Lung cancer, also known as lung carcinoma, is a malignant lung tumor characterized by uncontrolled cell growth in tissues of the lung. This growth can spread beyond the lung by the process of metastasis into nearby tissue or other parts of the body. Most cancers that start in the lung, known as primary lung cancers, are carcinomas. The two main types are small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC). The most common symptoms are coughing (including coughing up blood), weight loss, shortness of breath, and chest pains.
The vast majority (85%) of cases of lung cancer are due to long-term tobacco smoking. About 10–15% of cases occur in people who have never smoked. These cases are often caused by a combination of genetic factors and exposure to radon gas, asbestos, second-hand smoke, or other forms of air pollution. Lung cancer may be seen on chest radiographs and computed tomography (CT) scans. The diagnosis is confirmed by biopsy which is usually performed by bronchoscopy or CT-guidance.
Avoidance of risk factors, including smoking and air pollution, is the primary method of prevention. Treatment and long-term outcomes depend on the type of cancer, the stage (degree of spread), and the person's overall health. Most cases are not curable. Common treatments include surgery, chemotherapy, and radiotherapy. NSCLC is sometimes treated with surgery, whereas SCLC usually responds better to chemotherapy and radiotherapy.
Worldwide in 2012, lung cancer occurred in 1.8 million people and resulted in 1.6 million deaths. This makes it the most common cause of cancer-related death in men and second most common in women after breast cancer. The most common age at diagnosis is 70 years. Overall, 17.4% of people in the United States diagnosed with lung cancer survive five years after the diagnosis, while outcomes on average are worse in the developing world.
|A chest X-ray showing a tumor in the lung (marked by arrow)|
|Symptoms||Coughing (including coughing up blood), weight loss, shortness of breath, chest pains|
|Usual onset||~70 years|
|Types||Small-cell lung carcinoma (SCLC), non-small-cell lung carcinoma (NSCLC)|
|Diagnostic method||Medical imaging, tissue biopsy|
|Treatment||Surgery, chemotherapy, radiotherapy|
|Prognosis||Five-year survival rate 17.4% (US)|
|Frequency||3.3 million affected as of 2015|
|Deaths||1.7 million (2015)|
Signs and symptoms which may suggest lung cancer include:
If the cancer grows in the airways, it may obstruct airflow, causing breathing difficulties. The obstruction can lead to accumulation of secretions behind the blockage, and predispose to pneumonia.
Depending on the type of tumor, paraneoplastic phenomena—symptoms not due to the local presence of cancer—may initially attract attention to the disease. In lung cancer, these phenomena may include hypercalcemia, syndrome of inappropriate antidiuretic hormone (SIADH, abnormally concentrated urine and diluted blood), ectopic ACTH production, or Lambert–Eaton myasthenic syndrome (muscle weakness due to autoantibodies). Tumors in the top of the lung, known as Pancoast tumors, may invade the local part of the sympathetic nervous system, leading to Horner's syndrome (dropping of the eyelid and a small pupil on that side), as well as damage to the brachial plexus.
Many of the symptoms of lung cancer (poor appetite, weight loss, fever, fatigue) are not specific. In many people, the cancer has already spread beyond the original site by the time they have symptoms and seek medical attention. Symptoms that suggest the presence of metastatic disease include weight loss, bone pain and neurological symptoms (headaches, fainting, convulsions, or limb weakness). Common sites of spread include the brain, bone, adrenal glands, opposite lung, liver, pericardium, and kidneys. About 10% of people with lung cancer do not have symptoms at diagnosis; these cancers are incidentally found on routine chest radiography.
Cancer develops after genetic damage to DNA and epigenetic changes. Those changes affect the cell's normal functions, including cell proliferation, programmed cell death (apoptosis), and DNA repair. As more damage accumulates, the risk of cancer increases.
Tobacco smoking is by far the main contributor to lung cancer. Cigarette smoke contains at least 73 known carcinogens, including benzo[a]pyrene, NNK, 1,3-butadiene, and a radioactive isotope of polonium – polonium-210. Across the developed world, 90% of lung cancer deaths in men and 70% of those in women during the year 2000 were attributed to smoking. Smoking accounts for about 85% of lung cancer cases.
Passive smoking – the inhalation of smoke from another's smoking – is a cause of lung cancer in nonsmokers. A passive smoker can be defined as someone either living or working with a smoker. Studies from the US, Europe, and the UK have consistently shown a significantly-increased risk among those exposed to passive smoking. Those who live with someone who smokes have a 20–30% increase in risk while those who work in an environment with secondhand smoke have a 16–19% increase in risk. Investigations of sidestream smoke suggest that it is more dangerous than direct smoke. Passive smoking results in roughly 3,400 lung cancer-related deaths each year in the U.S.
Marijuana smoke contains many of the same carcinogens as those in tobacco smoke. However, the effect of smoking cannabis on lung cancer risk is not clear. A 2013 review did not find an increased risk from light to moderate use. A 2014 review found that smoking cannabis doubled the risk of lung cancer.
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 become cancerous. Radon is the second-most common cause of lung cancer in the US, causing about 21,000 deaths each year. The risk increases 8–16% for every 100 Bq/m³ increase in the radon concentration. Radon gas levels vary by locality and the composition of the underlying soil and rocks. About one in 15 homes in the US have radon levels above the recommended guideline of 4 picocuries per liter (pCi/l) (148 Bq/m³).
