Lung cancer

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.

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]

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 designated 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]

• 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

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]

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 chemotherapeutic – cisplatin 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]

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]

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]

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.[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]

Tobacco smoking is by far the major contributor to lung cancer, causing 80% to 90% of cases.[86] Lung cancer risk increases with quantity of cigarettes consumed.[87] Tobacco smoking's carcinogenic effect is due to various chemicals in tobacco smoke that cause DNA mutations, increasing the chance of cells becoming cancerous.[88] 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.[87] Exposure to these chemicals causes several kinds of DNA damage: DNA adducts, oxidative stress, and breaks in the DNA strands.[89] 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.[90]

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.[91]

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.[92]

Exposure to a variety of other toxic chemicals – typically encountered in certain occupations – are associated with an increased risk of lung cancer.[93] In all, occupational exposures to carcinogens cause 9–15% of lung cancers.[93] A prominent example is asbestos, which causes lung cancer either directly or indirectly by inflamming the lung.[93] Exposure to all commercially available forms of asbestos increase cancer risk, and cancer risk increases with time of exposure.[93] 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.[93] 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.[93] Radon exposure is responsible for between 3% and 14% of lung cancer cases.[94]

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.[93]

Exposure to air pollution, especially fine particulates, increases the risk of lung cancer.[95] Fine particulates (PM_2.5) and sulfate aerosols, which may be released in traffic exhaust fumes, are associated with a slightly increased risk.[3][96] For nitrogen dioxide, an incremental increase of 10 parts per billion increases the risk of lung cancer by 14%.[97] 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.[98] The International Agency for Research on Cancer has classified emission from household burning of coal and biomass as "carcinogenic" and "probably carcinogenic" respectively.[98]

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.[99] 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.[99] 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.[100] 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.[100]

About 8% of lung cancer cases are caused by inherited (genetic) factors.[101] In relatives of people who are diagnosed with lung cancer, the risk is doubled, likely due to a combination of genes.[102] Genome-wide association studies have identified many gene variants associated with lung cancer risk, each of which contributes a small risk increase.[103] 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.[103]

Those who smoke can reduce their lung cancer risk by quitting smoking – the risk reduction is greater the longer a person goes without smoking.[107] Self-help programs tend to have little influence on success of smoking cessation, whereas combined counseling and pharmacotherapy improve cessation rates.[107] 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.[107]

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.[108]

Policy interventions to decrease passive smoking in public areas such as restaurants and workplaces have become more common in many Western countries.[109] Bhutan has banned the sale of tobacco since 2004[110] while India introduced a ban on smoking in public in October 2008.[111] The World Health Organization has called for governments to institute a total ban on tobacco advertising to prevent young people from taking up smoking.[112] They assess that such bans have reduced tobacco consumption by 16% where instituted.[112]

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.[113] 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.[113] 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.[113] Dietary supplementation with vitamin E or retinoids similarly had no effect.[114] The long-term use of supplemental vitamin A, B vitamins, vitamin D or vitamin E does not reduce the risk of lung cancer.[115] Some studies have found vitamins A, B, and E may increase the risk of lung cancer in those who have a history of smoking.[115] Consumption of polyunsaturated fats, tea, alcoholic beverages, and coffee are all associated with reduced risk of developing lung cancer.[113]

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.[116] Similarly, being underweight is associated with a reduced lung cancer risk.[116] Some studies have shown those who exercise regularly or have better cardiovascular fitness to have a lower risk of developing lung cancer.[116]

Books

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  • 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.
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  • 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

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• Bade BC, Dela Cruz CS (March 2020). "Lung Cancer 2020: Epidemiology, Etiology, and Prevention". Clin Chest Med. 41 (1): 1–24. doi:10.1016/j.ccm.2019.10.001. PMID 32008623. S2CID 211015015.
• Cavalheri V, Granger CL (November 2020). "Exercise training as part of lung cancer therapy". Respirology. 25 Suppl 2: 80–87. doi:10.1111/resp.13869. hdl:11343/275802. PMID 32567236. S2CID 219970473.
• Goldstraw P, Chansky K, Crowley J, Rami-Porta R, Asamura H, Eberhardt WE, Nicholson AG, Groome P, Mitchell A, Bolejack V (January 2016). "The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer". J Thorac Oncol. 11 (1): 39–51. doi:10.1016/j.jtho.2015.09.009. PMID 26762738. S2CID 5368645.
• Jones KD (December 2013). "Whence lepidic?: the history of a Canadian neologism". Arch Pathol Lab Med. 137 (12): 1822–1824. doi:10.5858/arpa.2013-0144-HP. PMID 23937575.
• Ligibel JA, Bohlke K, May AM, et al. (August 2022). "Exercise, Diet, and Weight Management During Cancer Treatment: ASCO Guideline". J Clin Oncol. 40 (22): 2491–2507. doi:10.1200/JCO.22.00687. PMID 35576506. S2CID 248832115.
• Nasim F, Sabath BF, Eapen GA (May 2019). "Lung Cancer". Med Clin North Am. 103 (3): 463–473. doi:10.1016/j.mcna.2018.12.006. PMID 30955514. S2CID 102349766.
• Rudin CM, Brambilla E, Faivre-Finn C, Sage J (January 2021). "Small-cell lung cancer". Nat Rev Dis Primers. 7 (1): 3. doi:10.1038/s41572-020-00235-0. PMC 8177722. PMID 33446664.
• Schabath MB, Cote ML (October 2019). "Cancer Progress and Priorities: Lung Cancer". Cancer Epidemiol Biomarkers Prev. 28 (10): 1563–1579. doi:10.1158/1055-9965.EPI-19-0221. PMC 6777859. PMID 31575553.
• Temel JS, Petrillo LA, Greer JA (February 2022). "Patient-Centered Palliative Care for Patients With Advanced Lung Cancer". J Clin Oncol. 40 (6): 626–634. doi:10.1200/JCO.21.01710. PMID 34985932. S2CID 245772225.
• Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS (August 2021). "Lung cancer". Lancet. 398 (10299): 535–554. doi:10.1016/S0140-6736(21)00312-3. PMID 34273294. S2CID 236034814.