Lung cancer

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Lung cancer
Other namesLung carcinoma
LungCACXR.PNG
A chest X-ray showing a tumor in the lung (marked by arrow)
SpecialtyOncology, pulmonology
SymptomsCoughing (including coughing up blood), shortness of breath, chest pain
Usual onset~71 years[1]
TypesSmall-cell lung carcinoma (SCLC), non-small-cell lung carcinoma (NSCLC)[2]
Risk factors
Diagnostic methodMedical imaging, tissue biopsy[2]
PreventionAvoid smoking, radon gas, asbestos, second-hand smoke, or other forms of air pollution exposure
TreatmentSurgery, chemotherapy, radiotherapy[2]
PrognosisFive-year survival rate: 10 to 20% (most countries)[5]
Frequency3.3 million affected as of 2015[6]
Deaths1.8 million (2020)[5]

Lung cancer, also known as lung carcinoma[7] (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.[8] 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. 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.[9] 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).[2] 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.[3] About 10–15% of cases occur in people who have never smoked.[10] 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.[3][4][11] Lung cancer may be seen on chest radiographs and computed tomography (CT) scans.[12] The diagnosis is confirmed by biopsy, which is usually performed by bronchoscopy or CT-guidance.[2][13]

The major method of prevention is the avoidance of risk factors, including smoking and air pollution.[14] Treatment and long-term outcomes depend on the type of cancer, the stage (degree of spread), and the person's overall health.[12] Most cases are not curable.[2] Common treatments include surgery, chemotherapy, and radiotherapy.[12] NSCLC is sometimes treated with surgery, whereas SCLC usually responds better to chemotherapy and radiotherapy.[15]

Worldwide in 2020, lung cancer occurred in 2.2 million people and resulted in 1.8 million deaths.[5] It is the most common cause of cancer-related death in both men and women.[16][17] The average age at diagnosis is 71 years.[1] In most countries the five-year survival rate is around 10 to 20%,[5] although outcomes typically are worse in the developing world.[18]

Signs and symptoms[edit]

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.[19] Those who experience coughing tend to report either a new cough, or an increase in the frequency or strength of a pre-existing cough.[19] Around one in four cough up blood, ranging from small streaks in the sputum to large amounts.[20][19] 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.[19] In addition to respiratory symptoms, some experience systemic symptoms including loss of appetite, weight loss, general weakness, fever, and night sweats.[19][21]

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.[19][21] 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.[21] Swollen lymph nodes above the collarbone can indicate a tumor that has spread within the chest.[19] Tumors obstructing bloodflow to the heart can cause superior vena cava syndrome (swelling of the upper body and shortness of breath), while tumors infiltrating the area around the heart can cause fluid buildup around the heart, arrythmia (irregular heartbeat), and heart failure.[21]

About one in three people diagnosed with lung cancer have symptoms caused by metastases in sites distant from the lung.[21] 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).[21] Liver metastases can cause liver enlargement, pain in the right upper quadrant of the abdomen, fever, and weight loss.[21]

Lung tumors also often cause the release of body-altering hormones, which themselves cause unusual symptoms, called paraneoplastic syndromes.[21] Inappropriate hormone release can cause dramatic shifts in concentrations of blood minerals. Most common is hypercalcemia (high blood calcium) caused by over-production of parathyroid hormone-related protein or parathyroid hormone. Hypercalcemia can manifest as nausea, vomiting, abdominal pain, constipation, increased thirst, frequent urination, and altered mental status.[21] Those with lung cancer also commonly experience hypokalemia (low potassium) due to inappropriate secretion of adrenocorticotropic hormone, as well as hyponatremia (low sodium) due to overproduction of antidiuretic hormone or atrial natriuretic peptide.[21] About one of three 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.[21] Up to one in twelve people with lung cancer have paraneoplastic blood clotting, including migratory venous thrombophlebitis, clots in the heart, and disseminated intravascular coagulation.[21] Paraneoplastic syndromes involving the skin and kidneys are rare, each occurring in up to 1% of those with lung cancer.[21]

Diagnosis[edit]

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 have imaging tests done to evaluate the presence, extent, and location of tumors. First, many primary care providers perform a chest X-ray to look for a mass inside the lung.[22] 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;[12] however, some lung tumors are not visible by X-ray.[19] Next, many undergo computed tomography (CT) scanning, which can reveal the sizes and locations of tumors.[22][23]

A definitive diagnosis of lung cancer requires a biopsy of the suspected tissue be histologically examined for cancer cells.[24] Given the location of lung cancer tumors, biopsies can often be obtained by minimally invasive techniques: a fiberoptic bronchoscope that can retrieve tissue (sometimes guided by endobronchial ultrasound), fine needle aspiration, or other imaging-guided biopsy through the skin.[24] Those who cannot undergo a typical biopsy procedure may instead have a liquid biopsy taken (that is, a sample of some body fluid) which may contain circulating tumor DNA that can be used for molecular testing.[25]

Imaging is also used to assess the extent of cancer spread. Positron emission tomography (PET) scanning or combined PET-CT scanning is often used to locate metastases in the body. Since PET scanning is less sensitive 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.[26] When imaging suggests the tumor has spread, the suspected metastasis is often biopsied to confirm that it is cancerous.[24] Lung cancers most commonly metastasize to the brain, bones, liver, and adrenal glands.[2]

Lung cancer can often appear as a solitary pulmonary nodule on a chest radiograph or CT scan. In lung cancer screening studies as many as 30% of those screened appear to have a lung nodule, the majority of which turn out to be benign.[27] Besides lung cancer many other diseases can also give this appearance, including hamartomas, and infectious granulomas caused by tuberculosis, histoplasmosis, or coccidioidomycosis.[28]

Classification[edit]

Age-adjusted incidence of lung cancer by histological type[3]
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

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).[29] SCLC tumors are often found near the center of the lungs, in the major airways.[30] Their cells appear small with ill-defined boundaries, not much cytoplasm, many mitochondria, and have distinctive nuclei with granular-looking DNA and no visible nucleoli.[31] NSCLCs comprise a group of three cancer types: adenocarcinoma, squamous-cell carcinoma, and large-cell carcinoma.[31] Nearly 40% of lung cancers are adenocarcinomas, which usually come from peripheral lung tissue.[2] Their cells grow in three-dimensional clumps, resemble glandular cells, and may produce mucin.[31] Squamous-cell carcinoma causes about 30% of lung cancers. They typically occur close to large airways.[2] The tumors consist of sheets of cells, with layers of keratin.[31] A hollow cavity and associated cell death are commonly found at the center of the tumor.[2] Less than 10% of lung cancers are large-cell carcinomas,[31] so named because the cells are large, with excess cytoplasm, large nuclei, and conspicuous nucleoli.[2]

Pie chart showing incidences of NSCLCs as compared to SCLCs shown at right, with fractions of smokers versus nonsmokers shown for each type[32]

Several lung cancer types are subclassified based on the growth characteristics of the cancer cells. Adenocarcinomas are classified as lepidic (growing along the surface of intact alveolar walls),[33] acinar and papillary, or micropapillary and solid pattern. Lepidic adenocarcinomas tend to be least aggressive; micropapillary and solid pattern adenocarcinomas most aggressive.[34]