Asbestos can cause a variety of lung diseases such as lung cancer. Tobacco smoking and asbestos both have synergistic effects on the development of lung cancer. In smokers who work with asbestos, the risk of lung cancer is increased 45-fold compared to the general population. Asbestos can also cause cancer of the pleura, called mesothelioma – which actually is different from lung cancer.
Outdoor air pollutants, especially chemicals released from the burning of fossil fuels, increase the risk of lung cancer. Fine particulates (PM2.5) and sulfate aerosols, which may be released in traffic exhaust fumes, are associated with a slightly-increased risk. For nitrogen dioxide, an incremental increase of 10 parts per billion increases the risk of lung cancer by 14%. Outdoor air pollution is estimated to cause 1–2% of lung cancers.
Tentative evidence supports an increased risk of lung cancer from indoor air pollution in relation to the burning of wood, charcoal, dung, or crop residue for cooking and heating. Women who are exposed to indoor coal smoke have roughly twice the risk, and many of the by-products of burning biomass are known or suspected carcinogens. This risk affects about 2.4 billion people worldwide, and it is believed to result in 1.5% of lung cancer deaths.
About 8% of lung cancer is caused by inherited factors. In relatives of people that are diagnosed with lung cancer, the risk is doubled, likely due to a combination of genes. Polymorphisms on chromosomes 5, 6, and 15 are known to affect the risk of lung cancer. Single-nucleotide polymorphisms (SNPs) of the genes encoding the nicotinic acetylcholine receptor (nAChR) – CHRNA5, CHRNA3, and CHRNB4 – are of those associated with an increased risk of lung cancer, as well as RGS17 – a gene regulating G-protein signaling.
Numerous other substances, occupations, and environmental exposures have been linked to lung cancer. The International Agency for Research on Cancer (IARC) states that there is some "sufficient evidence" to show that the following are carcinogenic in the lungs:
Similar to many other cancers, lung cancer is initiated by either the activation of oncogenes or the inactivation of tumor suppressor genes. Carcinogens cause mutations in these genes that induce the development of cancer.
Epigenetic changes such as alteration of DNA methylation, histone tail modification, or microRNA regulation may result in the inactivation of tumor suppressor genes. Importantly, cancer cells develop resistance to oxidative stress, which enables them to withstand and exacerbate inflammatory conditions that inhibit the activity of the immune system against the tumor.
The epidermal growth factor receptor (EGFR) regulates cell proliferation, apoptosis, angiogenesis, and tumor invasion. Mutations and amplification of EGFR are common in non-small-cell lung carcinoma, and they provide the basis for treatment with EGFR-inhibitors. Her2/neu is affected less frequently. Other genes that are often mutated or amplified include c-MET, NKX2-1, LKB1, PIK3CA, and BRAF.
The cell lines of origin are not fully understood. The mechanism may involve the abnormal activation of stem cells. In the proximal airways, stem cells that express keratin 5 are more likely to be affected, typically leading to squamous-cell lung carcinoma. In the middle airways, implicated stem cells include club cells and neuroepithelial cells that express club cell secretory protein. Small-cell lung carcinoma may originate from these cell lines or neuroendocrine cells, and it may express CD44.
Performing a chest radiograph is one of the first investigative steps if a person reports symptoms that may be suggestive of lung cancer. This may reveal an obvious mass, the widening of the mediastinum (suggestive of spread to lymph nodes there), atelectasis (lung collapse), consolidation (pneumonia), or pleural effusion. CT imaging is typically used to provide more information about the type and extent of disease. Bronchoscopic or CT-guided biopsy is often used to sample the tumor for histopathology.
Lung cancer often appears as a solitary pulmonary nodule on a chest radiograph. However, the differential diagnosis is wide. Many other diseases can also give this appearance, including metastatic cancer, hamartomas, and infectious granulomas caused by tuberculosis, histoplasmosis or coccidioidomycosis. Lung cancer can also be an incidental finding, as a solitary pulmonary nodule on a chest radiograph or CT scan done for an unrelated reason. The definitive diagnosis of lung cancer is based on the histological examination of the suspicious tissue in the context of the clinical and radiological features.
Clinical practice guidelines recommend frequencies for pulmonary nodule surveillance. CT imaging should not be used for longer or more frequently than indicated, as the extended surveillance exposes people to increased radiation and is costly.
|Histological type||Incidence per 100,000 per year|
Lung cancers are classified according to histological type. This classification is important for determining both the management and predicting outcomes of the disease. Lung cancers are carcinomas – malignancies that arise from epithelial cells. Lung carcinomas are categorized by the size and appearance of the malignant cells seen by a histopathologist under a microscope. For therapeutic purposes, two broad classes are distinguished: non-small-cell lung carcinoma and small-cell lung carcinoma.
Nearly 40% of lung cancers are adenocarcinoma, which usually comes from peripheral lung tissue. Although most cases of adenocarcinoma are associated with smoking, adenocarcinoma is also the most-common form of lung cancer among people who have smoked fewer than 100 cigarettes in their lifetimes ("never-smokers") and ex-smokers with a modest smoking history. A subtype of adenocarcinoma, the bronchioloalveolar carcinoma, is more common in female never-smokers, and may have a better long-term survival.
In SCLC, the cells contain dense neurosecretory granules (vesicles containing neuroendocrine hormones), which give this tumor an endocrine or paraneoplastic syndrome association. Most cases arise in the larger airways (primary and secondary bronchi). Sixty to seventy percent have extensive disease (which cannot be targeted within a single radiation therapy field) at presentation.
