Lung cancer

This article is about lung carcinomas. For other lung tumors, see Lung tumor.

Lung cancer
Other names	Lung carcinoma
A chest X-ray showing a tumor in the lung (marked by arrow)
Specialty	Oncology, pulmonology
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)
Risk factors	Tobacco smoking genetic factors radon gas asbestos air pollution
Diagnostic method	Medical imaging, tissue biopsy
Prevention	Avoid smoking, radon gas, asbestos, second-hand smoke, or other forms of air pollution exposure
Treatment	Surgery, chemotherapy, radiotherapy
Prognosis	Five-year survival rate: 10 to 20% (most countries)
Frequency	3.3 million affected as of 2015
Deaths	1.8 million (2020)

Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissues of the lung. Lung carcinomas derive from transformed, malignant cells that originate as epithelial cells, or from tissues composed of epithelial cells. Other lung cancers, such as the rare sarcomas of the lung, are generated by the malignant transformation of connective tissues (i.e. nerve, fat, muscle, bone), which arise from mesenchymal cells. Lymphomas and melanomas (from lymphoid and melanocyte cell lineages) can also rarely result in lung cancer.

In time, this uncontrolled growth can metastasize (spreading beyond the lung) either by direct extension, by entering the lymphatic circulation, or via hematogenous, bloodborne spread – into nearby tissue or other, more distant parts of the body. Most cancers that originate from within the lungs, 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.

The major method of prevention is the avoidance of risk factors, including smoking and air pollution. 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 2020, lung cancer occurred in 2.2 million people and resulted in 1.8 million deaths. It is the most common cause of cancer-related death in both men and women. The most common age at diagnosis is 70 years. In most countries the five-year survival rate is around 10 to 20%, while in Japan it is 33%, in Israel 27%, and in the Republic of Korea 25%. Outcomes typically are worse in the developing world.

Signs and symptoms

Early lung cancer often has no symptoms. When symptoms do arise they are often nonspecific respiratory problems – coughing, shortness of breath, and/or chest pain – that can differ from person to person. Those who experience coughing tend to report either a new cough, or an increase in the frequency or strength of a pre-existing cough. Around a quarter cough up blood, ranging from small streaks in the sputum to large amounts. Around half of those diagnosed with lung cancer experience shortness of breath, while 25–50% experience a dull, persistent chest pain that remains in the same location over time. In addition to respiratory symptoms, some experience systemic symptoms including loss of appetite, weight loss, general weakness, fever, and night sweats.

Some less common symptoms suggest tumors in particular locations. Tumors in the thorax can cause breathing problems by obstructing the trachea or disrupting the nerve to the diaphragm, difficulty swallowing by compressing the esophagus, hoarseness by disrupting the nerves of the larynx, and Horner's syndrome by disrupting the sympathetic nervous system. Horner's syndrome is also common in tumors at the top of the lung, known as Pancoast tumors, which also cause shoulder pain that radiates down the little finger-side of the arm as well as destruction of the topmost ribs. Swollen lymph nodes above the collarbone can indicate a tumor that has spread within the chest. Tumors obstructing bloodflow to the heart can cause superior vena cava syndrome, while tumors infiltrating the area around the heart can cause fluid buildup around the heart, arrythmia, and heart failure.

Around a third of people diagnosed with lung cancer have symptoms caused by metastases in sites distant from the lung. Lung cancer can metastasize anywhere in the body, with different symptoms depending on the location. Brain metastases can cause headache, nausea, vomiting, seizures, and neurological deficits. Bone metastases can cause pain, bone fractures, and compression of the spinal cord. Metastasis into the bone marrow can deplete blood cells and cause leukoerythroblastosis (immature immune cells in the blood). Liver metastases can cause liver enlargement, pain in the right upper quadrant of the abdomen, fever, and weight loss.