In addition to examining cell morphology, biopsies are often stained with immunohistochemistry to confirm lung cancer classification. SLCLs bear the markers of neuroendocrine cells, such as chromogranin, synaptophysin, and CD56.[35] Adenocarcinomas tend to express Napsin-A and TTF-1; squamous cell carcinomas lack Napsin-A and TTF-1, but express p63 and its cancer-specific isoform p40.[31] CK7 and CK20 are also commonly used to differentiate lung cancers. CK20 is found in several cancers, but typically absent from lung cancer. CK7 is present in many lung cancers, but absent from squamous cell carcinomas.[36] Additionally, biopsy material of the original tumor or metastases are often tested for their molecular profile to determine eligibility for targeted therapies.[citation needed]

Around 10% of lung cancers are rarer types.[31] These include mixes of the above subtypes like adenosquamous carcinoma.[2] Rare subtypes include carcinoid tumors, bronchial gland carcinomas, and sarcomatoid carcinomas.[2] A subgroup of lung adenocarcinomas show lepidic growth. Formerly known as bronchioloalveolar carcinoma, these cancers typically have a better prognosis that other types of lung cancer.[37]

Staging[edit]

Stage group according to TNM classification in lung cancer[38]
TNM Stage group
T1a N0 M0 IA1
T1b N0 M0 IA2
T1c N0 M0 IA3
T2a N0 M0 IB
T2b N0 M0 IIA
T1–T2 N1 M0 IIB
T3 N0 M0
T1–T2 N2 M0 IIIA
T3 N1 M0
T4 N0–N1 M0
T1–T2 N3 M0 IIIB
T3–T4 N2 M0
T3–T4 N3 M0 IIIC
Any T, any N, M1a–M1b IVA
Any T, any N, M1c IVB

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 treatment of lung cancer.[39]

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.[39] 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.[39]

NSCLC – and sometimes SCLC – is typically staged with the American Joint Committee on Cancer's Tumor, Node, Metastasis (TNM) staging system.[40] 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.[41]

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.[41][42] 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.[41][42] 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).[42] 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).[41]

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.[43] Around 40% of those diagnosed with NSCLC have stage IV disease at the time of diagnosis.[44]

TNM classification in lung cancer[45][46]
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

Screening[edit]

Screening programs attempt to detect lung tumors in asymptomatic individuals early enough that the tumors can be successfully treated. Regular low-dose CT scans in individuals at high risk of developing lung cancer reduce total lung cancer deaths by as much as 20%.[27] The United States Preventive Services Task Force recommends yearly screening using low-dose CT in people between 55 and 80 who have a smoking history of at least 30 pack-years.[47]

Treatment[edit]

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

Treatment for lung cancer depends on the cancer's specific cell type, how far it has spread, and the person's health. Common treatments for early stage cancers include surgical removal of the tumor, chemotherapy, and radiation therapy. For later stage cancers, chemotherapy and radiation therapy are combined with newer targeted molecular therapies and immune checkpoint inhibitors.[48] All lung cancer treatment regimens are combined with lifestyle changes and palliative care to improve quality of life.[49]

Small-cell lung cancer[edit]

Limited-stage SCLC is typically treated with a combination of chemotherapy and radiotherapy.[50] For chemotherapy, the National Comprehensive Cancer Network and American College of Chest Physicians guidelines recommend four to six cycles of a platinum-based chemotherapeuticcisplatin or carboplatin – combined with either etoposide or irinotecan.[51] This is typically combined with thoracic radiation therapy – 45 Gray (Gy) twice-daily – alongside the first two chemotherapy cycles.[50] 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.[50] Irinotecan, paclitaxel, docetaxel, vinorelbine, etoposide, and gemcitabine are also sometimes used, and are similarly efficacious.[50] Prophylactic cranial irradiation can also reduce the risk of brain metastases and improve survival in those with limited-stage disease.[52][50]

Similarly, extensive-stage SCLC is treated first with etoposide along with either cisplatin or carboplatin. Radiotherapy is used only to shrink tumors that are causing particularly severe symptoms. Combining standard chemotherapy with an immune checkpoint inhibitor can improve survival for a minority of those affected, extending the average person's lifespan by around 2 months.[53]

Non-small-cell lung cancer[edit]

For stage I and stage II NSCLC the first line of treatment is often surgical removal of the affected lobe of the lung.[54] 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.[54] Those with centrally located tumors and otherwise-healthy respiratory systems may have more extreme surgery to remove an entire lung (pneumonectomy).[54] Experienced thoracic surgeons, and a high-volume surgery clinic improve chances of survival.[54] 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.[54] 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.[54]

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.[55] Combined chemotherapy and radiation enhances survival compared to chemotherapy followed by radiation, though the combination therapy comes with harsher side effects.[55]

Those with stage IV disease are treated with combinations of pain medication, radiotherapy, immunotherapy, and chemotherapy.[44] Many cases of advanced disease can be treated with targeted therapies depending on the genetic makeup of the cancerous cells. Up to 30% of tumors have mutations in the EGFR gene that result in an overactive EGFR protein;[56] 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.[44] 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.[44] Those treated with ALK inhibitors who relapse can then be treated with the third-generation ALK inhibitor lorlatinib.[44] Up to 5% with NSCLC have overactive MET, which can be inhibited with MET inhibitors capmatinib or tepotinib.[44] 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.[44]

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

People whose NSCLC is not targetable by current molecular 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.[57] Immune checkpoint inhibitors are most effective against cancers that express the protein PD-L1, but are sometimes effective in those that do not.[58] Treatment with pembrolizumab, atezolizumab, or combination nivolumab plus ipilimumab are all superior to chemotherapy alone against tumors expressing PD-L1.[58] Those who relapse on the above are treated with second-line chemotherapeutics docetaxel and ramucirumab.[59]

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.[60] Laser photosection involves the delivery of laser light inside the airway via a bronchoscope to remove the obstructing tumor.[61]

Palliative care[edit]

Integrating palliative care (medical care focused on improving symptoms and lessening discomfort) into lung cancer treatment from the time of diagnosis improves the survival time and quality of life of those with lung cancer.[62] Particularly common symptoms of lung cancer are shortness of breath and pain. Supplemental oxygen, improved airflow, re-orienting an effected person in bed, and low-dose morphine can all improve shortness of breath.[63] Other causes of lung cancer-associated shortness of breath can be treated directly, such as antibiotics for a lung infection, diuretics for pulmonary edema, benzodiazepines for anxiety, and steroids for airway obstruction.[63] Up to 92% of those with lung cancer report pain, either from tissue damage at the tumor site(s) or nerve damage.[64] The World Health Organization (WHO) has developed a three-tiered system for managing cancer pain. For those with mild pain (tier one), the WHO recommends acetominophen or a nonsteroidal anti-inflammatory drug.[64] Around a third of people experience moderate (tier two) or severe (tier three) pain, for which the WHO recommends opioid painkillers.[64] Opioids are typically effective at easing nociceptive pain (pain caused by damage to various body tissues). Opioids are occasionally effective at easing neuropathic pain (pain cauesd by nerve damage). Neuropathic agents such as anticonvulsants, tricyclic antidepressants, and serotonin–norepinephrine reuptake inhibitors, are often used to ease neuropathic pain, either alone or in combination with opioids.[64]

For both NSCLC and SCLC patients, smaller doses of radiation to the chest may be used for symptom control (palliative radiotherapy).[65][66] With adequate physical fitness maintaining chemotherapy during lung cancer palliation offers one and a half to three months of prolongation of survival, symptomatic relief, and an improvement in quality of life, with better results seen with modern agents.[67][68]