Four main histological subtypes are recognised, although some cancers may contain a combination of different subtypes, such as adenosquamous carcinoma. Rare subtypes include carcinoid tumors, bronchial gland carcinomas, and sarcomatoid carcinomas.
The lungs are a common place for the spread of tumors from other parts of the body. Secondary cancers are classified by the site of origin; for example, breast cancer that has been spread to the lung is called metastatic breast cancer. Metastases often have a characteristic round appearance on chest radiograph.
Primary lung cancers also most commonly metastasize to the brain, bones, liver, and adrenal glands. Immunostaining of a biopsy usually helps determine the original source. The presence of Napsin-A, TTF-1, CK7, and CK20 help confirm the subtype of lung carcinoma. SCLC that originates from neuroendocrine cells may express CD56, neural cell adhesion molecule, synaptophysin, or chromogranin.
Lung cancer staging is an assessment of the degree of spread of the cancer from its original source. It is one of the factors affecting both the prognosis and the potential treatment of lung cancer.
The evaluation of non-small-cell lung carcinoma (NSCLC) staging uses the TNM classification (tumor, node, metastasis). This is based on the size of the primary tumor, lymph node involvement, and distant metastasis.
Using the TNM descriptors, a group is assigned, ranging from occult cancer, through stages 0, IA (one-A), IB, IIA, IIB, IIIA, IIIB, and IV (four). This stage group assists with the choice of treatment and estimation of prognosis.
|T1a–T1b N0 M0||IA|
|T2a N0 M0||IB|
|T1a–T2a N1 M0||IIA|
|T2b N0 M0|
|T2b N1 M0||IIB|
|T3 N0 M0|
|T1a–T3 N2 M0||IIIA|
|T3 N1 M0|
|T4 N0–N1 M0|
|T4 N2 M0|
SCLC 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). However, the TNM classification and grouping are useful in estimating prognosis.
For both NSCLC and SCLC, the two general types of staging evaluations are clinical staging and surgical staging. Clinical staging is performed before definitive surgery. It is based on the results of imaging studies (such as CT scans and PET scans) and biopsy results. Surgical staging is evaluated either during or after the operation. It is based on the combined results of surgical and clinical findings, including surgical sampling of thoracic lymph nodes.
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.
Policy interventions to decrease passive smoking in public areas such as restaurants and workplaces have become more common in many Western countries. Bhutan has had a complete smoking ban since 2005 while India introduced a ban on smoking in public in October 2008. 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 instituted.
Cancer screening uses medical tests to detect disease in large groups of people who have no symptoms. For individuals with high risk of developing lung cancer, computed tomography (CT) screening can detect cancer and give a person options to respond to it in a way that prolongs life. This form of screening reduces the chance of death from lung cancer by an absolute amount of 0.3% (relative amount of 20%). High risk people are those age 55–74 who have smoked equivalent amount of a pack of cigarettes daily for 30 years including time within the past 15 years.
CT screening is associated with a high rate of falsely positive tests which may result in unneeded treatment. For each true positive scan there are about 19 falsely positives scans. Other concerns include radiation exposure and the cost of testing along with follow up. Research has not found two other available tests—sputum cytology or chest radiograph (CXR) screening tests—to have any benefit.
The United States Preventive Services Task Force (USPSTF) recommends yearly screening using low-dose computed tomography in those who have a total smoking history of 30 pack-years and are between 55 and 80 years old until a person has not been smoking for more than 15 years. Screening should not be done in those with other health problems that would make treatment of lung cancer if found not an option. The English National Health Service was in 2014 re-examining the evidence for screening.
The long-term use of supplemental vitamin A, vitamin C, vitamin D or vitamin E does not reduce the risk of lung cancer. Some studies suggest that people who eat diets with a higher proportion of vegetables and fruit tend to have a lower risk, but this may be due to confounding—with the lower risk actually due to the association of a high fruit and vegetables diet with less smoking. Several rigorous studies have not demonstrated a clear association between diet and lung cancer risk, although meta-analysis that accounts for smoking status may show benefit from a healthy diet.
Treatment for lung cancer depends on the cancer's specific cell type, how far it has spread, and the person's performance status. Common treatments include palliative care, surgery, chemotherapy, and radiation therapy. Targeted therapy of lung cancer is growing in importance for advanced lung cancer.
If investigations confirm NSCLC, the stage is assessed to determine whether the disease is localized and amenable to surgery or if it has spread to the point where it cannot be cured surgically. CT scan and positron emission tomography are used for this determination. If mediastinal lymph node involvement is suspected, the nodes may be sampled to assist staging. Techniques used for this include transthoracic needle aspiration, transbronchial needle aspiration (with or without endobronchial ultrasound), endoscopic ultrasound with needle aspiration, mediastinoscopy, and thoracoscopy. Blood tests and pulmonary function testing are used to assess whether a person is well enough for surgery. If pulmonary function tests reveal poor respiratory reserve, surgery may not be possible.
In most cases of early-stage NSCLC, removal of a lobe of lung (lobectomy) is the surgical treatment of choice. In people who are unfit for a full lobectomy, a smaller sublobar excision (wedge resection) may be performed. However, wedge resection has a higher risk of recurrence than lobectomy. Radioactive iodine brachytherapy at the margins of wedge excision may reduce the risk of recurrence. Rarely, removal of a whole lung (pneumonectomy) is performed. Video-assisted thoracoscopic surgery (VATS) and VATS lobectomy use a minimally invasive approach to lung cancer surgery. VATS lobectomy is equally effective compared to conventional open lobectomy, with less postoperative illness.