Lung tumors also often cause the release of body-altering hormones, which themselves cause unusual symptoms, called paraneoplastic syndromes. Inappropriate hormone release can cause dramatic shifts in concentrations of blood minerals. Most common is hypercalcemia caused by over-production of parathyroid hormone-related protein or, less commonly, parathyroid hormone. Hypercalcemia can manifest as nausea, vomiting, abdominal pain, constipation, increased thirst, frequent urination, and altered mental status. Those with lung cancer also commonly experience hypokalemia due to inappropriate secretion of adrenocorticotropic hormone, as well as hyponatremia due to overproduction of antidiuretic hormone or atrial natriuretic peptide. Around a third of people with lung cancer develop nail clubbing, while up to one in ten experience hypertrophic primary osteoarthropathy. A variety of autoimmune disorders can arise as paraneoplastic syndromes in those with lung cancer, including Lambert–Eaton myasthenic syndrome (which causes muscle weakness), sensory neuropathies, muscle inflammation, brain swelling, and autoimmune deterioration of cerebellum, limbic system, or brainstem. Up to 1 in 12 people with lung cancer have paraneoplastic clotting issues, including migratory venous thrombophlebitis, clots in the heart, and disseminated intravascular coagulation. Paraneoplastic syndromes involving the skin and kidneys are rare, each occurring in up to 1% of those with lung cancer.

Diagnosis

Primary pulmonary sarcoma in an asymptomatic 72-year-old male

CT scan showing a cancerous tumor in the left lung

A person suspected of having lung cancer will often first have various imaging tests done to evaluate the presence, extent, and location of tumors. First, many primary care providers will perform a chest X-ray to look for a mass inside the lung. The x-ray 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; however, some lung tumors are not visible by X-ray. Next, many undergo computed tomography (CT) scanning, which can reveal the sizes and locations of tumors.

A definitive diagnosis of lung cancer requires a biopsy of the suspected tissue be histologically examined for cancer cells. Bronchoscopic or CT-guided biopsy is often used to sample the tumor for histopathology. Imaging is also used to assess the extent of cancer spread. Metastases on chest x-ray can appear as multiple nodules in the lower lobes. Positron emission tomography (PET) scanning or combined PET-CT scanning is often used to locate metastases in the body. Since PET scanning cannot be used in the brain, the National Comprehensive Cancer Network recommends magnetic resonance imaging (MRI) – or CT where MRI is unavailable – to scan the brain for metastases in those with NSCLC and large tumors, or tumors that have spread to the nearby lymph nodes. When spread to lymph nodes or to a single site is suspected, the suspected metastasis is often biopsied using a minimally invasive needle biopsy technique – typically using endobronchial ultrasound to guide a bronchoscope equipped with transbronchial needle aspiration. Primary lung cancers most commonly metastasize to the brain, bones, liver, and adrenal glands.

Additionally, biopsy material of the original tumor or metastases are often tested for their molecular profile to determine eligibility for targeted therapies.

Classification

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

Pie chart showing incidences of NSCLCs as compared to SCLCs shown at right, with fractions of smokers versus nonsmokers shown for each type

At diagnosis, lung cancers are classified based on the type of cells the tumor is derived from; tumors derived from different cells progress and respond to treatment differently. There are two main types of lung cancer, categorized by the size and appearance of the malignant cells seen by a histopathologist under a microscope: small cell lung cancer (SCLC; 15% of lung cancer diagnoses) and non-small-cell lung cancer (NSCLC; 85% of diagnoses). In SCLC, cancerous cells appear small with ill-defined boundaries, not much cytoplasm, many mitochondria, and have distinctive nuclei with granular-looking DNA and no visible nucleoli. 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). NSCLCs comprise a group of three cancer types: adenocarcinoma, squamous-cell carcinoma, and large-cell carcinoma. Nearly 40% of lung cancers are adenocarcinomas, which usually come from peripheral lung tissue. Squamous-cell carcinoma causes 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. Less than 10% of lung cancers are large-cell carcinomas, so named because the cells are large, with excess cytoplasm, large nuclei, and conspicuous nucleoli.

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.

Around 10% of lung cancers are rarer types rather than the classical four. These include mixes of the above subtypes like adenosquamous carcinoma. Rare subtypes include carcinoid tumors, bronchial gland carcinomas, and sarcomatoid carcinomas.

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

Staging

See also: Lung cancer 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 both the prognosis and the potential treatment of lung cancer.

SCLC is typically staged with a relatively simple system; cancers are scored as either "limited stage" or "extensive stage". Around a third of people are diagnosed at the limited stage, meaning cancer is confined to one side of the chest, within the scope of a single tolerable radiotherapy field. The other two thirds are diagnosed at the "extensive stage", with cancer spread to both sides of the chest, or to other parts of the body.

