Lung cancer

Tobacco smoking is by far the main contributor to lung cancer.[4] Cigarette smoke contains at least 73 known carcinogens,[24] including benzo[a]pyrene,[25] NNK, 1,3-butadiene, and a radioactive isotope of polonium – polonium-210.[24] Across the developed world, 90% of lung cancer deaths in men and 70% of those in women during 2000 were attributed to smoking.[26] Smoking accounts for about 85% of lung cancer cases.[14] 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.[27][28]

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,[29][30][31] the UK[32] and other European countries[33] have consistently shown a significantly-increased risk among those exposed to passive smoking.[34] The risk of developing lung cancer increases by 25–28%.[35] Investigations of sidestream smoke (the main component of second-hand smoke; around 85%) suggest that it is more dangerous than direct mainstream smoke.[36]

Cannabis smoke contains many of the same carcinogens as those found in tobacco smoke,[37] but the effect of smoking cannabis on lung cancer risk is not clear.[38][39] A 2013 review did not find an increased risk from light to moderate use.[40] A 2014 review found that smoking cannabis doubled the risk of lung cancer, though cannabis is in many countries commonly mixed with tobacco.[41]

Radon is a colorless and odorless gas generated by the breakdown of radioactive radium, which in turn is the decay product of uranium, found in the Earth's crust. The radiation decay products ionize genetic material, causing mutations that sometimes become cancerous. Radon is the second-most common cause of lung cancer in the US,[42] causing about 21,000 deaths each year.[43] The risk increases 8–16% for every 100 Bq/m³ increase in the radon concentration.[44] Radon gas levels vary by locality and the composition of the underlying soil and rocks. About one in 15 homes in the US has radon levels above the recommended guideline of 4 picocuries per liter (pCi/l) (148 Bq/m³).[45]

Asbestos can cause a variety of lung diseases such as lung cancer. Tobacco smoking and exposure to asbestos together have synergistic effects on the development of lung cancer.[5] In smokers who work with asbestos, the risk of lung cancer is increased 45-fold compared to the general population.[46] Asbestos can also cause cancer of the pleura, called mesothelioma – which actually is different from lung cancer.[47]

Outdoor air pollutants, especially chemicals released from the burning of fossil fuels, increase the risk of lung cancer.[4] Fine particulates (PM_2.5) and sulfate aerosols, which may be released in traffic exhaust fumes, are associated with a slightly increased risk.[4][48] For nitrogen dioxide, an incremental increase of 10 parts per billion increases the risk of lung cancer by 14%.[49] Outdoor air pollution is estimated to cause 1–2% of lung cancers.[4]

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.[50] 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.[51] This risk affects about 2.4 billion people worldwide,[50] and it is believed to result in 1.5% of lung cancer deaths.[51]

About 8% of lung cancer cases are caused by inherited (genetic) factors.[52] In relatives of people who are diagnosed with lung cancer, the risk is doubled, likely due to a combination of genes.[53] Polymorphisms on chromosomes 5, 6, and 15 have been identified and are associated with an increased risk of lung cancer.[54] 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.[54] 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.[55]

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:[56]

• 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.

Pie chart showing incidences of NSCLCs as compared to SCLCs shown at right, with fractions of smokers versus nonsmokers shown for each type[70]

Lung cancers are classified according to histological type.[3] This classification is important for determining both the management and predicting outcomes of the disease. Lung cancers are carcinomas – malignancies that arise from epithelial cells. Lung carcinomas are categorized by the size and appearance of the malignant cells seen by a histopathologist under a microscope. For therapeutic purposes, two broad classes are distinguished: non-small-cell lung carcinoma (NSCLC) and small-cell lung carcinoma (SCLC).[71]

The three main subtypes of NSCLC are adenocarcinoma, squamous-cell carcinoma, and large-cell carcinoma.[1] Rare subtypes include pulmonary enteric adenocarcinoma.[72]

Nearly 40% of lung cancers are adenocarcinomas, which usually come from peripheral lung tissue.[3] 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")[1][73] and ex-smokers with a modest smoking history.[1] A subtype of adenocarcinoma, the bronchioloalveolar carcinoma, is more common in female never-smokers, and may have a better long-term survival.[74]

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.[3]

About 10 to 15% of lung cancers are large-cell carcinoma.[75] These are so named because the cancer cells are large, with excess cytoplasm, large nuclei, and conspicuous nucleoli.[3]