In SCLC, chemotherapy and/or radiotherapy is typically used. However the role of surgery in SCLC is being reconsidered. Surgery might improve outcomes when added to chemotherapy and radiation in early stage SCLC.
Radiotherapy is often given together with chemotherapy, and may be used with curative intent in people with NSCLC who are not eligible for surgery. This form of high-intensity radiotherapy is called radical radiotherapy. 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. Postoperative (adjuvant) thoracic radiotherapy generally should not be used after curative-intent surgery for NSCLC. Some people with mediastinal N2 lymph node involvement might benefit from post-operative radiotherapy.
For potentially curable SCLC cases, chest radiotherapy is often recommended in addition to chemotherapy.
If cancer growth blocks a short section of bronchus, brachytherapy (localized radiotherapy) may be given directly inside the airway to open the passage. Compared to external beam radiotherapy, brachytherapy allows a reduction in treatment time and reduced radiation exposure to healthcare staff. Evidence for brachytherapy, however, is less than that for external beam radiotherapy.
Prophylactic cranial irradiation (PCI) is a type of radiotherapy to the brain, used to reduce the risk of metastasis. PCI is most useful in SCLC. In limited-stage disease, PCI increases three-year survival from 15% to 20%; in extensive disease, one-year survival increases from 13% to 27%.
Recent improvements in targeting and imaging have led to the development of stereotactic radiation in the treatment of early-stage lung cancer. In this form of radiotherapy, high doses are delivered over a number of sessions using stereotactic targeting techniques. Its use is primarily in patients who are not surgical candidates due to medical comorbidities.
The chemotherapy regimen depends on the tumor type. SCLC, even relatively early stage disease, is treated primarily with chemotherapy and radiation. In SCLC, cisplatin and etoposide are most commonly used. Combinations with carboplatin, gemcitabine, paclitaxel, vinorelbine, topotecan, and irinotecan are also used. In advanced NSCLC, chemotherapy improves survival and is used as first-line treatment, provided the person is well enough for the treatment. Typically, two drugs are used, of which one is often platinum-based (either cisplatin or carboplatin). Other commonly used drugs are gemcitabine, paclitaxel, docetaxel, pemetrexed, etoposide or vinorelbine. Platinum-based drugs and combinations that include platinum therapy may lead to a higher risk of serious adverse effects in people over 70 years old.
Adjuvant chemotherapy refers to the use of chemotherapy after apparently curative surgery to improve the outcome. In NSCLC, samples are taken of nearby lymph nodes during surgery to assist staging. If stage II or III disease is confirmed, adjuvant chemotherapy (including or not including postoperative radiotherapy) improves survival by 4% at five years. The combination of vinorelbine and cisplatin is more effective than older regimens. Adjuvant chemotherapy for people with stage IB cancer is controversial, as clinical trials have not clearly demonstrated a survival benefit. Chemotherapy before surgery in NSCLC that can be removed surgically may improve outcomes.
Chemotherapy may be combined with palliative care in the treatment of the NSCLC. In advanced cases, appropriate chemotherapy improves average survival over supportive care alone, as well as improving quality of life. With adequate physical fitness maintaining chemotherapy during lung cancer palliation offers 1.5 to 3 months of prolongation of survival, symptomatic relief, and an improvement in quality of life, with better results seen with modern agents. The NSCLC Meta-Analyses Collaborative Group recommends if the recipient wants and can tolerate treatment, then chemotherapy should be considered in advanced NSCLC.
Several drugs that target molecular pathways in lung cancer are available, especially for the treatment of advanced disease. Erlotinib, gefitinib and afatinib inhibit tyrosine kinase at the epidermal growth factor receptor. Denosumab is a monoclonal antibody directed against receptor activator of nuclear factor kappa-B ligand. It may be useful in the treatment of bone metastases.
Several treatments can be administered via bronchoscopy for the management of airway obstruction or bleeding. If an airway becomes obstructed by cancer growth, options include rigid bronchoscopy, balloon bronchoplasty, stenting, and microdebridement. Laser photosection involves the delivery of laser light inside the airway via a bronchoscope to remove the obstructing tumor.
Palliative care when added to usual cancer care benefits people even when they are still receiving chemotherapy. These approaches allow additional discussion of treatment options and provide opportunities to arrive at well-considered decisions. Palliative care may avoid unhelpful but expensive care not only at the end of life, but also throughout the course of the illness. For individuals who have more advanced disease, hospice care may also be appropriate.
|Clinical stage||Five-year survival (%)|
|Non-small-cell lung carcinoma||Small-cell lung carcinoma|
Of all people with lung cancer in the US, 16.8% survive for at least five years after diagnosis. In England and Wales, between 2010 and 2011, overall five-year survival for lung cancer was estimated at 9.5%. Outcomes are generally worse in the developing world. Stage is often advanced at the time of diagnosis. At presentation, 30–40% of cases of NSCLC are stage IV, and 60% of SCLC are stage IV. Survival for lung cancer falls as the stage at diagnosis becomes more advanced: the English data suggest that around 70% of patients survive at least a year when diagnosed at the earliest stage, but this falls to just 14% for those diagnosed with the most advanced disease (stage IV).
Prognostic factors in NSCLC include presence of pulmonary symptoms, large tumor size (>3 cm), non-squamous cell type (histology), degree of spread (stage) and metastases to multiple lymph nodes, and vascular invasion. For people with inoperable disease, outcomes are worse in those with poor performance status and weight loss of more than 10%. Prognostic factors in small cell lung cancer include performance status, biological sex, stage of disease, and involvement of the central nervous system or liver at the time of diagnosis.
