Lung cancer , also known as lung carcinoma , [350] is a malignant lung tumor characterized by uncontrolled cell growth in tissues of the lung . [356] 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). [347] 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. [358] 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 . [349] [361] Lung cancer may be seen on chest radiographs and computed tomography (CT) scans. [350] The diagnosis is confirmed by biopsy which is usually performed by bronchoscopy or CT-guidance. [363]

Avoidance of risk factors, including smoking and air pollution, is the primary method of prevention. [364] Treatment and long-term outcomes depend on the type of cancer, the stage (degree of spread), and the person's overall health. [350] Most cases are not curable. [347] Common treatments include surgery , chemotherapy , and radiotherapy . [350] 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. [346] Overall, 17.4% of people in the United States diagnosed with lung cancer survive five years after the diagnosis, [346] while outcomes on average are worse in the developing world. [365]

Signs and symptoms

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. [369] 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. [363]

Causes

Cancer develops following genetic damage to DNA and epigenetic changes. These changes affect the normal functions of the cell, including cell proliferation, programmed cell death ( apoptosis ) and DNA repair. As more damage accumulates, the risk of cancer increases.

Smoking

Tobacco smoking is by far the main contributor to lung cancer. Cigarette smoke contains at least 73 known carcinogens , [371] including benzo[a]pyrene , NNK , 1,3-butadiene and a radioactive isotope of polonium, polonium-210 . [371] Across the developed world, 90% of lung cancer deaths in men during the year 2000 were attributed to smoking (70% for women). [373] Smoking accounts for about 85% of lung cancer cases. [350]

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 living or working with a smoker. Studies from the US, [377] [382] Europe [385] and the UK [387] have consistently shown a significantly increased risk among those exposed to passive smoke. [391] 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. [392] Investigations of sidestream smoke suggest it is more dangerous than direct smoke. [394] Passive smoking causes about 3,400 deaths from lung cancer each year in the USA. [382]

Marijuana smoke contains many of the same carcinogens as those in tobacco smoke. [397] However, the effect of smoking cannabis on lung cancer risk is not clear. [400] [402] A 2013 review did not find an increased risk from light to moderate use. [404] A 2014 review found that smoking cannabis doubled the risk of lung cancer. [406]

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 is the second-most common cause of lung cancer in the USA, [408] causing about 21,000 deaths each year. [409] The risk increases 8–16% for every 100 Bq / increase in the radon concentration. [411] Radon gas levels vary by locality and the composition of the underlying soil and rocks. About one in 15 homes in the US has radon levels above the recommended guideline of 4 picocuries per liter (pCi/l) (148 Bq/m³). [413]

Asbestos

Asbestos can cause a variety of lung diseases, including lung cancer. Tobacco smoking and asbestos have a synergistic effect on the formation of lung cancer. [349] 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 is different from lung cancer).

Air pollution

Outdoor air pollutants, especially chemicals released from the burning of fossil fuels, increase the risk of lung cancer. Fine particulates (PM 2.5 ) and sulfate aerosols , which may be released in traffic exhaust fumes, are associated with slightly increased risk. [415] For nitrogen dioxide , an incremental increase of 10 parts per billion increases the risk of lung cancer by 14%. [417] Outdoor air pollution is estimated to account for 1–2% of lung cancers.

Tentative evidence supports an increased risk of lung cancer from indoor air pollution related to the burning of wood, charcoal, dung or crop residue for cooking and heating. [420] Women who are exposed to indoor coal smoke have about twice the risk and a number of the by-products of burning biomass are known or suspected carcinogens. [422] This risk affects about 2.4 billion people globally, [420] and is believed to account for 1.5% of lung cancer deaths. [422]

Genetics

About 8% of lung cancer is due to inherited factors. [425] In relatives of people with lung cancer, the risk is doubled. This is likely due to a combination of genes . Polymorphisms on chromosomes 5, 6 and 15 are known to affect the risk of lung cancer. [428]

Other causes

Numerous other substances, occupations, and environmental exposures have been linked to lung cancer. The International Agency for Research on Cancer (IARC) states there is "sufficient evidence" to show the following are carcinogenic in the lungs: [433]

Pathogenesis

Image
Risk of death from lung cancer is strongly correlated with smoking

Similar to many other cancers, lung cancer is initiated by activation of oncogenes or inactivation of tumor suppressor genes . Carcinogens cause mutations in these genes which induce the development of cancer.