NSCLC – and sometimes SCLC – is typically staged with the American Joint Committee on Cancer's Tumor, Node, Metastasis (TNM) staging system. The size and extent of the tumor (T), spread to regional lymph nodes (N), and distant metastases (M) are scored individually, and combined to form "stage groups". Relatively small tumors are designated T1, which are subdivided by size: tumors ≤ 1 centimeter (cm) across are T1a; 1–2 cm T1b; 2–3 cm T1c. Tumors up to 5 cm across, or those that have spread to the visceral pleura (tissue covering the lung) or main bronchi, are desginated T2. T2a designates 3–4 cm tumors; T2b 4–5 cm tumors. T3 tumors are up to 7 cm across, have multiple nodules in the same lobe of the lung, or invade the chest wall, diaphragm (or the nerve that controls it), or area around the heart. Tumors that are larger than 7 cm, have nodules spread in different lobes of a lung, or invade the mediastinum (center of the chest cavity), heart, largest blood vessels that supply the heart, trachea, esophagus, or spine are designated T4. Lymph node staging depends on the extent of local spread: with the cancer metastasized to no lymph nodes (N0), pulmonary or hilar nodes (along the bronchi) on the same side as the tumor (N1), mediastinal or subcarinal lymph nodes (in the middle of the lungs, N2), or lymph nodes on the opposite side of the lung from the tumor (N3). Metastases are staged as no metastases (M0), nearby metastases (M1a; the space around the lung or the heart, or the opposite lung), a single distant metastasis (M1b), or multiple metastases (M1c). These T, N, and M scores are combined to designate a "stage grouping" for the cancer. Cancers limited to smaller tumors are designated stage I. Those with larger tumors or spread to the nearest lymph nodes are stage II. Those with the largest tumors or extensive lymph node spread are stage III. Cancers that have metastasized are stage IV. Each stage is further subdivided based on the combination of T, N, and M scores. Around 40% of those diagnosed with NSCLC have stage IV disease at the time of diagnosis.

TNM classification in lung cancer

T: Primary tumor T0 No primary tumor Tis Carcinoma in situ T1 Tumor ≤ 3 cm across, surrounded by lung or visceral pleura T1mi Minimally invasive adenocarcinoma T1a Tumor ≤ 1 cm across T1b Tumor > 1 cm but ≤ 2 cm across T1c Tumor > 2 cm but ≤ 3 cm across T2 Any of: Tumor size > 3 cm but ≤ 5 cm across Involvement of the main bronchus but not the carina Invasion of visceral pleura Atelectasis/obstructive pneumonitis extending to the hilum T2a Tumor > 3 cm but ≤ 4 cm across T2b Tumor > 4 cm but ≤ 5 cm across T3 Any of: Tumor size > 5 cm but ≤ 7 cm across Invasion into the chest wall, phrenic nerve, or parietal pericardium Separate tumor nodule in the same lobe T4 Any of: Tumor size > 7 cm Invasion of the diaphragm, mediastinum, heart, great vessels, trachea, carina, recurrent laryngeal nerve, esophagus, or vertebral body Separate tumor nodule in a different lobe of the same lung

N: Lymph nodes N0 No 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 M0 No distant metastasis M1a Any of: Separate tumor nodule in the other lung Tumor with pleural or pericardial nodules Malignant pleural or pericardial effusion M1b A single metastasis outside the chest M1c Two or more metastases outside the chest

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

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.

• Diagrams of main features of staging
• 
  Stage IA and IB lung cancer
• 
  Stage IIA lung cancer
• 
  Stage IIB lung cancer
• 
  One option for stage IIB lung cancer, with T2b; but if tumor is within 2 cm of the carina, this is stage 3
• 
  Stage IIIA lung cancer
• 
  Stage IIIA lung cancer, if there is one feature from the list on each side
• 
  Stage IIIA lung cancer
• 
  Stage IIIB lung cancer
• 
  Stage IIIB lung cancer
• 
  Stage IV lung cancer

Treatment

Main article: Treatment of lung cancer

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. In addition, smoking cessation and exercise is sometimes suggested.