For individuals who have more advanced disease, hospice care may also be appropriate.[13][69]

Noninvasive interventions[edit]

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.[70] Those with lung cancer who quit smoking tend to survive longer, with fewer side effects and higher quality of life, than those who continue to smoke.[71]

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.[needs update][72] 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).[72] Counseling may help people cope with emotional symptoms related to lung cancer.[72] Reflexology may be effective in the short-term, however more research is needed.[72] 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.[72]

For those with operable lung cancer, regular aerobic and/or resistance exercise in the weeks leading up to the surgery can reduce hospital stays and postoperative complications,[73] and the American Society for Clinical Oncology recommends preoperative exercise regimens for those with lung cancer.[74]

Prognosis[edit]

Percent of people who survive five years from a lung cancer diagnosis over time, according to the NIH SEER program
Five-year survival in those diagnosed with lung cancer, by stage[75]
Clinical stage Five-year survival (%)
IA1 92
IA2 83
IA3 77
IB 68
IIA 60
IIB 53
IIIA 36
IIIB 26
IIIC 13
IVA 10
IVB 0

Around 19% of people diagnosed with lung cancer survive five years from diagnosis.[48] Five-year survival is higher in women (22%) than men (16%);[48] women tend to be diagnosed with less-advanced disease, and have better outcomes than men diagnosed at the same stage.[76] In England and Wales, between 2013 and 2017, overall five-year survival for lung cancer was estimated at 13.8%.[77] In Japan it is 33%, in Israel 27%, and in the Republic of Korea 25%.[5] Outcomes are generally worse in the developing world.[18] In the US, people with medical insurance are more likely to have a better outcome.[78]

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).[79]

SCLC is particularly aggressive. 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.[50] 10–15% of people with SCLC survive 5 years after diagnosis.[50] Most people treated for SCLC relapse and eventually develop chemotherapy-resistant cancer.[50] The average person whose SCLC relapses after treatment survives 3–4 months from the time of relapse.[51] 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.[51]

For NSCLC, the best prognosis is achieved with complete surgical resection of stage-IA disease, with up to 70% five-year survival.[80] The prognosis of patients with NSCLC improved significantly in the last years with the introduction of immunotherapy.[81] 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.[54]

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.[76]

Experience[edit]

The uncertainty of lung cancer prognosis often causes stress, and makes future planning difficult, for those with lung cancer and their families.[82] Those whose cancer goes into remission often experience fear of their cancer returning or progressing, associated with poor quality of life, negative mood, and functional impairment. This fear is exacerbated by frequent or prolonged surveillance imaging, and other reminders of cancer risks.[82]

Causes[edit]

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.[83]

Smoking[edit]

Tobacco smoking is by far the major contributor to lung cancer, causing 80% to 90% of cases.[84] Lung cancer risk increases with quantity of cigarettes consumed.[85] Tobacco smoking's carcinogenic effect is due to various chemicals in tobacco smoke that cause DNA mutations, increasing the chance of cells becoming cancerous.[86] The International Agency for Research on Cancer identifies at least 50 chemicals in tobacco smoke as carcinogenic, with the most potent being the tobacco-specific nitrosamines.[85] Exposure to these chemicals causes several kinds of DNA damage: DNA adducts, oxidative stress, and breaks in the DNA strands.[87] Being around tobacco smoke – called passive smoking – can also cause lung cancer. Living with a tobacco smoker increases one's risk of developing lung cancer by 24%. An estimated 17% of lung cancer cases in those who do not smoke are caused by high levels of environmental tobacco smoke.[88]

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.[89]

The smoking of non-tobacco products is not known to be associated with lung cancer development. Marijuana smoking does not seem to independently cause lung cancer – despite the relatively high levels of tar and known carcinogens in marijuana smoke. The relationship between smoking cocaine and developing lung cancer has not been studied.[90]

Environmental exposures[edit]

Exposure to a variety of other toxic chemicals – typically encountered in certain occupations – are associated with an increased risk of lung cancer.[91] In all, occupational exposures to carcinogens are estimated to cause 9–15% of lung cancers.[91] A prominent example is asbestos, which causes lung cancer either directly or indirectly by inflamming the lung.[91] Exposure to all commercially available forms of asbestos increase cancer risk, and cancer risk increases with time of exposure.[91] 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.[91] 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.[91] Radon exposure is responsible for between 3% and 14% of lung cancer cases.[92]

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.[91]

Exposure to air pollution, especially fine particulates, increases the risk of lung cancer.[93] Fine particulates (PM2.5) and sulfate aerosols, which may be released in traffic exhaust fumes, are associated with a slightly increased risk.[3][94] For nitrogen dioxide, an incremental increase of 10 parts per billion increases the risk of lung cancer by 14%.[95] Outdoor air pollution is estimated to cause 1–2% of lung cancers.[3] Indoor air pollution from burning wood, charcoal, or crop residue for cooking and heating has also been linked to an increased risk of developing lung cancer.[96] The International Agency for Research on Cancer has classified emission from household burning of coal and biomass as "carcinogenic" and "probably carcinogenic" respectively.[96]

Other diseases[edit]

Several other diseases that cause inflammation of the lung increase one's risk of lung cancer. This association is strongest for chronic obstructive pulmonary disorder – the risk is highest in those with the most inflammation, and reduced in those whose inflammation is treated with inhaled corticosteroids.[97] Other inflammatory lung and immune system diseases such as alpha-1 antitrypsin deficiency, interstitial fibrosis, scleroderma, Chlamydia pneumoniae infection, tuberculosis, and HIV infection are also associated with increased risk of developing lung cancer.[97] Epstein-Barr virus is associated with the development of the rare lung cancer lymphoepithelioma-like carcinoma in people from Asia, but not in people from Western nations.[98] A role for several other infectious agents in lung cancer development has been studied but remain inconclusive, namely human papillomaviruses, BK virus, JC virus, human cytomegalovirus, SV40, measles virus, and Torque teno virus.[98]

Genetics[edit]

About 8% of lung cancer cases are caused by inherited (genetic) factors.[99] In relatives of people who are diagnosed with lung cancer, the risk is doubled, likely due to a combination of genes.[100] Genome-wide association studies have identified many gene variants associated with lung cancer risk, each of which contributes a small risk increase.[101] Many of these genes participate in pathways known to be involved in carcinogenesis, namely DNA repair, inflammation, the cell division cycle, cellular stress responses, and chromatin remodeling.[101]

Pathogenesis[edit]

As with all cancers, lung cancer is triggered by mutations that allow tumor cells to endlessly multiply, stimulate blood vessel growth, avoid apoptosis (programmed cell death), generate pro-growth signalling molecules, ignore anti-growth signalling molecules, and eventually spread into surrounding tissue or metastasize throughout the body.[102] Different tumors can acquire these abilities through different mutations, though generally cancer-contributing mutations activate oncogenes and inactivate tumor suppressors.[102] Some mutations – called "driver mutations" – are particularly common in adenocarcinomas, and contribute disproportionately to tumor development. These typically occur in the receptor tyrosine kinases EGFR, BRAF, MET, KRAS, and PIK3CA.[102] Similarly, some adenocarcinomas are driven by chromosomal rearrangements that result in overexpression of tyrosine kinases ALK, ROS1, NTRK, and RET. A given tumor will typically have just one driver mutation.[102] In contrast, SCLCs rarely have these driver mutations, and instead often have mutations that have inactivated the tumor suppressors p53 and RB.[103] A cluster of tumor suppressor genes on the short arm of chromosome 3 are often lost early in the development of all lung cancers.[102]