For NSCLC, the best prognosis is achieved with complete surgical resection of stage IA disease, with up to 70% five-year survival. People with extensive-stage SCLC have an average five-year survival rate of less than 1%. The average survival time for limited-stage disease is 20 months, with a five-year survival rate of 20%.
According to data provided by the National Cancer Institute, the median age at diagnosis of lung cancer in the US is 70 years, and the median age at death is 72 years. In the US, people with medical insurance are more likely to have a better outcome.
Worldwide, lung cancer is the most-common cancer among men in terms of both incidence and mortality, and among women has the third-highest incidence, and is second after breast cancer in mortality. In 2012, there were 1.82 million new cases worldwide, and 1.56 million deaths due to lung cancer, representing 19.4% of all deaths from cancer. The highest rates are in North America, Europe, and East Asia, with over a third of new cases in China that year. Rates in Africa and South Asia are much lower.
The population segment that is most likely to develop lung cancer is people aged over 50 who have a history of smoking. Unlike the mortality rate in men – which began declining more than 20 years ago, women's lung cancer mortality rates have risen over the last decades, and are just recently beginning to stabilize. In the US, the lifetime risk of developing lung cancer is 8% in men and 6% in women.
For every 3–4 million cigarettes smoked, one lung cancer death can occur. The influence of "Big Tobacco" plays a significant role in smoking. Young nonsmokers who see tobacco advertisements are more likely to smoke. The role of passive smoking is increasingly being recognized as a risk factor for lung cancer, resulting in policy interventions to decrease the undesired exposure of nonsmokers to others' tobacco smoke.
In the US, both black men and black women have a higher incidence. Lung cancer rates are currently lower in developing countries. With increased smoking in developing countries, the rates are expected to increase in the next few years, notably in both China and India.
Also in the US, military veterans have a 25–50% higher rate of lung cancer primarily due to higher rates of smoking. During World War II and the Korean War, asbestos also played a role, and Agent Orange may have caused some problems during the Vietnam War.
Lung cancer is the third most-common cancer in the UK (around 46,400 people were diagnosed with the disease in 2014), and it is the most common cause of cancer-related death (around 35,900 people died in 2014).
From the 1960s, the rates of lung adenocarcinoma started to rise in relation to other kinds of lung cancer, partially 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. The incidence of lung adenocarcinoma continue to rise.
Lung cancer was uncommon before the advent of cigarette smoking; it was not even recognized as a distinct disease until 1761. Different aspects of lung cancer were described further in 1810. 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. Case reports in the medical literature numbered only 374 worldwide in 1912, but a review of autopsies showed the incidence of lung cancer had increased from 0.3% in 1852 to 5.66% in 1952. In Germany in 1929, physician Fritz Lickint recognized the link between smoking and lung cancer, which led to an aggressive antismoking campaign. The British Doctors' Study, published in the 1950s, was the first solid epidemiological evidence of the link between lung cancer and smoking. As a result, in 1964 the Surgeon General of the United States recommended smokers should stop smoking.
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. Despite this discovery, mining continued into the 1950s, due to the USSR's demand for uranium. Radon was confirmed as a cause of lung cancer in the 1960s.
The first successful pneumonectomy for lung cancer was performed in 1933. Palliative radiotherapy has been used since the 1940s. 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. In 1997, CHART was seen as an improvement over conventional radical radiotherapy. With SCLC, initial attempts in the 1960s at surgical resection and radical radiotherapy were unsuccessful. In the 1970s, successful chemotherapy regimens were developed.
Current research directions for lung cancer treatment include immunotherapy, which encourages the body's immune system to attack the tumor cells, epigenetics, and new combinations of chemotherapy and radiotherapy, both on their own and together. Many of these new treatments work through immune checkpoint blockade, disrupting cancer's ability to evade the immune system.
Ipilimumab blocks signaling through a receptor on T cells known as CTLA-4 which dampens down the immune system. It has been approved by the US Food and Drug Administration (FDA) for treatment of melanoma and is undergoing clinical trials for both NSCLC and SCLC.
Other immunotherapy treatments interfere with the binding of programmed cell death 1 (PD-1) protein with its ligand PD-1 ligand 1 (PD-L1), and have been approved as first- and subsequent-line treatments for various subsets of lung cancers. Signaling through PD-1 inactivates T cells. Some cancer cells appear to exploit this by expressing PD-L1 in order to switch off T cells that might recognise them as a threat. Monoclonal antibodies targeting both PD-1 and PD-L1, such as pembrolizumab, nivolumab, atezolizumab, and durvalumab are currently in clinical trials for treatment for lung cancer.
Epigenetics is the study of small, usually heritable, molecular modifications—or "tags"—that bind to DNA and modify gene expression levels. Targeting these tags with drugs can kill cancer cells. Early-stage research in NSCLC using drugs aimed at epigenetic modifications shows that blocking more than one of these tags can kill cancer cells with fewer side effects. Studies also show that giving patients these drugs before standard treatment can improve its effectiveness. Clinical trials are underway to evaluate how well these drugs kill lung cancer cells in humans. Several drugs that target epigenetic mechanisms are in development. Histone deacetylase inhibitors in development include valproic acid, vorinostat, belinostat, panobinostat, entinostat, and romidepsin. DNA methyltransferase inhibitors in development include decitabine, azacytidine, and hydralazine.