Small-cell lung cancer

Limited stage SCLC is typically treated with a combination of chemotherapy and radiotherapy. For chemotherapy, the National Comprehensive Cancer Network and American College of Chest Physicians guidelines recommend four to six cycles of a platinum-based chemotherapeutic – cisplatin or carboplatin – combined with either etoposide or irinotecan. This is typically combined with thoracic radiation therapy – 45 Gray (Gy) twice-daily – alongside the first two chemotherapy cycles. First-line therapy causes remission in up to 80% of those who receive it; however most people relapse with chemotherapy-resistant disease. Those who relapse are given second-line chemotherapies. Topotecan and lurbinectedin are approved by the US FDA for this purpose. Irinotecan, paclitaxel, docetaxel, vinorelbine, etoposide, and gemcitabine are also sometimes used, and are similarly efficacious. Prophylactic cranial irradiation can also improve survival in those with limited stage disease.

Non-small-cell lung cancer

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

For stage I and stage II NSCLC the first line of treatment is often surgical removal of the affected lobe of the lung. For those not well enough to tolerate full lobe removal, a smaller chunk of lung tissue can be removed by wedge resection or segmentectomy surgery. Those with centrally located tumors and otherwise-healthy respiratory systems may have more extreme surgery to remove an entire lung (pneumonectomy). Experienced thoracic surgeons, and a high-volume surgery clinic improve chances of survival. Those who are unable or unwilling to undergo surgery can instead receive radiation therapy. Stereotactic body radiation therapy is best practice, typically administered several times over 1–2 weeks. Chemotherapy has little effect in those with stage I NSCLC, and may worsen disease outcomes in those with the earliest disease. In those with stage II disease, chemotherapy is usually initiated six to twelve weeks after surgery, with up to four cycles of cisplatin – or carboplatin in those with kidney problems, neuropathy, or hearing impairment – combined with vinorelbine, pemetrexed, gemcitabine, or docetaxel.

Brachytherapy (internal radiotherapy) for lung cancer given via the airway

Treatment for those with stage III NSCLC depends on the nature of their disease. Those with more limited spread may undergo surgery to have the tumor and affected lymph nodes removed, followed by chemotherapy and potentially radiotherapy. Those with particularly large tumors (T4) and those for whom surgery is impractical are treated with combination chemotherapy and radiotherapy along with the immunotherapy durvalumab. Combined chemotherapy and radiation enhances survival compared to chemotherapy followed by radiation, though the combination therapy comes with harsher side effects.

Those with stage IV disease are treated with combinations of pain medication, radiotherapy, immunotherapy, and chemotherapy. Many cases of advanced disease can be treated with targeted therapies depending on the genetic makeup of the cancerous cells. Some tumors have mutations in the EGFR gene that result in an overactive EGFR protein; these can be treated with EGFR inhibitors osimertinib, erlotinib, gefitinib, afatinib, or dacomitinib – with osimertinib known to be superior to erlotinib and gefitinib, and all superior to chemotherapy alone. Up to 7% of those with NSCLC harbor mutations that result in hyperactive ALK protein, which can be treated with ALK inhibitors crizotinib, or its successors alectinib, brigatinib, and ceritinib. Those treated with ALK inhibitors who relapse can then be treated with the third-generation ALK inhibitor lorlatinib. Up to 5% with NSCLC have overactive MET, which can be inhibited with MET inhibitors capmatinib or tepotinib. Targeted therapies are also available for some cancers with rare mutations. Cancers with hyperactive BRAF (around 2% of NSCLC) can be treated by dabrafenib combined with the MEK inhibitor trametinib; those with activated ROS1 (around 1% of NSCLC) can be inhibited by crizotinib, lorlatinib, or entrectinib; overactive NTRK (<1% of NSCLC) by entrectinib or larotrectinib; active RET (around 1% of NSCLC) by selpercatinib.

People whose NSCLC is not targetable by current molecular targeted therapies instead can be treated with combination chemotherapy plus immune checkpoint inhibitors, which prevent cancer cells from inactivating immune T cells. The chemotherapeutic agent of choice depends on the NSCLC subtype: cisplatin plus gemcitabine for squamous cell carcinoma, cisplatin plus pemetrexed for non-squamous cell carcinoma. Immune checkpoint inhibitors are most effective against cancers that express the protein PD-L1, but are sometimes effective in those that do not. Treatment with pembrolizumab, atezolizumab, or combination nivolumab plus ipilimumab are all superior to chemotherapy alone against tumors expressing PD-L1. Those who relapse on the above are treated with second-line chemotherapeutics docetaxel and ramucirumab.