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.[104]

Prevention[edit]

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[edit]

Those who smoke can reduce their lung cancer risk by quitting smoking – the risk reduction is greater the longer a person goes without smoking.[105] Self-help programs tend to have little influence on success of smoking cessation, whereas combined counseling and pharmacotherapy improve cessation rates.[105] 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.[105]

Tobacco control[edit]

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.[106]

Policy interventions to decrease passive smoking in public areas such as restaurants and workplaces have become more common in many Western countries.[107] Bhutan has banned the sale of tobacco since 2004[108] while India introduced a ban on smoking in public in October 2008.[109] The World Health Organization has called for governments to institute a total ban on tobacco advertising to prevent young people from taking up smoking.[110] They assess that such bans have reduced tobacco consumption by 16% where instituted.[110]

Diet and lifestyle[edit]

Several foods and dietary supplements have been associated with lung cancer risk. High consumption of some animal products – red meat (but not other meats or fish), saturated fats, as well as nitrosodimethylamines and nitrites (found in salted and smoked meats) – is associated with an increased risk of developing lung cancer.[111] In contrast, high consumption of fruits and vegetables is associated with a reduced risk of lung cancer, particularly consumption of cruciferous vegetables and raw fruits and vegetables.[111] Based on the beneficial effects of fruits and vegetables, supplementation of several individual vitamins have been studied. Supplementation with vitamin A or beta-carotene had no effect on lung cancer, and instead slightly increased mortality.[111] Dietary supplementation with vitamin E or retinoids similarly had no effect.[112] The long-term use of supplemental vitamin A, B vitamins, vitamin D or vitamin E does not reduce the risk of lung cancer.[113] Some studies have found vitamins A, B, and E may increase the risk of lung cancer in those who have a history of smoking.[113] Consumption of polyunsaturated fats, tea, alcoholic beverages, and coffee are all associated with reduced risk of developing lung cancer.[111]

In addition to diet, body weight and exercise habits are also associated with lung cancer risk. Being overweight is associated with a lower risk of developing lung cancer, possibly due to the tendency of those who smoke cigarettes to have a lower body weight.[114] Similarly, being underweight is associated with a reduced lung cancer risk.[114] Some studies have shown those who exercise regularly or have better cardiovascular fitness to have a lower risk of developing lung cancer.[114]

Epidemiology[edit]

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.[115][116] In 2020, 2.2 million new cases were diagnosed, and 1.8 million people died from lung cancer, representing 18% of all cancer deaths.[5] 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.[116] Lung cancer is rare in those younger than 40; from there cancer rates increase with age, stabilizing around age 80.[117] The median age of a person diagnosed with lung cancer is 70; the median age of death is 72.[118]

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.[5] Globally, around 8% of men and 6% of women develop lung cancer in their lifetimes.[117] 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.[119] 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.[116] Lung cancer is the third-most common cancer in the UK (47,968 people were diagnosed with the disease in 2017),[120] and it is the most common cause of cancer-related death (around 34,600 people died in 2018).[121]

In the US, there are about 350 deaths from lung cancer every day.[122] Rates of lung cancer rates vary by racial and ethnic group, with the highest rates in African Americans, and the lowest rates in Hispanics, Native Americans and Asian Americans.[117] Also in the US, military veterans have a 25–50% higher rate of lung cancer primarily due to higher rates of smoking.[123] 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.[124]

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.[119] 85–90% of lung cancer cases are in people who have smoked cigarettes, and 15% of smokers develop lung cancer.[119] 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.[2] 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.[119]

For every 3–4 million cigarettes smoked, one lung cancer death can occur.[125] The influence of "Big Tobacco" plays a significant role in smoking.[126] Young nonsmokers who see tobacco advertisements are more likely to smoke.[127] The role of passive smoking is increasingly being recognized as a risk factor for lung cancer,[128] resulting in policy interventions to decrease the undesired exposure of nonsmokers to others' tobacco smoke.[129]

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.[130] Rates of lung adenocarcinoma continues to rise.[131]

History[edit]

Lung cancer was uncommon before the advent of cigarette smoking; it was not even recognized as a distinct disease until 1761.[132] Different aspects of lung cancer were described further in 1810.[133] 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.[134] Case reports in the medical literature numbered only 374 worldwide in 1912,[135] but a review of autopsies showed the incidence of lung cancer had increased from 0.3% in 1852 to 5.66% in 1952.[136] In Germany in 1929, physician Fritz Lickint recognized the link between smoking and lung cancer,[134] which led to an aggressive antismoking campaign.[137] The British Doctors' Study, published in the 1950s, was the first solid epidemiological evidence of the link between lung cancer and smoking.[138] As a result, in 1964, the Surgeon General of the United States recommended smokers should stop smoking.[139]

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.[140] Miners developed a disproportionate amount of lung disease, eventually recognized as lung cancer in the 1870s.[141] Despite this discovery, mining continued into the 1950s, due to the USSR's demand for uranium.[140] Radon was confirmed as a cause of lung cancer in the 1960s.[142]

The first successful pneumonectomy for lung cancer was performed in 1933.[143] Palliative radiotherapy has been used since the 1940s.[144] 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.[145] In 1997, CHART was seen as an improvement over conventional radical radiotherapy.[146] With SCLC, initial attempts in the 1960s at surgical resection[147] and radical radiotherapy[148] were unsuccessful. In the 1970s, successful chemotherapy regimens were developed.[149]

Research directions[edit]

Clinical trials involving radiotherapy, surgery, EGFR inhibitors, microtubule inhibitors and immunotherapy are ongoing as of 2021.[150]

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).[151] An alternative signaling pathway, c-Met, can be inhibited by tivantinib and onartuzumab. New ALK inhibitors include crizotinib and ceritinib.[152] If the MAPK/ERK pathway is involved, the BRAF kinase inhibitor dabrafenib and the MAPK/MEK inhibitor trametinib may be beneficial.[153]

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.[154]

Radiomics combined with artificial intelligence may be used on PET and CT images to help diagnose (or exclude) lung cancer.[155]

References[edit]