The TRACERx project is looking at how NSCLC develops and evolves, and how these tumors become resistant to treatment. The project will look at tumor samples from 850 NSCLC patients at various stages including diagnosis, after first treatment, post-treatment, and relapse. By studying samples at different points of tumor development, the researchers hope to identify the changes that drive tumor growth and resistance to treatment. The results of this project will help scientists and doctors gain a better understanding of NSCLC and potentially lead to the development of new treatments for the disease.
For lung cancer cases that develop resistance to epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors, new drugs are in development. New EGFR inhibitors include afatinib and dacomitinib. An alternative signaling pathway, c-Met, can be inhibited by tivantinib and onartuzumab. New ALK inhibitors include crizotinib and ceritinib. If the MAPK/ERK pathway is involved, the BRAF kinase inhibitor dabrafenib and the MAPK/MEK inhibitor trametinib may be beneficial.
Lung cancer stem cells are often resistant to conventional chemotherapy and radiotherapy. This may lead to relapse after treatment. New approaches target protein or glycoprotein markers that are specific to the stem cells. Such markers include CD133, CD90, ALDH1A1, CD44 and ABCG2. Signaling pathways such as Hedgehog, Wnt and Notch are often implicated in the self-renewal of stem cell lines. Thus treatments targeting these pathways may help to prevent relapse.
Secondhand smoke exposure causes disease and premature death in children and adults who do not smoke.Retrieved 2014-06-16
There is sufficient evidence that involuntary smoking (exposure to secondhand or 'environmental' tobacco smoke) causes lung cancer in humans. ... Involuntary smoking (exposure to secondhand or 'environmental' tobacco smoke) is carcinogenic to humans (Group 1).
Adenocarcinoma of the lung (also known as pulmonary adenocarcinoma) is the most common type of lung cancer, and like other forms of lung cancer, it is characterized by distinct cellular and molecular features. It is classified as one of several non-small cell lung cancers (NSCLC), to distinguish it from small cell lung cancer which has a different behavior and prognosis. Lung adenocarcinoma is further classified into several subtypes and variants. The signs and symptoms of this specific type of lung cancer are similar to other forms of lung cancer, and patients most commonly complain of persistent cough and shortness of breath. Adenocarcinoma is more common in patients with a history of cigarette smoking, and is the most common form of lung cancer in younger women and Asian populations. The pathophysiology of adenocarcinoma is complicated, but generally follows a histologic progression from cells found in healthy lungs to distinctly dysmorphic, or irregular, cells. There are several distinct molecular and genetic pathways that contribute to this progression. Like many lung cancers, adenocarcinoma of the lung is often advanced by the time of diagnosis. Once a lesion or tumor is identified with various imaging modalities, such as computed tomography (CT) or X-ray, a biopsy is required to confirm the diagnosis. Treatment of this lung cancer is based upon the specific subtype and the extent of spread from the primary tumor. Surgical resection, chemotherapy, radiotherapy, targeted therapy and immunotherapy are used in attempt to eradicate the cancerous cells based upon these factors.Cardiothoracic surgery
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Combined small cell lung carcinoma (or c-SCLC, and rarely rendered as "small-cell lung carcinoma") is a form of multiphasic lung cancer that is diagnosed by a pathologist when a malignant tumor arising from transformed cells originating in lung tissue contains a component of small cell lung carcinoma (SCLC) admixed with one (or more) components of non-small cell lung carcinoma (NSCLC).Erlotinib
Erlotinib hydrochloride (trade name Tarceva) is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a receptor tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR).
It is marketed in the United States by Genentech and OSI Pharmaceuticals and elsewhere by Roche. In the United States as of 2015 one 150 mg pill costs between 200 and 242 USD.Health effects of tobacco
Tobacco use has predominantly negative effects on human health and concern about health effects of tobacco has a long history. Research has focused primarily on cigarette tobacco smoking.Tobacco smoke contains more than fifty chemicals that cause cancer. Tobacco also contains nicotine, which is a highly addictive psychoactive drug. When tobacco is smoked, nicotine causes physical and psychological dependency. Cigarettes sold in underdeveloped countries tend to have higher tar content, and are less likely to be filtered, potentially increasing vulnerability to tobacco smoking related disease in these regions.Tobacco use is the single greatest cause of preventable death globally. As many as half of people who use tobacco die from complications of tobacco use. The World Health Organization (WHO) estimates that each year tobacco causes about 6 million deaths (about 10% of all deaths) with 600,000 of these occurring in non smokers due to second hand smoke. In the 20th century tobacco is estimated to have caused 100 million deaths. Similarly, the United States Centers for Disease Control and Prevention describes tobacco use as "the single most important preventable risk to human health in developed countries and an important cause of premature death worldwide." Currently, the number of premature deaths in the U.S. from tobacco use per year outnumber the number of workers employed in the tobacco industry 4 to 1. According to a 2014 review in the New England Journal of Medicine, tobacco will, if current smoking patterns persist, kill about 1 billion people in the 21st century, half of them before the age of 70.Tobacco use leads most commonly to diseases affecting the heart, liver and lungs. Smoking is a major risk factor for heart attacks, strokes, chronic obstructive pulmonary disease (COPD) (including emphysema and chronic bronchitis), and several cancers (particularly