Mutations in the K-ras proto-oncogene are responsible for 10–30% of lung adenocarcinomas. [440] [442] About 4% of non-small-cell lung carcinomas involve an EML4-ALK tyrosine kinase fusion gene.

Epigenetic changes—such as alteration of DNA methylation , histone tail modification, or microRNA regulation—may lead to inactivation of tumor suppressor genes.

The epidermal growth factor receptor (EGFR) regulates cell proliferation, apoptosis , angiogenesis , and tumor invasion. [440] Mutations and amplification of EGFR are common in non-small-cell lung carcinoma and provide the basis for treatment with EGFR-inhibitors. Her2/neu is affected less frequently. [440] Other genes that are often mutated or amplified are c-MET , NKX2-1 , LKB1 , PIK3CA , and BRAF . [440]

The cell lines of origin are not fully understood. The mechanism may involve 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 be derived from these cell lines [448] or neuroendocrine cells , and may express CD44 . [448]

Metastasis of lung cancer requires transition from epithelial to mesenchymal cell type. This may occur through activation of signaling pathways such as Akt / GSK3Beta , MEK-ERK , Fas , and Par6.

Diagnosis

Performing a chest radiograph is one of the first investigative steps if a person 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 . [350] CT imaging is typically used to provide more information about the type and extent of disease. Bronchoscopy or CT-guided biopsy is often used to sample the tumor for histopathology . [363]

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 such as tuberculosis , histoplasmosis and 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. [455] The definitive diagnosis of lung cancer is based on histological examination of the suspicious tissue in the context of the clinical and radiological features.

Clinical practice guidelines recommend frequencies for pulmonary nodule surveillance. [457] CT imaging should not be used for longer or more frequently than indicated as extended surveillance exposes people to increased radiation. [457]

Classification

Image
False-color scanning electron micrograph of a lung cancer cell dividing
Age-adjusted incidence of lung cancer by histological type
Histological type Incidence per 100,000 per year
All types 66.9
Adenocarcinoma 22.1
Squamous-cell carcinoma 14.4
Small-cell carcinoma 9.8

Lung cancers are classified according to histological type . This classification is important for determining 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 .

Non-small-cell lung carcinoma

Image
CT scan showing a cancerous tumor in the left lung

The three main subtypes of NSCLC are adenocarcinoma , squamous-cell carcinoma and large-cell carcinoma .

Nearly 40% of lung cancers are adenocarcinoma, which usually originates in 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") [464] 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. [466]

Squamous-cell carcinoma accounts for about 30% of lung cancers. They typically occur close to large airways. A hollow cavity and associated cell death are commonly found at the center of the tumor. About 9% of lung cancers are large-cell carcinoma. These are so named because the cancer cells are large, with excess cytoplasm , large nuclei and conspicuous nucleoli .

Small-cell lung carcinoma

In small-cell lung carcinoma (SCLC), the cells contain dense neurosecretory granules ( vesicles containing neuroendocrine hormones ), which give this tumor an endocrine/paraneoplastic syndrome association. [468] Most cases arise in the larger airways (primary and secondary bronchi ). [363] Sixty to seventy percent have extensive disease (which cannot be targeted within a single radiation therapy field) at presentation.

Others

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.