  1. ^ a b "Surveillance, Epidemiology and End Results Program". National Cancer Institute. Retrieved 1 January 2023.{{cite web}}: CS1 maint: url-status (link)
  2. ^ a b c d e f g h i j k l m n Lu C, Onn A, Vaporciyan AA, et al. (2017). "Chapter 84: Cancer of the Lung". Holland-Frei Cancer Medicine (9th ed.). Wiley Blackwell. ISBN 9781119000846.
  3. ^ a b c d e f Alberg AJ, Brock MV, Samet JM (2016). "Chapter 52: Epidemiology of lung cancer". Murray & Nadel's Textbook of Respiratory Medicine (6th ed.). Saunders Elsevier. ISBN 978-1-4557-3383-5.
  4. ^ a b Ramada Rodilla JM, Calvo Cerrada B, Serra Pujadas C, Delclos GL, Benavides FG (June 2021). "Fiber burden and asbestos-related diseases: an umbrella review". Gaceta Sanitaria. 36 (2): 173–183. doi:10.1016/j.gaceta.2021.04.001. PMC 8882348. PMID 34120777.
  5. ^ a b c d e f g Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (May 2021). "Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries". CA: A Cancer Journal for Clinicians. 71 (3): 209–249. doi:10.3322/caac.21660. PMID 33538338.
  6. ^ Vos T, Allen C, Arora M, Barber RM, Bhutta ZA, Brown A, et al. (GBD 2015 Disease and Injury Incidence and Prevalence Collaborators) (October 2016). "Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1545–602. doi:10.1016/S0140-6736(16)31678-6. PMC 5055577. PMID 27733282.
  7. ^ White V, Ruperelia P (2020). "28.Respiratory disease". In Feather A, Randall D, Waterhouse M (eds.). Kumar and Clark's Clinical Medicine (10th ed.). Elsevier. pp. 975–982. ISBN 978-0-7020-7870-5.
  8. ^ "Non-Small Cell Lung Cancer Treatment – Patient Version (PDQ®)". National Cancer Institute. 12 May 2015. Archived from the original on 29 February 2016. Retrieved 5 March 2016.
  9. ^ Falk S, Williams C (2010). "Chapter 1". Lung Cancer – the facts (3rd ed.). Oxford University Press. pp. 3–4. ISBN 978-0-19-956933-5.
  10. ^ Thun MJ, Hannan LM, Adams-Campbell LL, Boffetta P, Buring JE, Feskanich D, et al. (September 2008). "Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies". PLOS Medicine. 5 (9): e185. doi:10.1371/journal.pmed.0050185. PMC 2531137. PMID 18788891.
  11. ^ The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. U.S. Department of Health and Human Services. 2014. PMID 24455788.{{cite book}}: CS1 maint: url-status (link)
  12. ^ a b c d "Lung Carcinoma: Tumors of the Lungs". Merck Manual Professional Edition, Online edition. July 2020. Retrieved 21 July 2021.
  13. ^ a b Collins LG, Haines C, Perkel R, Enck RE (January 2007). "Lung cancer: diagnosis and management". American Family Physician. 75 (1): 56–63. PMID 17225705. Archived from the original on 29 September 2007.
  14. ^ "Lung Cancer Prevention–Patient Version (PDQ®)". National Cancer Institute. 4 November 2015. Archived from the original on 9 March 2016. Retrieved 5 March 2016.
  15. ^ Chapman S, Robinson G, Stradling J, West S, Wrightson J (2014). "Chapter 31". Oxford Handbook of Respiratory Medicine (3rd ed.). Oxford University Press. p. 284. ISBN 978-0-19-870386-0.
  16. ^ de Groot PM, Wu CC, Carter BW, Munden RF (June 2018). "The epidemiology of lung cancer". Translational Lung Cancer Research. 7 (3): 220–233. doi:10.21037/tlcr.2018.05.06. PMC 6037963. PMID 30050761.
  17. ^ Romaszko AM, Doboszyńska A (May 2018). "Multiple primary lung cancer: A literature review". Advances in Clinical and Experimental Medicine. 27 (5): 725–730. doi:10.17219/acem/68631. PMID 29790681. S2CID 46897665.
  18. ^ a b Majumder S (2009). Stem cells and cancer (Online-Ausg. ed.). New York: Springer. p. 193. ISBN 978-0-387-89611-3. Archived from the original on 18 October 2015.
  19. ^ a b c d e f g h Pastis, Gonzalez & Silvestri 2022, "Presentation/Initital Evaluation".
  20. ^ Nasim, Sabath & Eapen 2019, "Clinical Manifestations".
  21. ^ a b c d e f g h i j k l m Horn & Iams 2022, "Clinical Manifestations".
  22. ^ a b "Diagnosis – Lung Cancer". National Health Service. 1 November 2022. Retrieved 30 November 2022.
  23. ^ Pastis, Gonzalez & Silvestri 2022, "Noninvasive Staging".
  24. ^ a b c Horn & Iams 2022, "Diagnosing Lung Cancer".
  25. ^ Alexander, Kim & Cheng 2020, "Liquid Biopsy".
  26. ^ Pastis, Gonzalez & Silvestri 2022, "Suspected Metastatic Disease".
  27. ^ a b Tanoue, Mazzone & Tanner 2022, "Evidence for Lung Cancer Screening".
  28. ^ Ost D (2015). "Chapter 110: Approach to the patient with pulmonary nodules". In Grippi MA, Elias JA, Fishman JA, Kotloff RM, Pack AI, Senior RM (eds.). Fishman's Pulmonary Diseases and Disorders (5th ed.). McGraw-Hill. p. 1685. ISBN 978-0-07-179672-9.
  29. ^ Thai et al. 2021, "Histology".
  30. ^ Rudin et al. 2021, "Signs and Symptoms".
  31. ^ a b c d e f g Horn & Iams 2022, "Pathology".
  32. ^ Smokers defined as current or former smokers of more than 1 year of duration. See image page in Commons for percentages in numbers. Reference: Table 2 Archived 10 September 2017 at the Wayback Machine in: Kenfield SA, Wei EK, Stampfer MJ, Rosner BA, Colditz GA (June 2008). "Comparison of aspects of smoking among the four histological types of lung cancer". Tobacco Control. 17 (3): 198–204. doi:10.1136/tc.2007.022582. PMC 3044470. PMID 18390646.
  33. ^ Jones 2013, "Conclusion".
  34. ^ Pastis, Gonzalez & Silvestri 2022, "Histology and Prognosis".
  35. ^ Rudin et al. 2021, "Immunohistochemistry".
  36. ^ Horn & Iams 2022, "Immunohistochemistry".
  37. ^ Chakraborty RK, Sharma S (April 2022). Bronchoalveolar Cancer. PMID 30020653.
  38. ^ Lim W, Ridge CA, Nicholson AG, Mirsadraee S (August 2018). "The 8th lung cancer TNM classification and clinical staging system: review of the changes and clinical implications". Quantitative Imaging in Medicine and Surgery. 8 (7): 709–718. doi:10.21037/qims.2018.08.02. PMC 6127520. PMID 30211037.
  39. ^ a b c "Small Cell Lung Cancer Stages". American Cancer Society. 1 October 2019. Retrieved 2 December 2022.
  40. ^ "Non-small Cell Lung Cancer Stages". American Cancer Society. 1 October 2019. Retrieved 2 December 2022.
  41. ^ a b c d Horn & Iams 2022, "Staging System for Non-Small-Cell Lung Cancer".
  42. ^ a b c Pastis, Gonzalez & Silvestri 2022, "Eight Edition Lung Cancer Stage Classification".
  43. ^ Horn & Iams 2022, "Table 78–6 TNM Stage Groupings, Eighth Edition".
  44. ^ a b c d e f g Horn & Iams 2022, "Management of Metastatic NSCLC".
  45. ^ "8th edition lung cancer TNM staging summary" (PDF). International Association for the Study of Lung Cancer. Archived from the original (PDF) on 17 June 2018. Retrieved 30 May 2018.
  46. ^ Van Schil PE, Rami-Porta R, Asamura H (March 2018). "8th TNM edition for lung cancer: a critical analysis". Annals of Translational Medicine. 6 (5): 87. doi:10.21037/atm.2017.06.45. PMC 5890051. PMID 29666810.
  47. ^ Alexander, Kim & Cheng 2020, "Lung Cancer Screening".
  48. ^ a b c Rivera, Mody & Weiner 2022, "Introduction".
  49. ^ Rivera, Mody & Weiner 2022, "Palliative Care".
  50. ^ a b c d e f g h Horn & Iams 2022, "Treatment – Small-Cell Lung Cancer".
  51. ^ a b c Rivera, Mody & Weiner 2022, "Treatment of Small Cell Lung Cancer".
  52. ^ Rudin et al. 2021, "Locally advanced SCLC".
  53. ^ Rudin et al. 2021, "Metastatic Disease".
  54. ^ a b c d e f g Horn & Iams 2022, "Management of Stages I and II NSCLC".
  55. ^ a b Horn & Iams 2022, "Management of Stage III NSCLC".
  56. ^ Alexander, Kim & Cheng 2020, "Basis of Molecularly Targeted Therapy in Lung Cancer".
  57. ^ Horn & Iams 2022, "Cytotoxic Chemotherapy for Metastatic or Recurrent NSCLC".
  58. ^ a b Horn & Iams 2022, "Immunotherapy".
  59. ^ Horn & Iams 2022, "Second-Line Therapy and Beyond".
  60. ^ Lazarus DR, Eapen GA (2014). "Chapter 16: Bronchoscopic interventions for lung cancer". In Roth JA, Hong WK, Komaki RU (eds.). Lung Cancer (4th ed.). Wiley-Blackwell. ISBN 978-1-118-46874-6.