lung cancer, cancers of the larynx and mouth, bladder cancer, and pancreatic cancer). It also causes peripheral arterial disease and high blood pressure. The effects depend on the number of years that a person smokes and on how much the person smokes. Starting smoking earlier in life and smoking cigarettes higher in tar increases the risk of these diseases. Also, environmental tobacco smoke, or secondhand smoke, has been shown to cause adverse health effects in people of all ages. Tobacco use is a significant factor in miscarriages among pregnant smokers, and it contributes to a number of other health problems of the fetus such as premature birth, low birth weight, and increases by 1.4 to 3 times the chance of sudden infant death syndrome (SIDS). Incidence of erectile dysfunction is approximately 85 percent higher in male smokers compared to non-smokers.Several countries have taken measures to control the consumption of tobacco with usage and sales restrictions as well as warning messages printed on packaging. Additionally, smoke-free laws that ban smoking in public places such as workplaces, theaters, and bars and restaurants reduce exposure to secondhand smoke and help some people who smoke to quit, without negative economic effects on restaurants or bars. Tobacco taxes that increase the price are also effective, especially in developing countries.The coughing, throat irritation, and shortness of breath caused by smoking have always been obvious. The idea that tobacco use caused some diseases, including mouth cancers, was initially, in the late 1700s and the 1800s, widely accepted by the medical community. In the 1880s, automation slashed the cost of cigarettes, and use expanded. From the 1890s onwards, associations of tobacco use with cancers and vascular disease were regularly reported; a metaanalysis citing 167 other works was published in 1930, and concluded that tobacco use caused cancer. Increasingly solid observational evidence was published throughout the 1930s, and in 1938, Science published a paper showing that tobacco users live substantially shorter lives. Case-control studies were published in Germany in 1939 and 1943, and one in the Netherlands in 1948, but widespread attention was first drawn by five case-control studies published in 1950 by researchers from the US and UK. These studies were widely criticized as showing correlation, not causality. Follow up prospective cohort studies in the early 1950s clearly found that that smokers died faster, and were more likely to die of lung cancer and cardiovascular disease. These results were first widely accepted in the medical community, and publicized among the general public, in the mid-1960s.Kathryn Joosten
Kathryn Joosten (December 20, 1939 – June 2, 2012) was an American television actress. Her best known roles include Dolores Landingham on NBC's The West Wing from 1999 to 2002 and Karen McCluskey on ABC's Desperate Housewives from 2005 to 2012, for which she won two Primetime Emmy Awards in 2005 and 2008.Kim Manners
Kim Manners (January 13, 1951 – January 25, 2009) was an American television producer, director and actor best known for his work on The X-Files and Supernatural.Nintedanib
Nintedanib, marketed under the brand names Ofev and Vargatef, is an oral medication used for the treatment of idiopathic pulmonary fibrosis and along with other medications for some types of non-small-cell lung cancer.
Common side effects include abdominal pain, vomiting, and diarrhea. It is a small molecule tyrosine-kinase inhibitor, targeting vascular endothelial growth factor receptor, fibroblast growth factor receptor and platelet derived growth factor receptor.
It was developed by Boehringer Ingelheim. At an assumed cost of 39,300 pounds per year it does not appear to be cost effective for idiopathic pulmonary fibrosis in the United Kingdom.Nivolumab
Nivolumab, marketed as Opdivo, is a medication used to treat cancer. It is used as a first line treatment for inoperable or metastatic melanoma in combination with ipilimumab if the cancer does not have a mutation in BRAF, as a second-line treatment following treatment with ipilimumab and if the cancer has a mutation in BRAF, with a BRAF inhibitor, as a second-line treatment for squamous non-small cell lung cancer, and as a second-line treatment for renal cell carcinoma. Nivolumab has recently been approved for small cell lung cancer. It had not been tested in pregnant women but based on the mechanism of action and animal studies, is probably toxic to the fetus; it is not known if it is secreted in breast milk. Side effects include severe immune-related inflammation of the lungs, colon, liver, kidneys, and thyroid, and there are effects on skin, central nervous system, the heart, and the digestive system.
It is a human IgG4 anti-PD-1 monoclonal antibody. Nivolumab works as a checkpoint inhibitor, blocking a signal that would have prevented activated T cells from attacking the cancer, thus allowing the immune system to clear the cancer. It was discovered at Medarex, developed by Medarex and Ono Pharmaceutical, and brought to market by Bristol-Myers Squibb (which acquired Medarex in 2009) and Ono.Non-small-cell lung carcinoma
Non-small-cell lung carcinoma (NSCLC) is any type of epithelial lung cancer other than small cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to small cell carcinoma. When possible, they are primarily treated by surgical resection with curative intent, although chemotherapy has been used increasingly both pre-operatively (neoadjuvant chemotherapy) and post-operatively (adjuvant chemotherapy).Occupational lung disease
Occupational lung diseases are occupational, or work-related, lung conditions that have been caused or made worse by the materials a person is exposed to within the workplace. It includes a broad group of diseases, including occupational asthma, chronic obstructive pulmonary disease (COPD), bronchiolitis obliterans, inhalation injury, interstitial lung diseases (such as pneumoconiosis, hypersensitivity pneumonitis, lung fibrosis), infections, lung cancer and mesothelioma. These diseases can be caused directly or due to immunological response to a exposure to a variety of dusts, chemicals, proteins or organisms.