Monoclonal antibodies used in the treatment of NSCLC and their mechanism of action https://doi.org/10.3390/ph13110373

The main treatment arms of phase 3 clinical trials providing immunotherapy in the first line for patients with NSCLC https://doi.org/10.3390/ph13110373

Several treatments can be provided 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

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

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.

Noninvasive interventions

The most effective intervention for avoiding death from lung cancer is to stop smoking; even people who already have lung cancer are encouraged to stop smoking. There is no clear evidence which smoking cessation program is most effective for people who have been diagnosed with lung cancer.

Some weak evidence suggests that certain supportive care interventions (noninvasive) that focus on well-being for people with lung cancer may improve quality of life. Interventions such as nurse follow-ups, psychotherapy, psychosocial therapy, and educational programs may be beneficial, however, the evidence is not strong (further research is needed). Counseling may help people cope with emotional symptoms related to lung cancer. Reflexology may be effective in the short-term, however more research is needed. No evidence has been found to suggest that nutritional interventions or exercise programs for a person with lung cancer result in an improvement in the quality of life that are relevant or last very long.

Exercise training may benefit people with NSCLC who are recovering from lung surgery. In addition, exercise training may benefit people with NSCLC who have received radiotherapy, chemotherapy, chemoradiotherapy, or palliative care. Exercise training before lung cancer surgery may also improve outcomes. It is unclear if exercise training or exercise programs are beneficial for people who have advanced lung cancer. A home-based component in a personalized physical rehabilitation program may be useful for recovery. It is unclear if home-based prehabilitation (before surgery) leads to less adverse events or hospitalization time. Physical rehabilitation with a home-based component may improve recovery after treatment and overall lung health.

Prognosis

Outcomes in lung cancer according to clinical stage

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

Around 19% of people diagnosed with lung cancer survive five years from diagnosis. Five-year survival is higher in women (22%) than men (16%); women tend to be diagnosed with less-advanced disease, and have better outcomes than men diagnosed at the same stage. In England and Wales, between 2013 and 2017, overall five-year survival for lung cancer was estimated at 13.8%. Outcomes are generally worse in the developing world. 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.

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).

SCLC is particularly aggressive. Most people treated for SCLC relapse and eventually develop chemotherapy-resistant cancer. The average person diagnosed with SCLC at the limited stage survives 12–20 months from diagnosis; the average person diagnosed at the extensive stage survives around 12 months. 10–15% of people with SCLC survive 5 years after diagnosis. Those with limited stage SCLC that goes into complete remission after chemotherapy and radiotherapy have a 50% chance of brain metastases developing within the next two years – a chance reduced by prophylactic cranial irradiation.

For NSCLC, the best prognosis is achieved with complete surgical resection of stage-IA disease, with up to 70% five-year survival. The prognosis of patients with NSCLC improved significantly in the last years with the introduction of immunotherapy. 68–92% of those diagnosed with stage I NSCLC survive at least 5 years after diagnosis, as do 53–60% of those diagnosed with stage II NSCLC.

Several personal and disease factors are associated with improved outcomes. Those diagnosed at an earlier disease stage tend to have better prognoses, as do those diagnosed at a younger age. Those who smoke or experience weight loss as a symptom tend to have worse outcomes. Large/active metastases (by PET scan) and tumor mutations in KRAS are associated with reduced survival.

Overall survival in NSCLC patients treated with protocols incorporating immunotherapy in the first line for advanced or metastatic disease. Nasser NJ, Gorenberg M, Agbarya A. Pharmaceuticals 2020, 13(11), 373; https://doi.org/10.3390/ph13110373

Causes

Relationship between cigarette consumption per person (blue) and male lung cancer rates (dark yellow) in the US over the century

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

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 for cancer increases.

Smoking

Tobacco smoking is by far the major contributor to lung cancer, causing 80% to 90% of cases. Across the developed world, 90% of lung cancer deaths in men and 70% of those in women during 2000 were attributed to smoking. Cigarette smoke contains at least 73 known carcinogens, including benzo[a]pyrene, NNK, 1,3-butadiene, and a radioactive isotope of polonium – polonium-210. Vaping may be a risk factor for lung cancer, but less than that of cigarettes, and further research is necessary due to the length of time it can take for lung cancer to develop following an exposure to carcinogens. Although most cases of adenocarcinoma are associated with smoking, it 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.

