total ban on smoking in public places on 2 October 2008.

Arguments cited against such bans are criminalization of smoking, increased risk of smuggling, and the risk that such a ban cannot be enforced.[81]

The long-term use of supplemental multivitamins—such as vitamin C, vitamin E, and folate—does not reduce the risk of lung cancer. Indeed long-term intake of high doses of vitamin E supplements may even increase the risk of lung cancer.[82] However, eating at least five servings of fruits and vegetables per day and following a diet that conforms to the American Cancer Society's guidelines may help lower risk.[83]

The World Health Organization has called for governments to institute a total ban on tobacco advertising to prevent young people from taking up smoking. They assess that such bans have reduced tobacco consumption by 16% where already instituted.[84]

Screening

Screening refers to the use of medical tests to detect disease in asymptomatic people. Possible screening tests for lung cancer include chest radiograph, or computed tomography (CT). As of December 2009, screening programs for lung cancer have not demonstrated any benefit.[85][86]

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 palliative care,[87] surgery, chemotherapy, and radiation therapy.[2][88]

Surgery

Pneumonectomy specimen containing a squamous cell carcinoma, seen as a white area near the bronchi.

If investigations confirm lung cancer, CT scan and often positron emission tomography (PET) are used to determine whether the disease is localized 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 poor respiratory reserve (often due to chronic obstructive pulmonary disease), surgery may be contraindicated.

Surgery for lung cancer has an operative death rate of about 4.4%, depending on the patient's lung function and other risk factors.[89] In non-small-cell lung carcinoma, surgery is usually only an option if the cancer is limited to one lung, up to stage IIIA. This is assessed with medical imaging (computed tomography, positron emission tomography). A sufficient preoperative respiratory reserve must be present to allow adequate lung function after the tissue is removed.

Procedures include wedge resection (removal of part of a lobe), segmentectomy (removal of an anatomic division of a particular lobe of the lung), 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 resection may be performed.[90] Radioactive iodine brachytherapy at the margins of wedge excision may reduce recurrence to that of lobectomy.[91]

Video-assisted thoracoscopic surgery and VATS lobectomy have allowed for minimally invasive approaches to lung cancer surgery that may have the advantages of quicker recovery, shorter hospital stay and diminished hospital costs.[92]

Early studies suggested that small-cell lung carcinoma (SCLC) fared better when treated with chemotherapy and/or radiation than when treated surgically.[93][94] While this approach to treating SCLC remains the current standard of care,[95] the role of surgery in SCLC is being reconsidered, recent reviews indicating that surgery might improve outcomes when added to chemotherapy and radiation in early stage SCLC[96] and combined forms of SCLC and NSCLC.[97]

Radiotherapy

Radiotherapy is often given together with chemotherapy, and may be used with curative intent in patients with non-small-cell lung carcinoma who are not eligible for surgery. This form of high intensity radiotherapy is called radical radiotherapy.[98] A refinement of this technique is continuous hyperfractionated accelerated radiotherapy (CHART), in which a high dose of radiotherapy is given in a short time period.[99] For small-cell lung carcinoma cases that are potentially curable, chest radiation is often recommended in addition to chemotherapy.[100] The use of adjuvant thoracic radiotherapy following curative intent surgery for non-small-cell lung carcinoma is not well established and is controversial. Benefits, if any, may only be limited to those in whom the tumor has spread to the mediastinal lymph nodes.[101][102]

For both non-small-cell lung carcinoma and small-cell lung carcinoma patients, smaller doses of radiation to the chest may be used for symptom control (palliative radiotherapy). Unlike other treatments, it is possible to deliver palliative radiotherapy without confirming the histological diagnosis of lung cancer.

Brachytherapy (localized radiotherapy) may be given directly inside the airway when cancer affects a short section of bronchus.[103] It is used when inoperable lung cancer causes blockage of a large airway.[104]

Patients with limited-stage small-cell lung carcinoma are usually given prophylactic cranial irradiation (PCI). This is a type of radiotherapy to the brain, used to reduce the risk of metastasis.[105] More recently, PCI has also been shown to be beneficial in those with extensive small-cell lung cancer. In patients whose cancer has improved following a course of chemotherapy, PCI has been shown to reduce the cumulative risk of brain metastases within one year from 40.4% to 14.6%.[106]

Recent improvements in targeting and imaging have led to the development of extracranial stereotactic radiation in the treatment of early-stage lung cancer. In this form of radiation therapy, very high doses are delivered in a small number of sessions using stereotactic targeting techniques. Its use is primarily in patients who are not surgical candidates due to medical comorbidities.[107]

Chemotherapy

The chemotherapy regimen depends on the tumor type.

Small-cell lung carcinoma

Even if relatively early stage, small-cell lung carcinoma is treated primarily with chemotherapy and radiation.[108] In small-cell lung carcinoma, cisplatin and etoposide are most commonly used.[109] Combinations with carboplatin, gemcitabine, paclitaxel, vinorelbine, topotecan, and irinotecan are also used.[110][111] Celecoxib showed a potential signal of response in a small study.[112]

Non-small-cell lung carcinoma

Primary chemotherapy is also given in advanced and metastatic non-small-cell lung carcinoma.