  61. ^ Khemasuwan D, Mehta AC, Wang KP (December 2015). "Past, present, and future of endobronchial laser photoresection". Journal of Thoracic Disease. 7 (Suppl 4): S380–88. doi:10.3978/j.issn.2072-1439.2015.12.55. PMC 4700383. PMID 26807285.
  62. ^ Aragon 2020, "Integrating palliative care into lung cancer care".
  63. ^ a b Aragon 2020, "Dyspnea".
  64. ^ Fairchild A, Harris K, Barnes E, Wong R, Lutz S, Bezjak A, et al. (August 2008). "Palliative thoracic radiotherapy for lung cancer: a systematic review". Journal of Clinical Oncology. 26 (24): 4001–11. doi:10.1200/JCO.2007.15.3312. PMID 18711191.
  65. ^ Stevens R, Macbeth F, Toy E, Coles B, Lester JF (January 2015). Stevens R (ed.). "Palliative radiotherapy regimens for patients with thoracic symptoms from non-small cell lung cancer". The Cochrane Database of Systematic Reviews. 1 (1): CD002143. doi:10.1002/14651858.CD002143.pub4. PMC 7017846. PMID 25586198.
  66. ^ Sörenson S, Glimelius B, Nygren P (2001). "A systematic overview of chemotherapy effects in non-small cell lung cancer". Acta Oncologica. 40 (2–3): 327–39. doi:10.1080/02841860151116402. PMID 11441939.
  67. ^ Clegg A, Scott DA, Sidhu M, Hewitson P, Waugh N (2001). "A rapid and systematic review of the clinical effectiveness and cost-effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine in non-small-cell lung cancer". Health Technology Assessment. 5 (32): 1–195. doi:10.3310/hta5320. PMID 12065068. Archived from the original on 30 August 2017.
  68. ^ Prince-Paul M (April 2009). "When hospice is the best option: an opportunity to redefine goals". Oncology. 23 (4 Suppl Nurse Ed): 13–17. PMID 19856592.
  69. ^ Zeng L, Yu X, Yu T, Xiao J, Huang Y (June 2019). "Interventions for smoking cessation in people diagnosed with lung cancer". The Cochrane Database of Systematic Reviews. 6 (6): CD011751. doi:10.1002/14651858.CD011751.pub3. PMC 6554694. PMID 31173336.
  70. ^ Horn & Iams 2022, "Smoking Cessation".
  71. ^ a b c d e Rueda JR, Solà I, Pascual A, Subirana Casacuberta M (September 2011). "Non-invasive interventions for improving well-being and quality of life in patients with lung cancer". The Cochrane Database of Systematic Reviews. 2011 (9): CD004282. doi:10.1002/14651858.CD004282.pub3. PMC 7197367. PMID 21901689.
  72. ^ Cavalheri & Granger 2020, "Exercise Training in People with Early Stage Lung Cancer.
  73. ^ Ligibel et al. 2022, "The Bottom Line".
  74. ^ Goldstraw et al. 2016, "Figure 2".
  75. ^ a b Rivera, Mody & Weiner 2022, "Prognostic and Predictive Factors in Lung Cancer".
  76. ^ "Lung cancer survival statistics". Cancer Research UK. 2 April 2020.
  77. ^ Slatore CG, Au DH, Gould MK (November 2010). "An official American Thoracic Society systematic review: insurance status and disparities in lung cancer practices and outcomes". American Journal of Respiratory and Critical Care Medicine. 182 (9): 1195–1205. doi:10.1164/rccm.2009-038ST. PMID 21041563.
  78. ^ "Lung cancer survival statistics". Cancer Research UK. Archived from the original on 9 October 2014. Retrieved 28 October 2014.
  79. ^ Spiro SG (2010). "18.19.1". Oxford Textbook Medicine (5th ed.). OUP Oxford. ISBN 978-0-19-920485-4.
  80. ^ Nasser NJ, Gorenberg M, Agbarya A (November 2020). "First line Immunotherapy for Non-Small Cell Lung Cancer". Pharmaceuticals. 13 (11): 373. doi:10.3390/ph13110373. PMC 7695295. PMID 33171686.
  81. ^ a b Temel, Petrillo & Greer 2022, "Coping with Prognostic Uncertainty".
  82. ^ Brown KM, Keats JJ, Sekulic A, et al. (2010). "Chapter 8". Holland-Frei Cancer Medicine (8th ed.). People's Medical Publishing House. ISBN 978-1-60795-014-1.
  83. ^ Schabath & Cote 2019, "Introduction".
  84. ^ a b Bade & Dela Cruz 2020, "Tobacco Smoke Carcinogens".
  85. ^ "Tobacco and Cancer". Centers for Disease Control and Prevention. Retrieved 29 December 2022.
  86. ^ Massion & Lehman 2022, "DNA Damage Response.
  87. ^ Bade & Dela Cruz 2020, "Environmental Tobacco Smoke".
  88. ^ Bracken-Clarke D, Kapoor D, Baird AM, Buchanan PJ, Gately K, Cuffe S, Finn SP (March 2021). "Vaping and lung cancer – A review of current data and recommendations". Lung Cancer. 153: 11–20. doi:10.1016/j.lungcan.2020.12.030. PMID 33429159.
  89. ^ Bade & Dela Cruz 2020, "Marijuana and Other Recreational Drugs".
  90. ^ a b c d e f g Christiani & Amos 2022, "Occupational Exposures".
  91. ^ Schabath & Cote 2019, "Radon".
  92. ^ Christiani & Amos 2022, "Air Pollution".
  93. ^ Chen H, Goldberg MS, Villeneuve PJ (October–December 2008). "A systematic review of the relation between long-term exposure to ambient air pollution and chronic diseases". Reviews on Environmental Health. 23 (4): 243–97. doi:10.1515/reveh.2008.23.4.243. PMID 19235364. S2CID 24481623.
  94. ^ Clapp RW, Jacobs MM, Loechler EL (January–March 2008). "Environmental and occupational causes of cancer: new evidence 2005–2007". Reviews on Environmental Health. 23 (1): 1–37. doi:10.1515/REVEH.2008.23.1.1. PMC 2791455. PMID 18557596.
  95. ^ a b Bade & Dela Cruz 2020, "Biomass Burning".
  96. ^ a b Bade & Dela Cruz 2020, "Chronic Lung Diseases".
  97. ^ a b Bade & Dela Cruz 2020, "Infections".
  98. ^ Yang IA, Holloway JW, Fong KM (October 2013). "Genetic susceptibility to lung cancer and co-morbidities". Journal of Thoracic Disease. 5 (Suppl. 5): S454–62. doi:10.3978/j.issn.2072-1439.2013.08.06. PMC 3804872. PMID 24163739.
  99. ^ Dela Cruz CS, Tanoue LT, Matthay RA (2015). "Chapter 109: Epidemiology of lung cancer". In Grippi MA, Elias JA, Fishman JA, Kotloff RM, Pack AI, Senior RM (eds.). Fishman's Pulmonary Diseases and Disorders (5th ed.). McGraw-Hill. p. 1673. ISBN 978-0-07-179672-9.
  100. ^ a b Bade & Dela Cruz 2020, "Genetic Predisposition and History of Cancer".
  101. ^ a b c d e Horn & Iams 2022, "Molecular Pathogenesis".
  102. ^ Rudin et al. 2021, "Mechanisms/Pathophysiology".
  103. ^ Powell CA, Halmos B, Nana-Sinkam SP (July 2013). "Update in lung cancer and mesothelioma 2012". American Journal of Respiratory and Critical Care Medicine. 188 (2): 157–66. doi:10.1164/rccm.201304-0716UP. PMC 3778761. PMID 23855692.
  104. ^ a b c Horn & Iams 2022, "Risk Factors".
  105. ^ Dela Cruz CS, Tanoue LT, Matthay RA (December 2011). "Lung cancer: epidemiology, etiology, and prevention". Clinics in Chest Medicine. 32 (4): 605–44. doi:10.1016/j.ccm.2011.09.001. PMC 3864624. PMID 22054876.
  106. ^ Nogueira SO, Fernández E, Driezen P (January 2022). "Secondhand Smoke Exposure in European Countries With Different Smoke-Free Legislation: Findings From the EUREST-PLUS ITC Europe Surveys". Nicotine & Tobacco Research. 24 (1): 85–92.
  107. ^ Yadav A, Singh A, Khadka BB, et al. (July 2018). "Smokeless tobacco control: Litigation & judicial measures from Southeast Asia". Indian Journal of Medical Research. 148 (1): 25–34. doi:10.4103/ijmr.IJMR_2063_17. PMC 6172917. PMID 30264751.
  108. ^ Pandey G (2 October 2008). "Indian ban on smoking in public". BBC. Archived from the original on 15 January 2009. Retrieved 25 April 2012.
  109. ^ a b "UN health agency calls for total ban on tobacco advertising to protect young" (Press release). United Nations News service. 30 May 2008. Archived from the original on 4 March 2016.
  110. ^ a b c d Bade & Dela Cruz 2020, "Diet".
  111. ^ Bade & Dela Cruz 2020, "Chemopreventive Agents".
  112. ^ a b Alsharairi NA (March 2019). "The effects of dietary supplements on asthma and lung cancer risk in smokers and non-smokers: a review of the literature". Nutrients. 11 (4): 725. doi:10.3390/nu11040725. PMC 6521315. PMID 30925812.
  113. ^ a b c Bade & Dela Cruz 2020, "Obesity and Exercise".
  114. ^ Schabath & Cote 2019, "Descriptive Epidemiology".