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, the UK and other European countries have consistently shown a significantly-increased risk among those exposed to passive smoking. The risk of developing lung cancer increases by 25–28%. Investigations of sidestream smoke (the main component of second-hand smoke; around 85%) suggest that it is more dangerous than direct mainstream smoke.

Cannabis smoke contains many of the same carcinogens as those found in tobacco smoke, but the effect of smoking cannabis on lung cancer risk is not clear.

Other environmental exposures

Exposure to a variety of other toxic chemicals – typically encountered in certain occupations – are associated with an increased risk of lung cancer. In all, occupational exposures to carcinogens are estimated to cause 9–15% of lung cancers. A prominent example is asbestos, which causes lung cancer either directly or indirectly by inflamming the lung. Exposure to all commercially available forms of asbestos increase cancer risk, and cancer risk increases with time of exposure. Asbestos and cigarette smoking increase risk synergestically – i.e. the risk of someone who smokes and has asbestos exposure dying from lung cancer is much higher than would be expected from adding the two risks together. Similarly, exposure to radon, a naturally occurring breakdown product of the Earth's uranium, is associated with increased lung cancer risk. This is particularly true in underground miners, who have the greatest exposure; but also in indoor air in residential spaces. Like asbestos, cigarette smoking and radon exposure increase risk synergistically. Radon exposure is responsible for between 3% and 14% of lung cancer cases.

Several other chemicals encountered in various occupations are also associated with increased lung cancer risk including arsenic used in wood preservation, pesticide application, and some ore smelting; ionizing radiation encountered during uranium mining; vinyl chloride in papermaking; beryllium in jewelers, ceramics workers, missile technicians, and nuclear reactor workers; chromium in stainless steel production, welding, and hide tanning; nickel in electroplaters, glass workers, metal workers, welders, and those who make batteries, ceramics, and jewelry; and diesel exhaust encountered by miners.

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 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.

Genetics

About 8% of lung cancer cases are caused by inherited (genetic) factors. In relatives of people who are diagnosed with lung cancer, the risk is doubled, likely due to a combination of genes. Polymorphisms on chromosomes 5, 6, and 15 have been identified and are associated with an increased risk of lung cancer. Single-nucleotide polymorphisms 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. Newer genetic studies, have identified 18 susceptibility loci achieving genome-wide significance. These loci highlight a heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, again identifying the cholinergic nicotinic receptors, e.g. CHRNA2.

Other causes

Numerous other substances, occupations, and environmental exposures have been linked to lung cancer. The International Agency for Research on Cancer states that "sufficient evidence" exists to show that the following are carcinogenic in the lungs:

• Some metals (aluminium production, cadmium and cadmium compounds, chromium(VI) compounds, beryllium and beryllium compounds, iron and steel founding, nickel compounds, arsenic and inorganic arsenic compounds, and underground hematite mining)
• Some products of combustion (incomplete combustion, coal (indoor emissions from household coal burning), coal gasification, coal-tar pitch, coke production, soot, and diesel engine exhaust)
• Ionizing radiation (X-ray and gamma)
• Some toxic gases (methyl ether (technical grade), and bis-(chloromethyl) ether, mustard gas, MOPP (vincristine-prednisone-nitrogen mustard-procarbazine mixture) and fumes from painting)
• Rubber production and crystalline silica dust
• A small increase in the risk of lung cancer is seen in people affected by systemic sclerosis.

Pathogenesis

See also: Carcinogenesis

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.

Mutations in the K-ras proto-oncogene contribute to roughly 10–30% of lung adenocarcinomas. Nearly 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 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 NSCLC, 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. SCLC may originate from these cell lines or neuroendocrine cells, and it may express CD44.

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

Prevention

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

Smoking prevention and smoking cessation are effective ways of reducing the risk of lung cancer.