Metastasis

Typical Napsin-A and TTF-1 immunostaining in primary lung carcinoma
Histological type Napsin-A TTF-1
Squamous-cell carcinoma Negative Negative
Adenocarcinoma Positive Positive
Small-cell carcinoma Negative Positive

The lung is a common place for the spread 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 metastatic breast cancer. Metastases often have a characteristic round appearance on chest radiograph. [471]

Primary lung cancers themselves most commonly metastasize to the brain, bones, liver and adrenal glands . Immunostaining of a biopsy is often helpful to determine the original source. [472] The presence of Napsin-A , TTF-1 , CK7 and CK20 are helpful in confirming the subtype of lung carcinoma. SCLC derived from neuroendocrine cells may express CD56 , neural cell adhesion molecule , synaptophysin or chromogranin .

Staging

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 the prognosis and potential treatment of lung cancer.

The evaluation of non-small-cell lung carcinoma (NSCLC) staging uses the TNM classification . This is based on the size of the primary t umor, lymph n ode involvement, and distant m etastasis.

TNM classification in lung cancer [475]
T: Primary tumor
TX Any of: Primary tumor cannot be assessed
Tumor cells present in sputum or bronchial washing, but tumor not seen with imaging or bronchoscopy
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor size less than or equal to 3 cm across, surrounded by lung or visceral pleura, without invasion proximal to the lobar bronchus
T1a Tumor size less than or equal to 2 cm across
T1b Tumor size more than 2 cm but less than or equal to 3 cm across
T2 Any of: Tumor size more than 3 cm but less than or equal to 7 cm across
Involvement of the main bronchus at least 2 cm distal to the carina
Invasion of visceral pleura
Atelectasis/obstructive pneumonitis extending to the hilum but not involving the whole lung
T2a Tumor size more than 3 cm but less than or equal to 5 cm across
T2b Tumor size more than 5 cm but less than or equal to 7 cm across
T3 Any of: Tumor size more than 7 cm across
Invasion into the chest wall, diaphragm, phrenic nerve , mediastinal pleura or parietal pericardium
Tumor less than 2 cm distal to the carina, but not involving the carina
Atelectasis/obstructive pneumonitis of the whole lung
Separate tumor nodule in the same lobe
T4 Any of: Invasion of the mediastinum, heart, great vessels, trachea, carina, recurrent laryngeal nerve, esophagus, or vertebra
Separate tumor nodule in a different lobe of the same lung
N: Lymph nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis to ipsilateral peribronchial and/or hilar lymph nodes
N2 Metastasis to ipsilateral mediastinal and/or subcarinal lymph nodes
N3 Any of: Metastasis to scalene or supraclavicular lymph nodes
Metastasis to contralateral hilar or mediastinal lymph nodes
M: Metastasis
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1a Any of: Separate tumor nodule in the other lung
Tumor with pleural nodules
Malignant pleural or pericardial effusion
M1b 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. [478]

Stage group according to TNM classification in lung cancer
TNM Stage group
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
N3 M0 IIIB
T4 N2 M0
M1 IV

Small-cell lung carcinoma (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. [478]

For both NSCLC and SCLC, the two general types of staging evaluations are clinical staging and surgical staging. Clinical staging is performed prior to 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 and is based on the combined results of surgical and clinical findings, including surgical sampling of thoracic lymph nodes.

Prevention

Smoking prevention and smoking cessation are effective ways of preventing the development of lung cancer.

Smoking ban

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 . [488] Bhutan has had a complete smoking ban since 2005 [490] while India introduced a ban on smoking in public in October 2008. [491] 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.