In SCLC, the cells contain dense neurosecretory granules (vesicles containing neuroendocrine hormones), which give this tumor an endocrine or paraneoplastic syndrome association.[76] Most cases arise in the larger airways (primary and secondary bronchi).[15] About 60–70% have extensive disease (which cannot be targeted within a single radiation therapy field) at presentation.[1]

Four main histological subtypes are recognised, although some cancers may contain a combination of different subtypes,[71] such as adenosquamous carcinoma.[3] Rare subtypes include carcinoid tumors, bronchial gland carcinomas, and sarcomatoid carcinomas.[3]

The lungs are a common place for the spread of tumors from other parts of the body. These tumors are called metastases or secondary tumors. The most common appearance on chest x-ray is the presence of multiple nodules in the lower lobes.[77]

Primary lung cancers also most commonly metastasize to the brain, bones, liver, and adrenal glands.[3] Immunostaining of a biopsy usually helps determine the original source.[78] 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.[1]

Lung cancer staging is an assessment of the degree of spread of the cancer from its original source.[3] It is one of the factors affecting both the prognosis and the potential treatment of lung cancer.[1][3]

The evaluation of NSCLC staging uses the TNM classification (tumor, node, metastasis). This is based on the size of the primary tumor, lymph node involvement, and distant metastasis.[1]

Using the TNM descriptors, a group is assigned, ranging from occult cancer, through stages 0, IA (one-A), IB, IIA, IIB, IIIA, IIIB, and IV (four). This stage group assists with the choice of treatment and estimation of prognosis.[81]

SCLC has traditionally been classified as "limited stage" (confined to one-half of the chest and within the scope of a single tolerable radiotherapy field) or "extensive stage" (more widespread disease).[1] However, the TNM classification and grouping are useful in estimating prognosis.[81]

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.[3]

• 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

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.[82]

Policy interventions to decrease passive smoking in public areas such as restaurants and workplaces have become more common in many Western countries.[83] Bhutan has had a complete smoking ban since 2005[84] while India introduced a ban on smoking in public in October 2008.[85] The World Health Organization has called for governments to institute a total ban on tobacco advertising to prevent young people from taking up smoking.[86] They assess that such bans have reduced tobacco consumption by 16% where instituted.[86]

Cancer screening uses medical tests to detect disease in large groups of people who have no symptoms.[87] 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.[69][88] This form of screening reduces the chance of death from lung cancer by an absolute amount of 0.3% (relative amount of 20%).[89][90] 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.[69]

CT screening is associated with a high rate of falsely positive tests, which may result in unneeded treatment.[91] For each accurate positive scan there are about 19 false positive scans.[90] Other concerns include radiation exposure[91] and the cost of testing along with follow up.[69] Research has not found two other available tests – sputum cytology or chest radiograph (CXR) screening tests – to have any benefit.[88][92]

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.[93] Their recommendation excludes those with other health problems that would make treatment of lung cancer if found not an option.[93] The English National Health Service was in 2014 re-examining the evidence for screening.[94]

The long-term use of supplemental vitamin A,[95] B vitamins,[95] vitamin D[95] or vitamin E[95] does not reduce the risk of lung cancer. Vitamin C supplementation might reduce the risk of lung cancer.[96][97] Some studies have found vitamins A, B, and E may increase the risk of lung cancer in those who have a history of smoking.[95]

Some studies suggest that people who eat food with a higher proportion of vegetables and fruit tend to have a lower risk,[31][98] 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.[99] Several rigorous studies have not demonstrated a clear association between diet and lung cancer risk,[1][98] although meta-analysis that accounts for smoking status may show benefit from a healthy diet.[100]

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

If investigations confirm NSCLC, the stage is assessed to determine whether the disease is localized and amenable to surgery or if it has spread to the point where it cannot be cured surgically. CT scan and PET-CT, noninvasive tests, can be used to help rule out malignancy or mediastinal lymph node involvement.[1][105] If mediastinal lymph node involvement is suspected using PET-CT, the nodes can be sampled (using a biopsy) to assist staging, a PET-CT scan is not accurate enough to be used alone.[105] Techniques used for obtaining a sample include transthoracic needle aspiration, transbronchial needle aspiration (with or without endobronchial ultrasound), endoscopic ultrasound with needle aspiration, mediastinoscopy, and thoracoscopy.[106] Blood tests and pulmonary function testing are used to assess whether a person is well enough for surgery.[15] If pulmonary function tests reveal poor respiratory reserve, surgery may not be possible.[1]