Smoking cessation

Those who smoke can reduce their lung cancer risk by quitting smoking – the risk reduction is greater the longer a person goes without smoking. Self-help programs tend to have little influence on success of smoking cessation, whereas combined counseling and pharmacotherapy improve cessation rates. The U.S. FDA has approved antidepressant therapies and the nicotine replacement varenicline as first-line therapies to aid in smoking cessation. Clonidine and nortriptyline are recommended second-line therapies.

Tobacco control

See also: Tobacco control

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.

Screening

Main article: Lung cancer screening

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 accurate positive scan there are about 19 false positive 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 recommends yearly screening using low-dose CT 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. Their recommendation excludes 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.

Lung cancer can often appear as a solitary pulmonary nodule on a chest radiograph. However, the differential diagnosis is wide and 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. Clinical practice guidelines recommend specific frequencies (suggested intervals of time between tests) for pulmonary nodule surveillance. CT imaging is not suggested to be used for longer or more frequently than indicated in the clinical guidelines, as any additional surveillance exposes people to increased radiation and is costly.

Other prevention strategies

The long-term use of supplemental vitamin A, B vitamins, vitamin D or vitamin E does not reduce the risk of lung cancer. Vitamin C supplementation might reduce the risk of lung cancer. Some studies have found vitamins A, B, and E may increase the risk of lung cancer in those who have a history of smoking.

Some studies suggest that people who eat food 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.

Epidemiology

Trachea, bronchus, and lung cancers deaths per million persons in 2012

  0–7

  8–12

  13–32

  33–53

  54–81

  82–125

  126–286

  287–398

  399–527

  528–889

Lung cancer, incidence, mortality, and survival, England 1971–2011

Worldwide, lung cancer is the most diagnosed type of cancer, and the leading cause of cancer death. In 2020, 2.2 million new cases were diagnosed, and 1.8 million people died from lung cancer, representing 18% of all cancer deaths. Lung cancer deaths are expected to rise globally to nearly 3 million annual deaths by 2035, due to high rates of tobacco use and aging populations. Lung cancer is rare in those younger than 40; from there cancer rates increase with age, stabilizing around age 80.

Lung cancer incidence varies dramatically by geography and sex, with the highest rates in Micronesia, Polynesia, Europe, Asia, and North America; and lowest rates in Africa and Central America. Globally, around 8% of men and 6% of women develop lung cancer in their lifetimes. However, the ratio of lung cancer cases in men to women varies dramatically by geography, as high as nearly 12:1 in Belarus, to 1:1 in Brazil, likely due to differences in smoking patterns. In the United States, lung cancer remains the most common cause of cancer deaths, despite a nearly 50% decrease in the death rate from its peak in 1990. Lung cancer is the third-most common cancer in the UK (47,968 people were diagnosed with the disease in 2017), and it is the most common cause of cancer-related death (around 34,600 people died in 2018).

In the US, lung cancer rates also vary by racial and ethnic group, with the highest rates in African Americans, and the lowest rates in Hispanics, Native Americans and Asian Americans. 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 risk is dramatically influenced by environmental exposure, namely cigarette smoking, as well as occupational risks in mining, shipbuilding, petroleum refining, and occupations that involve asbestos exposure. 85–90% of lung cancer cases are in people who have smoked cigarettes, and 15% of smokers develop lung cancer. People who have a long history of smoking have the highest risk of developing lung cancer, with the risk increasing with duration of smoking. The incidence in men rose until the mid-1980s, and has declined since then. In women, the incidence rose until the late 1990s, and has since been stable. Non-smokers' risk of developing lung cancer is also influenced by tobacco smoking; secondhand smoke (i.e. being around tobacco smoke) increases risk of developing lung cancer around 30%, with risk correlated to duration of exposure.

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.

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. Rates of lung adenocarcinoma continues to rise.

History

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.

Research directions

The search for new treatment options continues. Many clinical trials involving radiotherapy, surgery, EGFR inhibitors, microtubule inhibitors and immunotherapy are currently underway.

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 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 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 people 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 people with NSCLC 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. EGFR inhibitors include erlotinib, gefitinib, afatinib and icotinib (the last one is only available in China). 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.

The PI3K pathway has been investigated as a target for lung cancer therapy. The most promising strategies for targeting this pathway seem to be selective inhibition of one or more members of the class I PI3Ks, and co-targeted inhibition of this pathway with others such as MEK.

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.

See also

• Recurrence of lung cancer

References

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