Occupational cases of interstitial lung disease may be misdiagnosed as COPD, idiopathic pulmonary fibrosis, or a myriad of other diseases; leading to a delay in identification of the causative agent.Passive smoking
Passive smoking is the inhalation of smoke, called second-hand smoke (SHS), or environmental tobacco smoke (ETS), by persons other than the intended "active" smoker. It occurs when tobacco smoke permeates any environment, causing its inhalation by people within that environment. Exposure to second-hand tobacco smoke causes disease, disability, and death. The health risks of second-hand smoke are a matter of scientific consensus. These risks have been a major motivation for smoke-free laws in workplaces and indoor public places, including restaurants, bars and night clubs, as well as some open public spaces.Concerns around second-hand smoke have played a central role in the debate over the harms and regulation of tobacco products. Since the early 1970s, the tobacco industry has viewed public concern over second-hand smoke as a serious threat to its business interests. Harm to bystanders was perceived as a motivator for stricter regulation of tobacco products. Despite the industry's awareness of the harms of second-hand smoke as early as the 1980s, the tobacco industry coordinated a scientific controversy with the purpose of stopping regulation of their products.Pat Marsden
Patrick Francis Marsden (November 8, 1936 – April 27, 2006) was a Canadian sportscaster and voice of the Canadian Football League play-by-play coverage in the 1970s and 1980s. He also worked as host for the historic 1972 Canada-Soviet Union hockey Summit Series sports telecasts. He was inducted into the Canadian Football Hall of Fame in 1989.
Marsden was born in Ottawa and attended St. Patrick's High School and the University of Ottawa, where he started his sportscasting career at local station CKOY.
He later became sports director at CFTO in Toronto, and became immersed in all local and national sporting events. He even appeared as "John Marsden" in an episode of Bizarre (filmed at CFTO), in a Super Dave Osborne stunt at Toronto's CN Tower.
Fired in 1986 after a physical altercation with his boss Ted Stuebing, Marsden then was hired by his CTV football broadcasting partner Bill Stephenson at CFRB, went to TSN, and later surfaced at The Fan 590. After helping to rebuild and essentially help create the image for The Fan 590, he retired in 2004.
Marsden spent most of his time in Florida due to what he felt was the socialization of Canadian society, but he continued to maintain a home in Toronto.
He returned in 1996 to live in Toronto with his family joining him and died of lung cancer on April 27, 2006, aged 69, at Sunnybrook and Women's College Health Sciences Centre.Pneumonectomy
A pneumonectomy (or pneumectomy) is a surgical procedure to remove a lung. Removal of just one lobe of the lung is specifically referred to as a lobectomy, and that of a segment of the lung as a wedge resection (or segmentectomy).Radon
Radon is a chemical element with symbol Rn and atomic number 86. It is a radioactive, colorless, odorless, tasteless noble gas. It occurs naturally in minute quantities as an intermediate step in the normal radioactive decay chains through which thorium and uranium slowly decay into lead and various other short-lived radioactive elements; radon itself is the immediate decay product of radium. Its most stable isotope, 222Rn, has a half-life of only 3.8 days, making radon one of the rarest elements since it decays away so quickly. However, since thorium and uranium are two of the most common radioactive elements on Earth, and they have three isotopes with very long half-lives, on the order of several billions of years, radon will be present on Earth long into the future in spite of its short half-life as it is continually being generated. The decay of radon produces many other short-lived nuclides known as radon daughters, ending at stable isotopes of lead.Unlike all the other intermediate elements in the aforementioned decay chains, radon is, under normal conditions, gaseous and easily inhaled. Radon gas is considered a health hazard. It is often the single largest contributor to an individual's background radiation dose, but due to local differences in geology, the level of the radon-gas hazard differs from location to location. Despite its short lifetime, radon gas from natural sources, such as uranium-containing minerals, can accumulate in buildings, especially, due to its high density, in low areas such as basements and crawl spaces. Radon can also occur in ground water – for example, in some spring waters and hot springs.Epidemiological studies have shown a clear link between breathing high concentrations of radon and incidence of lung cancer. Radon is a contaminant that affects indoor air quality worldwide. According to the United States Environmental Protection Agency, radon is the second most frequent cause of lung cancer, after cigarette smoking, causing 21,000 lung cancer deaths per year in the United States. About 2,900 of these deaths occur among people who have never smoked. While radon is the second most frequent cause of lung cancer, it is the number one cause among non-smokers, according to EPA estimates. As radon itself decays, it produces decay products, which are other radioactive elements called radon daughters (also known as radon progeny). Unlike the gaseous radon itself, radon daughters are solids and stick to surfaces, such as dust particles in the air. If such contaminated dust is inhaled, these particles can also cause lung cancer.Rosemary Clooney
Rosemary Clooney (May 23, 1928 – June 29, 2002) was an American singer and actress. She came to prominence in the early 1950s with the song "Come On-a My House", which was followed by other pop numbers such as "Botch-a-Me", "Mambo Italiano", "Tenderly", "Half as Much", "Hey There" and "This Ole House". She also had success as a jazz vocalist. Clooney's career languished in the 1960s, partly due to problems related to depression and drug addiction, but revived in 1977, when her White Christmas co-star Bing Crosby asked her to appear with him at a show marking his 50th anniversary in show business. She continued recording until her death in 2002.Small-cell carcinoma
Small-cell carcinoma (also known as small-cell lung cancer, or oat-cell carcinoma) is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix, prostate, and gastrointestinal tract. Compared to non-small cell carcinoma, small cell carcinoma has a shorter doubling time, higher growth fraction, and earlier development of metastases.
Tumours and neoplasia in the respiratory tract (C30–C34/D14, 160–163/212.0–212.4)