In most cases of early-stage NSCLC, removal of a lobe of lung (lobectomy) is the surgical treatment of choice. In people who are unfit for a full lobectomy, a smaller sublobar excision (wedge resection) may be performed. However, wedge resection has a higher risk of recurrence than lobectomy. Radioactive iodine brachytherapy at the margins of wedge excision may reduce the risk of recurrence. Rarely, removal of a whole lung (pneumonectomy) is performed.[107] Video-assisted thoracoscopic surgery (VATS) and VATS lobectomy use a minimally invasive approach to lung cancer surgery.[108] VATS lobectomy is equally effective compared to conventional open lobectomy, with less postoperative illness.[109]

In SCLC, chemotherapy or radiotherapy is typically used, or sometimes both.[110] However, the role of surgery in SCLC is being reconsidered. Surgery might improve outcomes when added to chemotherapy and radiation in early-stage SCLC.[111]

The effectiveness of lung cancer surgery (resection) for people with stage I – IIA NSCLC is not clear, but weak evidence suggests that a combined approach of lung cancer resection and removing the mediastinal lymph nodes (mediastinal lymph node dissection) may improve survival compared to lung resection and a sample of mediastinal nodes (not a complete node dissection).[112]

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

Radiotherapy is often given together with chemotherapy, and may be used with curative intent in people with NSCLC who are not eligible for surgery.[113] This form of high-intensity radiotherapy is called radical radiotherapy.[46] A refinement of this technique is continuous hyperfractionated accelerated radiotherapy (CHART), in which a high dose of radiotherapy is given in a short time period.[114] Radiosurgery refers to the radiotherapy technique of giving a precise high-dose of radiotherapy that is guided by a computer.[115] Postoperative (adjuvant) thoracic radiotherapy generally is not used after curative-intent surgery for NSCLC.[116] Some people with mediastinal N2 lymph node involvement might benefit from post-operative radiotherapy.[117]

For potentially curable SCLC cases treated with surgery, post-operative chest radiotherapy is recommended.[3] The ideal timing of these therapies (the optimal time to give radiotherapy and chemotherapy for improving survival) is not known.[118]

If cancer growth blocks a short section of bronchus, brachytherapy (localized radiotherapy) may be given directly inside the airway to open the passage. Compared to external beam radiotherapy, brachytherapy allows a reduction in treatment time and reduced radiation exposure to healthcare staff.[119] Evidence for brachytherapy, however, is less than that for external beam radiotherapy.[120]

Prophylactic cranial irradiation is a type of radiotherapy to the brain, used to reduce the risk of metastasis. PCI is used in SCLC.[46] In limited-stage disease, PCI increases three-year survival from 15% to 20%; in extensive disease, one-year survival increases from 13% to 27%.[121] For people who have NSCLC and a single brain metastasis, it is not clear if surgery is more effective than radiosurgery.[115]

Improvements in targeting and imaging have led to the development of stereotactic radiation in the treatment of early-stage lung cancer. In this form of radiotherapy, high doses are delivered over a number of sessions using stereotactic targeting techniques. Its use is primarily in patients who are not surgical candidates due to medical comorbidities.[122]

For both NSCLC and SCLC patients, smaller doses of radiation to the chest may be used for symptom control (palliative radiotherapy).[123][124] The use of higher doses of radiotherapy for palliative care are not shown to prolong survival.[124]

The chemotherapy regimen depends on the tumor type.[3] SCLC, even relatively early-stage disease, is treated primarily with chemotherapy and radiation.[125] In SCLC, cisplatin/carboplatin and etoposide are most commonly used.[126] Combinations with carboplatin, gemcitabine, paclitaxel, vinorelbine, topotecan, and irinotecan are also used.[127][128] In advanced NSCLC, chemotherapy improves survival and is used as first-line treatment, provided the person is well enough for the treatment.[129] Typically, two drugs are used, of which one is often platinum-based (either cisplatin or carboplatin). Other commonly used drugs are gemcitabine, paclitaxel, docetaxel,[130][131] pemetrexed,[132] etoposide or vinorelbine.[131] Platinum-based drugs and combinations that include platinum therapy do not appear to be more beneficial for prolonging survival compared to other nonplatinum medications, and may lead to a higher risk of serious adverse effects, such as nausea, vomiting, anaemia, and thrombocytopenia,[133] especially in people over the age of 70.[134] Evidence is insufficient to determine which chemotherapy approach is associated with the highest quality of life.[133] Also, evidence is lacking to determine if treating people with NSCLC a second time when the first round of chemotherapy was not successful (second-line chemotherapy) causes more benefit or harm.[135]