Screening

Cancer screening uses medical tests to detect disease in large groups of people who have no symptoms. [494] 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. [457] [497] This form of screening reduces the chance of death from lung cancer by an absolute amount of 0.3% ( relative amount of 20%). [499] [501] 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. [457]

CT screening is associated with a high rate of falsely positive tests which may result in unneeded treatment. [505] For each true positive scan there are about 19 falsely positives scans. Other concerns include radiation exposure [505] and the cost of testing along with follow up. [457] Research has not found two other available tests— sputum cytology or chest radiograph (CXR) screening tests—to have any benefit. [497] [508]

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. [510] Screening should not be done in those with other health problems that would make treatment of lung cancer if found not an option. [510] The English National Health Service was in 2014 re-examining the evidence for screening. [512]

Other prevention strategies

The long-term use of supplemental vitamin A, [513] [515] vitamin C, [513] vitamin D [518] or vitamin E [513] 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, [382] [521] but this may be due to confounding —with the lower risk actually due to the association of a high fruit/vegetables diet with less smoking. [525] Several rigorous studies have not demonstrated a clear association between diet and lung cancer risk, [521] although meta-analysis that accounts for smoking status may show benefit from a healthy diet. [527]

Management

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 , [530] surgery , chemotherapy , and radiation therapy . Targeted therapy of lung cancer is growing in importance for advanced lung cancer.

Surgery

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. [363] 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. [532] VATS lobectomy is equally effective compared to conventional open lobectomy, with less postoperative illness. [356]

In SCLC, chemotherapy and/or radiotherapy is typically used. [537] However the role of surgery in SCLC is being reconsidered. Surgery might improve outcomes when added to chemotherapy and radiation in early stage SCLC. [356]

Radiotherapy

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. [356] Postoperative thoracic radiotherapy generally should not be used after curative intent surgery for NSCLC. [543] Some people with mediastinal N2 lymph node involvement might benefit from post-operative radiotherapy. [356]

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. [356] Evidence for brachytherapy, however, is less than that for external beam radiotherapy. [356]

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%. [356]

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 . [554]

For both NSCLC and SCLC patients, smaller doses of radiation to the chest may be used for symptom control ( palliative radiotherapy). [557]

Chemotherapy

The chemotherapy regimen depends on the tumor type. Small-cell lung carcinoma (SCLC), even relatively early stage disease, is treated primarily with chemotherapy and radiation. [558] In SCLC, cisplatin and etoposide are most commonly used. [559] Combinations with carboplatin , gemcitabine , paclitaxel , vinorelbine , topotecan , and irinotecan are also used. [561] [563] In advanced non-small cell lung carcinoma (NSCLC), chemotherapy improves survival and is used as first-line treatment, provided the person is well enough for the treatment. [565] Typically, two drugs are used, of which one is often platinum-based (either cisplatin or carboplatin ). Other commonly used drugs are gemcitabine , paclitaxel , docetaxel , [568] pemetrexed , [571] etoposide or vinorelbine . [568]

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 improves survival by 5% at five years. [573] [575] The combination of vinorelbine and cisplatin is more effective than older regimens. [575] Adjuvant chemotherapy for people with stage IB cancer is controversial, as clinical trials have not clearly demonstrated a survival benefit. [577] Chemotherapy before surgery in NSCLC that can be removed surgically also appears to improve outcomes. [580]

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. [583] 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. [585] [588] The NSCLC Meta-Analyses Collaborative Group recommends if the recipient wants and can tolerate treatment, then chemotherapy should be considered in advanced NSCLC. [565] [590]

Targeted therapy

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. [592]

Bronchoscopy

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. [595]

Palliative care

Palliative care when added to usual cancer care benefits people even when they are still receiving chemotherapy. [598] These approaches allow additional discussion of treatment options and provide opportunities to arrive at well-considered decisions. [601] [602] 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. [363] [602]

Prognosis

Outcomes in lung cancer according to clinical stage [478]
Clinical stage Five-year survival (%)
Non-small-cell lung carcinoma Small-cell lung carcinoma
IA 50 38
IB 47 21
IIA 36 38
IIB 26 18
IIIA 19 13
IIIB 7 9
IV 2 1

Of all people with lung cancer in the US, 16.8% survive for at least five years after diagnosis. [346] [604] In England and Wales, between 2010 and 2011, overall five-year survival for lung cancer was estimated at 9.5%. [606] Outcomes are generally worse in the developing world . [365] 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. [607]