  115. ^ a b c Christiani & Amos 2022, "Introduction".
  116. ^ a b c Horn & Iams 2022, "Epidemiology".
  117. ^ Bade & Dela Cruz 2020, "Age".
  118. ^ a b c d Christiani & Amos 2022, "Geographic, Gender, and Ethnic Variability".
  119. ^ "Cancer incidence statistics". Cancer Research UK. 13 May 2015. Retrieved 23 July 2021.
  120. ^ "Lung cancer statistics". Cancer Research UK. 14 May 2015. Retrieved 23 July 2021.
  121. ^ Spiegel RL, Miller KD, Fuchs HE, Jemal A (January 2022). "Cancer statistics, 2022". CA: A Cancer Journal for Clinicians. 72 (1): 7–33. doi:10.3322/caac.21708. PMID 35020204. S2CID 245878846.
  122. ^ "Honoring veterans with good health". Gibbs Cancer Center & Research Institute. 7 November 2014. Archived from the original on 28 November 2015. Retrieved 1 December 2015.
  123. ^ "Lung Cancer As It Affects Veterans And Military". Lung Cancer Alliance. Archived from the original on 8 December 2015. Retrieved 1 December 2015.
  124. ^ Proctor RN (March 2012). "The history of the discovery of the cigarette-lung cancer link: evidentiary traditions, corporate denial, global toll". Tobacco Control. 21 (2): 87–91. doi:10.1136/tobaccocontrol-2011-050338. PMID 22345227.
  125. ^ Lum KL, Polansky JR, Jackler RK, Glantz SA (October 2008). "Signed, sealed and delivered: "big tobacco" in Hollywood, 1927-1951". Tobacco Control. 17 (5): 313–23. doi:10.1136/tc.2008.025445. PMC 2602591. PMID 18818225. Archived from the original on 4 April 2009.
  126. ^ Lovato C, Watts A, Stead LF (October 2011). "Impact of tobacco advertising and promotion on increasing adolescent smoking behaviours". The Cochrane Database of Systematic Reviews. 2011 (10): CD003439. doi:10.1002/14651858.CD003439.pub2. PMC 7173757. PMID 21975739.
  127. ^ Dubin S, Griffin D (2020). "Lung Cancer in Non-Smokers". Missouri Medicine. 117 (4): 375–379. PMC 7431055. PMID 32848276.
  128. ^ Kemp FB (July–September 2009). "Smoke free policies in Europe. An overview". Pneumologia. 58 (3): 155–58. PMID 19817310.
  129. ^ Charloux A, Quoix E, Wolkove N, Small D, Pauli G, Kreisman H (February 1997). "The increasing incidence of lung adenocarcinoma: reality or artefact? A review of the epidemiology of lung adenocarcinoma". International Journal of Epidemiology. 26 (1): 14–23. doi:10.1093/ije/26.1.14. PMID 9126499.
  130. ^ Kadara H, Kabbout M, Wistuba II (January 2012). "Pulmonary adenocarcinoma: a renewed entity in 2011". Respirology. 17 (1): 50–65. doi:10.1111/j.1440-1843.2011.02095.x. PMC 3911779. PMID 22040022.
  131. ^ Morgagni GB (1761). De sedibus et causis morborum per anatomen indagatis. OL 24830495M.
  132. ^ Bayle GL (1810). Recherches sur la phthisie pulmonaire (in French). Paris. OL 15355651W.
  133. ^ a b Witschi H (November 2001). "A short history of lung cancer". Toxicological Sciences. 64 (1): 4–6. doi:10.1093/toxsci/64.1.4. PMID 11606795.
  134. ^ Adler I (1912). Primary Malignant Growths of the Lungs and Bronchi. New York: Longmans, Green, and Company. OCLC 14783544. OL 24396062M., cited in Spiro SG, Silvestri GA (September 2005). "One hundred years of lung cancer". American Journal of Respiratory and Critical Care Medicine. 172 (5): 523–29. doi:10.1164/rccm.200504-531OE. PMID 15961694.
  135. ^ [unreliable source?] Grannis FW. "History of cigarette smoking and lung cancer". smokinglungs.com. Archived from the original on 18 July 2007. Retrieved 6 August 2007.
  136. ^ Proctor R (2000). The Nazi War on Cancer. Princeton University Press. pp. 173–246. ISBN 978-0-691-00196-8.
  137. ^ Doll R, Hill AB (November 1956). "Lung cancer and other causes of death in relation to smoking; a second report on the mortality of British doctors". British Medical Journal. 2 (5001): 1071–81. doi:10.1136/bmj.2.5001.1071. PMC 2035864. PMID 13364389.
  138. ^ US Department of Health Education and Welfare (1964). "Smoking and health: report of the advisory committee to the Surgeon General of the Public Health Service" (PDF). US Government Printing Office. Archived (PDF) from the original on 17 December 2008.
  139. ^ a b Greaves M (2000). Cancer: the Evolutionary Legacy. Oxford University Press. pp. 196–97. ISBN 978-0-19-262835-0.
  140. ^ Greenberg M, Selikoff IJ (February 1993). "Lung cancer in the Schneeberg mines: a reappraisal of the data reported by Harting and Hesse in 1879". The Annals of Occupational Hygiene. 37 (1): 5–14. doi:10.1093/annhyg/37.1.5. PMID 8460878.
  141. ^ Samet JM (April 2011). "Radiation and cancer risk: a continuing challenge for epidemiologists". Environmental Health. 10 (Suppl. 1): S4. doi:10.1186/1476-069X-10-S1-S4. PMC 3073196. PMID 21489214.
  142. ^ Horn L, Johnson DH (July 2008). "Evarts A. Graham and the first pneumonectomy for lung cancer". Journal of Clinical Oncology. 26 (19): 3268–75. doi:10.1200/JCO.2008.16.8260. PMID 18591561.
  143. ^ Edwards AT (March 1946). "Carcinoma of the bronchus". Thorax. 1 (1): 1–25. doi:10.1136/thx.1.1.1. PMC 1018207. PMID 20986395.
  144. ^ Kabela M (1956). "[Experience with radical irradiation of bronchial cancer]" [Experience with radical irradiation of bronchial cancer]. Ceskoslovenska Onkologia (in German). 3 (2): 109–15. PMID 13383622.
  145. ^ Saunders M, Dische S, Barrett A, Harvey A, Gibson D, Parmar M (July 1997). "Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee". Lancet. 350 (9072): 161–5. doi:10.1016/S0140-6736(97)06305-8. PMID 9250182. S2CID 6087156.
  146. ^ Lennox SC, Flavell G, Pollock DJ, Thompson VC, Wilkins JL (November 1968). "Results of resection for oat-cell carcinoma of the lung". Lancet. 2 (7575): 925–27. doi:10.1016/S0140-6736(68)91163-X. PMID 4176258.
  147. ^ Miller AB, Fox W, Tall R (September 1969). "Five-year follow-up of the Medical Research Council comparative trial of surgery and radiotherapy for the primary treatment of small-celled or oat-celled carcinoma of the bronchus". Lancet. 2 (7619): 501–5. doi:10.1016/S0140-6736(69)90212-8. PMID 4184834.
  148. ^ Cohen MH, Creaven PJ, Fossieck BE, Broder LE, Selawry OS, Johnston AV, et al. (1977). "Intensive chemotherapy of small cell bronchogenic carcinoma". Cancer Treatment Reports. 61 (3): 349–54. PMID 194691.
  149. ^ Batra H, Pawar S, Bahl D (February 2021). "Current clinical trials and patent update on lung cancer: a retrospective review". Lung Cancer Management. 10 (5): LMT45. doi:10.2217/lmt-2020-0029. PMC 8162165. PMID 34084211.
  150. ^ Greenhalgh J, Boland A, Bates V, Vecchio F, Dundar Y, Chaplin M, Green JA (18 March 2021). "First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer". The Cochrane Database of Systematic Reviews. 2021 (3): CD010383. doi:10.1002/14651858.CD010383.pub3. PMC 8092455. PMID 33734432.
  151. ^ Spaans JN, Goss GD (August 2014). "Trials to Overcome Drug Resistance to EGFR and ALK Targeted Therapies – Past, Present, and Future". Frontiers in Oncology. 4 (233): 233. doi:10.3389/fonc.2014.00233. PMC 4145253. PMID 25221748.
  152. ^ Weart TC, Miller KD, Simone CB (April 2018). "Spotlight on dabrafenib/trametinib in the treatment of non-small-cell lung cancer: place in therapy". Cancer Management and Research. 10: 647–52. doi:10.2147/CMAR.S142269. PMC 5892608. PMID 29662327.
  153. ^ Prabavathy D, Swarnalatha Y, Ramadoss N (March 2018). "Lung cancer stem cells-origin, characteristics and therapy". Stem Cell Investigation. 5 (6): 6. doi:10.21037/sci.2018.02.01. PMC 5897668. PMID 29682513.
  154. ^ Manafi-Farid R, Askari E, Shiri I, Pirich C, Asadi M, Khateri M, Zaidi H, Beheshti M (November 2022). "[18F]FDG-PET/CT Radiomics and Artificial Intelligence in Lung Cancer: Technical Aspects and Potential Clinical Applications". Seminars in Nuclear Medicine. 52 (6): 759–780. doi:10.1053/j.semnuclmed.2022.04.004. PMID 35717201. S2CID 249720514.