Adjuvant chemotherapy refers to the use of chemotherapy after apparently curative surgery to improve the outcome. In NSCLC, samples are taken of nearby lymph nodes during surgery to assist staging. If stage-II or -III disease is confirmed, adjuvant chemotherapy (including or not including postoperative radiotherapy) improves survival by 4% at five years.[136][137][138] The combination of vinorelbine and cisplatin is more effective than older regimens.[137] Adjuvant chemotherapy for people with stage IB cancer is controversial, as clinical trials have not clearly demonstrated a survival benefit.[139] Chemotherapy before surgery in NSCLC that can be removed surgically may improve outcomes.[140][141]

Chemotherapy may be combined with palliative care in the treatment of the NSCLC.[142] In advanced cases, appropriate chemotherapy improves average survival over supportive care alone, as well as improving quality of life.[142][143] 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.[144][145] The NSCLC Meta-Analyses Collaborative Group recommends if the recipient wants and can tolerate treatment, then chemotherapy can be considered in advanced NSCLC.[129][146]

Several drugs that target molecular pathways in lung cancer are available, especially for the treatment of advanced disease. Erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib inhibit tyrosine kinase activity of the epidermal growth factor receptor (EGFR). These EGFR inhibitors may help delay the spread of cancer cells for people with EGFR M+ lung cancer and may improve a person's quality of life.[147] EGFR inhibitors have not been shown to help people survive longer.[147] For people with EGFR mutations, treatment with gefitinib may result in an improved quality of life compared to treatment with chemotherapy.[148]

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

Immunotherapy may be used for both SCLC and NSCLC.[149][150] NSCLC cells expressing programmed death-ligand 1 (PD-L1) could interact with programmed death receptor 1 (PD-1) expressed on the surface of T cells, and result in decreased tumor cell kill by the immune system.[151] Atezolizumab is an anti PD-L1 monoclonal antibody. Nivolumab and Pembrolizumab are anti PD-1 monoclonal antibodies. Ipilimumab is a monoclonal antibody that targets Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of T cells. Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor in the circulation, and functions as an angiogenesis inhibitor.[151] Multiple phase 3 clinical trials utilizing immunotherapy in the first line for treatment of NSCLC were published, including Pembrolizumab in KEYNOTE-024, KEYNOTE-042, KEYNOTE-189 and KEYNOTE-407; Nivolumab and Ipilimumab in CHECKMATE-227 and CHECKMATE 9LA; and Atezolizumab in IMpower110, IMpower130 and IMpower150.[151] Denosumab, a monoclonal antibody directed against receptor activator of nuclear factor kappa-B ligand, and zoledronic acid may be useful in the treatment of bone metastases.[152]

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

Vaccine-based immunotherapy treatment after surgery or radiotherapy may not lead to improved survival for people with stages I-III NSCLC.[153]

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.[154] Laser photosection involves the delivery of laser light inside the airway via a bronchoscope to remove the obstructing tumor.[155]

Palliative care when added to usual cancer care benefits people even when they are still receiving chemotherapy.[156] These approaches allow additional discussion of treatment options and provide opportunities to arrive at well-considered decisions.[157][158] 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.[15][158]

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.[104] There is no clear evidence which smoking cessation program is most effective for people who have been diagnosed with lung cancer.[104]

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.[159] 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).[159] Counseling may help people cope with emotional symptoms related to lung cancer.[159] Reflexology may be effective in the short-term, however more research is needed.[159] 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.[159]

Exercise training may benefit people with NSCLC who are recovering from lung surgery.[160] In addition, exercise training may benefit people with NSCLC who have received radiotherapy, chemotherapy, chemoradiotherapy, or palliative care.[161] Exercise training before lung cancer surgery may also improve outcomes.[103] It is unclear if exercise training or exercise programs are beneficial for people who have advanced lung cancer.[162][159] A home-based component in a personalized physical rehabilitation program may be useful for recovery.[161] It is unclear if home-based prehabilitation (before surgery) leads to less adverse events or hospitalization time.[161] Physical rehabilitation with a home-based component may improve recovery after treatment and overall lung health.[161]

In the US, both black men and black women have a higher incidence.[179][180] The lifetime risk of developing lung cancer is 8% in men and 6% in women.[1]

Also in the US, military veterans have a 25–50% higher rate of lung cancer primarily due to higher rates of smoking.[181] 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.[182]

Lung cancer is the third-most common cancer in the UK (47,968 people were diagnosed with the disease in 2017),[183] and it is the most common cause of cancer-related death (around 34,600 people died in 2018).[184]

Lung cancer rates are currently lower in developing countries.[185] With increased smoking in developing countries, the rates are expected to increase in the next few years, notably in both China[186] and India.[187]