Prognostic factors in NSCLC include presence of pulmonary symptoms, large tumor size (>3 cm), nonsquamous 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, gender , stage of disease, and involvement of the central nervous system or liver at the time of diagnosis. [609]

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%. [350]

According to data provided by the National Cancer Institute , the median age at diagnosis of lung cancer in the United States is 70 years, [610] and the median age at death is 72 years. [611] In the US, people with medical insurance are more likely to have a better outcome. [613]

Epidemiology

Image
Cross section of a human lung: The white area in the upper lobe is cancer; the black areas are discoloration due to smoking .

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 globally, 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 2012 in China. Rates in Africa and South Asia are much lower.

The population segment most likely to develop lung cancer is people aged over 50 who have a history of smoking. 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. [615] In the USA, 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 occurs. [617] The influence of " Big Tobacco " plays a significant role in the smoking culture. [621] Young nonsmokers who see tobacco advertisements are more likely to take up smoking. [623] The role of passive smoking is increasingly being recognized as a risk factor for lung cancer, [391] leading to policy interventions to decrease undesired exposure of nonsmokers to others' tobacco smoke. [624]

In the United States, black men and women have a higher incidence. [625] Lung cancer rates are currently lower in developing countries. [626] With increased smoking in developing countries, the rates are expected to increase in the next few years, notably in China [628] and India. [630]

In the United States military veterans have a 25–50% higher rate of lung cancer primarily due to higher rates of smoking. [276] During World War Two and the Korean War asbestos also played a part and Agent Orange may have caused some problems during the Vietnam War. [277]

Lung cancer is the third most common cancer in the UK (around 46,400 people were diagnosed with the disease in 2014), [634] and it is the most common cause of cancer death (around 35,900 people died in 2014). [635]

From the 1960s, the rates of lung adenocarcinoma started to rise relative to other types of lung cancer. 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. [638] The incidence of lung adenocarcinoma continues to rise. [640]

History

Lung cancer was uncommon before the advent of cigarette smoking; it was not even recognized as a distinct disease until 1761. [641] Different aspects of lung cancer were described further in 1810. [642] 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. [645] Case reports in the medical literature numbered only 374 worldwide in 1912, [649] but a review of autopsies showed the incidence of lung cancer had increased from 0.3% in 1852 to 5.66% in 1952. [294] In Germany in 1929, physician Fritz Lickint recognized the link between smoking and lung cancer, [645] 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. [651] As a result, in 1964 the Surgeon General of the United States recommended smokers should stop smoking. [653]

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. [655] 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. [657]

The first successful pneumonectomy for lung cancer was performed in 1933. [660] Palliative radiotherapy has been used since the 1940s. [662] 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. [664] In 1997, continuous hyperfractionated accelerated radiotherapy was seen as an improvement over conventional radical radiotherapy. [666] With small-cell lung carcinoma, initial attempts in the 1960s at surgical resection [668] and radical radiotherapy [670] were unsuccessful. In the 1970s, successful chemotherapy regimens were developed. [671]

Research directions

Current research directions for lung cancer treatment include immunotherapy , [673] 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 . [673]

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 U.S. Food and Drug Administration (FDA) for treatment of melanoma and is undergoing clinical trials for both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). [673]

Other immunotherapy treatments interfere with the binding of programmed cell death 1 (PD-1) protein with its ligand PD-1 ligand 1 (PD-L1). 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 and nivolumab are currently in clinical trials for treatment for lung cancer. [673]

Epigenetics is the study of small, usually heritable, molecular modifications—or "tags"—that bind 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. [676] 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. [676] 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. [679] The project will look at tumor samples from 850 NSCLC patients at various stages including diagnosis, after first treatment, post-treatment, and relapse. [681] 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. [679]

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 . [683]