Cited[edit]

Books

  • Broaddus C, Ernst JD, King, TE, et al., eds. (2022). Murray & Nadel's Textbook of Respiratory Medicine (7 ed.). Elsevier. ISBN 978-0323655873.
    • Christiani DC, Amos CI (2022). "Lung Cancer: Epidemiology". In Broaddus C, Ernst JD, King, TE, et al. (eds.). Murray & Nadel's Textbook of Respiratory Medicine (7 ed.). Elsevier. pp. 1018–1028.
    • Massion PP, Lehman JM (2022). "Lung Cancer: Molecular Biology and Targets". In Broaddus C, Ernst JD, King, TE, et al. (eds.). Murray & Nadel's Textbook of Respiratory Medicine (7 ed.). Elsevier. pp. 1018–1028.
    • Pastis NJ, Gonzalez AV, Silvestri GA (2022). "Lung Cancer: Diagnosis and Staging". In Broaddus C, Ernst JD, King, TE, et al. (eds.). Murray & Nadel's Textbook of Respiratory Medicine (7 ed.). Elsevier. pp. 1039–1051.
    • Rivera P, Mody GN, Weiner AA (2022). "Lung Cancer: Treatment". In Broaddus C, Ernst JD, King, TE, et al. (eds.). Murray & Nadel's Textbook of Respiratory Medicine (7 ed.). Elsevier. pp. 1052–1065.
    • Tanoue L, Mazzone PJ, Tanner NT (2022). "Lung Cancer: Screening". In Broaddus C, Ernst JD, King, TE, et al. (eds.). Murray & Nadel's Textbook of Respiratory Medicine (7 ed.). Elsevier. pp. 1029–1038.
  • Horn L, Iams WT (2022). "78: Neoplasms of the Lung". In Loscalzo J, Fauci A, Kasper D, et al. (eds.). Harrison's Principles of Internal Medicine (21 ed.). McGraw Hill. ISBN 978-1264268504.

Journal articles

External links[edit]