Testing for the molecular genetic subtype of non-small-cell lung cancer may be of assistance in selecting the most appropriate initial therapy[113] For example, mutation of the epidermal growth factor receptor gene[114] may predict whether initial treatment with a specific inhibitor or with chemotherapy is more advantageous.[115]

Advanced non-small-cell lung carcinoma is often treated with cisplatin or carboplatin, in combination with gemcitabine, paclitaxel, docetaxel, etoposide, or vinorelbine.[116] Bevacizumab improves results in non-squamous cancers treated with paclitaxel and carboplatin in patients less than 70 years old who have reasonable general performance status.[117]

Pemetrexed has been approved for use in non-small-cell lung cancer.[118] For adenocarcinoma and large-cell lung cancer, cisplatin with pemetrexed was more beneficial than cisplatin and gemcitabine; squamous cancer had the opposite results.[119] As a consequence, subtyping of non-small lung cancer histology has become more important.[120]

The U.S. Food and Drug Administration (FDA) approved erlotinib (Tarceva)[121] for the treatment of locally advanced or metastatic non-small cell lung cancer that has failed at least one prior chemotherapy regimen,[122] and has also approved its use as maintenance treatment in locally advanced or metastatic non-small cell lung cancer that has not progressed after four cycles of platinum-based first-line chemotherapy.[122]

The U.S. Food and Drug Administration approved crizotinib (Xalkori) to treat certain late-stage (locally advanced or metastatic) non-small cell lung cancers that express the abnormal anaplastic lymphoma kinase (ALK) gene.[123]

Bronchoalveolar carcinoma is a subtype of non-small-cell lung carcinoma that may respond to gefitinib[124] and erlotinib.[125]

Maintenance therapy

In advanced non-small-cell lung cancer there are several approaches for continuing treatment after an initial response to therapy.[126] Switch maintenance changes to different medications than the initial therapy and can use pemetrexed,[127] erlotinib,[128] and docetaxel,[129] although pemetrexed is only used in non-squamous NSCLC.[130]

Adjuvant chemotherapy

Adjuvant chemotherapy refers to the use of chemotherapy after apparently curative surgery to improve the outcome. In non-small-cell lung cancer, samples are taken during surgery of nearby lymph nodes. If these samples contain cancer, the patient has stage II or III disease. In this situation, adjuvant chemotherapy may improve survival by up to 15%.[131][132] Standard practice has often been to offer platinum-based chemotherapy (including either cisplatin or carboplatin).[133] However, the benefit of platinum-based adjuvant chemotherapy was confined to patients who had tumors with low ERCC1 (excision repair cross-complementing 1) activity.[134]

Adjuvant chemotherapy for patients with stage IB cancer is controversial, as clinical trials have not clearly demonstrated a survival benefit.[135][136] Trials of preoperative chemotherapy (neoadjuvant chemotherapy) in resectable non-small-cell lung carcinoma have been inconclusive.[137]

Interventional radiology

Radiofrequency ablation should currently be considered an investigational technique in the treatment of bronchogenic carcinoma. It is done by inserting a small heat probe into the tumor to kill the tumor cells.[138]

Palliative care

In a 2010 study of patients with metastatic non–small-cell lung cancer, early palliative care led to significant improvements in both quality of life and mood. As compared with patients receiving standard care, patients receiving early palliative care had less aggressive care at the end of life but longer survival" (increased by 3 months).[87]

Other studies in advanced cancer also found benefit from palliative care,[139] or found hospice involvement to be beneficial.[140] These approaches allow additional discussion of treatment options and provide opportunities to arrive at well-considered decisions[141][142] and may avoid unhelpful but expensive care at the end of life.[142]

Chemotherapy may be combined with palliative care in the treatment of the non-small-cell lung cancer. In advanced NSCLC, a 1994 meta-analysis found that appropriate chemotherapy improved average survival over supportive care alone,[143] as well as improving quality of life.[144] With adequate physical fitness, maintaining chemotherapy during lung cancer palliation offers a 1.5 to 3 months prolongation of survival, symptomatic relief and an improvement in quality of life, with better results seen with modern agents.[145][146] Since 2008, the NSCLC Meta-Analyses Collaborative Group has recommended that if the recipient wants and can tolerate treatment then chemotherapy should be considered in advanced NSCLC.[147][148]

Prognosis

Prognostic factors in non-small-cell lung cancer include presence or absence of pulmonary symptoms, tumor size, cell type (histology), degree of spread (stage) and metastases to multiple lymph nodes, and vascular invasion. For patients with inoperable disease, prognosis is adversely affected by poor performance status and weight loss of more than 10%.[149] Prognostic factors in small-cell lung cancer include performance status, gender, stage of disease, and involvement of the central nervous system or liver at the time of diagnosis.[150]

For non-small-cell lung carcinoma (NSCLC), prognosis is generally poor. Following complete surgical resection of stage IA disease, five-year survival is 67%. With stage IB disease, five-year survival is 57%.[151] The five-year survival rate of patients with stage IV NSCLC is about 1%.[3]

For small-cell lung carcinoma, prognosis is also generally poor. The overall five-year survival for patients with SCLC is about 5%.[2] 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%.[3]

According to data provided by the National Cancer Institute, the median age at diagnosis of lung cancer in the United States is 70 years,[152] and the median age at death is 72 years.[153]

Epidemiology

Age-standardized death from tracheal, bronchial, and lung cancers per 100,000 inhabitants in 2004.[154]
  no data
  ≤ 5
  5-10
  10-15
  15-20
  20-25
  25-30
  30-35
  35-40
  40-45
  45-50
  50-55
  ≥ 55
Lung cancer distribution in the United States

Worldwide, lung cancer is the most common cancer in terms of both incidence and mortality (1.1 million new cases per year and 0.95 million deaths in males and 0.51 million new cases per year and 0.43 million deaths in females).[155] The highest rates are in Europe and North America.[156] The population segment most likely to develop lung cancer is over-fifties who 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. In contrast to the mortality rate in men, which began declining more than 20 years ago, women's lung cancer mortality rates have been rising over the last decades, and are just recently beginning to stabilize.[157] The evolution of "Big Tobacco" plays a significant role in the smoking culture.[158] Tobacco companies have focused their efforts since the 1970s at marketing their product toward women and girls, especially with "light" and "low-tar" cigarettes.[159] Among lifetime nonsmokers, men have higher age-standardized lung cancer death rates than women.

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 nonsmokers to others' tobacco smoke. Emissions from automobiles, factories, and power plants also pose potential risks.[9][11][160]

Eastern Europe has the highest lung cancer mortality among men, while northern Europe and the U.S. have the highest mortality among women. In the United States, black men and women have a higher incidence.[161] Lung cancer incidence is currently less common in developing countries.[162] With increased smoking in developing countries, the incidence is expected to increase in the next few years, notably in China[163] and India.[164]

Lung cancer incidence (by country) has an inverse correlation with sunlight and UVB exposure. One possible explanation is a preventive effect of vitamin D, which is produced in the skin on exposure to sunlight.[165]

From the 1950s, the incidence of lung adenocarcinoma started to rise relative to other types of lung cancer.[166] This is partly due to the introduction of filter cigarettes. The use of filters removes larger particles from tobacco smoke, thus reducing deposition in larger airways. However the smoker has to inhale more deeply to receive the same amount of nicotine, increasing particle deposition in small airways where adenocarcinoma tends to arise.[167] The incidence of lung adenocarcinoma in the U.S. has fallen since 1999. This may be due to reduction in environmental air pollution.[166] However, in some developing countries like India, there has been little change in the epidemiology with squamous cell carcinoma continuing to be the predominant histological type.[168][169][170] An absence of change in the type of tobacco smoking or the pattern of tobacco consumption in the population could be one of the possible reasons.

History

Lung cancer was uncommon before the advent of cigarette smoking; it was not even recognized as a distinct disease until 1761.[171] Different aspects of lung cancer were described further in 1810.[172] Malignant lung tumors made up only 1% of all cancers seen at autopsy in 1878, but had risen to 10–15% by the early 1900s.[173] Case reports in the medical literature numbered only 374 worldwide in 1912,[174] but a review of autopsies showed that the incidence of lung cancer had increased from 0.3% in 1852 to 5.66% in 1952.[175] In Germany in 1929, physician Fritz Lickint recognized the link between smoking and lung cancer,[173] which led to an aggressive antismoking campaign.[176] The British Doctors Study, published in the 1950s, was the first solid epidemiological evidence of the link between lung cancer and smoking.[177] As a result, in 1964 the Surgeon General of the United States recommended that smokers should stop smoking.[178]

The connection with radon gas was first recognized among miners in the Ore Mountains near Schneeberg, Saxony. Silver has been mined there since 1470, and these mines are rich in uranium, with its accompanying radium and radon gas. Miners developed a disproportionate amount of lung disease, eventually recognized as lung cancer in the 1870s. An estimated 75% of former miners died from lung cancer.[179] Despite this discovery, mining continued into the 1950s, due to the USSR's demand for uranium.[180]

The first successful pneumonectomy for lung cancer was performed in 1933.[181] Palliative radiotherapy has been used since the 1940s.[182] Radical radiotherapy, initially used in the 1950s, was an attempt to use larger radiation doses in patients with relatively early stage lung cancer but who were otherwise unfit for surgery.[183] In 1997, continuous hyperfractionated accelerated radiotherapy (CHART) was seen as an improvement over conventional radical radiotherapy.[99]

With small-cell lung carcinoma, initial attempts in the 1960s at surgical resection[184] and radical radiotherapy[185] were unsuccessful. In the 1970s, successful chemotherapy regimens were developed.[186]

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