Non-small-cell lung cancer

File:Pie chart of lung cancers.svg shown at right, with fractions of smokers versus nonsmokers shown for each typeSmokers defined as current or former smokers of more than 1 year of duration. See image page in Commons for percentages in numbers. Reference: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044470/table/T2/ Table 2] in: {{cite journal | vauthors = Kenfield SA, Wei EK, Stampfer MJ, Rosner BA, Colditz GA | title = Comparison of aspects of smoking among the four histological types of lung cancer | journal = Tobacco Control | volume = 17 | issue = 3 | pages = 198–204 | date = June 2008 | pmid = 18390646 | pmc = 3044470 | doi = 10.1136/tc.2007.022582 }}]]

The most common types of NSCLC are squamous-cell carcinoma, large-cell carcinoma, and adenocarcinoma, but several other types occur less frequently. A few of the less common types are pleomorphic, carcinoid tumor, salivary gland carcinoma, and unclassified carcinoma.{{Cite web|url=https://www.cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq|title=Non-Small Cell Lung Cancer Treatment|website=National Cancer Institute|language=en|access-date=4 December 2017|date=1 January 1980}} All types can occur in unusual histologic variants and as mixed cell-type combinations.{{cite web |url=http://www.cancer.gov/CANCERTOPICS/PDQ/TREATMENT/NON-SMALL-CELL-LUNG/PATIENT |title=Non-small cell lung cancer treatment – National Cancer Institute |access-date=19 October 2008|date=1 January 1980 }} Non-squamous-cell carcinoma almost occupies the half of NSCLC.{{dubious|date=October 2016}}{{citation needed|date=October 2016}} In the tissue classification, the central type contains about one-ninth.{{citation needed|date=October 2016}}

Sometimes, the phrase "not otherwise specified" (NOS) is used generically, usually when a more specific diagnosis cannot be made. This is most often the case when a pathologist examines a small number of malignant cells or tissue in a cytology or biopsy specimen.

Lung cancer in people who have never smoked is almost universally NSCLC, with a sizeable majority being adenocarcinoma.{{cite news | vauthors = Hanna N |title=Lung Cancer in the Never Smoker Population |year=2007 |work=Hematology-Oncology |publisher=Medscape |url=http://www.medscape.com/viewarticle/566978}}

On relatively rare occasions, malignant lung tumors are found to contain components of both SCLC and NSCLC. In these cases, the tumors are classified as combined small-cell lung carcinoma (c-SCLC),{{cite book |title=Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart | veditors = Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC |publisher=IARC Press |location=Lyon |year=2004 |series=World Health Organization Classification of Tumours |isbn=978-92-832-2418-1 |url=http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb10/bb10-cover.pdf |access-date=27 March 2010 |archive-url=https://web.archive.org/web/20090823210304/http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb10/bb10-cover.pdf |archive-date=23 August 2009 |url-status=dead}} and are (usually) treated as "pure" SCLC.{{cite journal | vauthors = Simon GR, Turrisi A | title = Management of small cell lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition) | journal = Chest | volume = 132 | issue = 3 Suppl | pages = 324S–339S | date = September 2007 | pmid = 17873178 | doi = 10.1378/chest.07-1385 | url = http://www.chestjournal.org/cgi/pmidlookup?view=long&pmid=17873178 | url-status = dead | archive-url = https://archive.today/20130112194222/http://www.chestjournal.org/cgi/pmidlookup?view=long&pmid=17873178 | archive-date = 12 January 2013 }}

{{Main|Adenocarcinoma of the lung}}

Adenocarcinoma of the lung is currently the most common type of lung cancer in "never smokers" (lifelong nonsmokers).{{cite journal | vauthors = Subramanian J, Govindan R | title = Lung cancer in never smokers: a review | journal = Journal of Clinical Oncology | volume = 25 | issue = 5 | pages = 561–570 | date = February 2007 | pmid = 17290066 | doi = 10.1200/JCO.2006.06.8015 }} Adenocarcinomas account for about 40% of lung cancers. Historically, adenocarcinoma was more often seen peripherally in the lungs than SCLC and squamous-cell lung cancer, both of which tended to be more often centrally located.{{cite book | vauthors = Mitchell RS, Kumar V, Abbas AK, Fausto N |chapter=morphology of adenocarcinoma |title=Robbins Basic Pathology|publisher=Saunders |location=Philadelphia |isbn=978-1-4160-2973-1 |edition=8th|year=2007 }}{{Page needed|date=July 2011}}{{cite journal | vauthors = Travis WD, Travis LB, Devesa SS | title = Lung cancer | journal = Cancer | volume = 75 | issue = 1 Suppl | pages = 191–202 | date = January 1995 | pmid = 8000996 | doi = 10.1002/1097-0142(19950101)75:1+<191::AID-CNCR2820751307>3.0.CO;2-Y | s2cid = 221577784 }} Recent studies, though, suggest that the "ratio of centrally to peripherally occurring" lesions may be converging toward unity for both adenocarcinoma and squamous-cell carcinoma.{{citation needed|date=October 2016}}

{{Main|Squamous-cell carcinoma of the lung}}

[[File:Ca bronchus.jpg|thumb|right|Photograph of a squamous-cell carcinoma: The tumour is on the left, obstructing the bronchus (lung).

Beyond the tumour, the bronchus is inflamed and contains mucus.]]

Squamous-cell carcinoma (SCC) of the lung is more common in men than in women. It is closely correlated with a history of tobacco smoking, more so than most other types of lung cancer. According to the Nurses' Health Study, the relative risk of SCC is around 5.5, both among those with a previous duration of smoking of 1 to 20 years and those with 20 to 30 years, compared to "never smokers" (lifelong nonsmokers).{{cite journal | vauthors = Kenfield SA, Wei EK, Stampfer MJ, Rosner BA, Colditz GA | title = Comparison of aspects of smoking among the four histological types of lung cancer | journal = Tobacco Control | volume = 17 | issue = 3 | pages = 198–204 | date = June 2008 | pmid = 18390646 | pmc = 3044470 | doi = 10.1136/tc.2007.022582 }} The relative risk increases to about 16 with a previous smoking duration of 30 to 40 years and roughly 22 with more than 40 years.

{{Main|Large-cell lung carcinoma}}

Large-cell lung carcinoma (LCLC) is a heterogeneous group of undifferentiated malignant neoplasms originating from transformed epithelial cells in the lung. LCLCs have typically comprised around 10% of all NSCLCs in the past, although newer diagnostic techniques seem to be reducing the incidence of diagnosis of "classic" LCLC in favor of more poorly differentiated SCCs and adenocarcinomas.{{cite journal |doi=10.1007/s12254-011-0245-8 |title=Large cell carcinoma of the lung – a vanishing entity? |year=2011 | vauthors = Popper HH |journal=Memo - Magazine of European Medical Oncology |volume=4 |pages=4–9|s2cid=71238993 }} LCLC is, in effect, a "diagnosis of exclusion", in that the tumor cells lack light microscopic characteristics that would classify the neoplasm as a small-cell carcinoma, squamous-cell carcinoma, adenocarcinoma, or another more specific histologic type of lung cancer. LCLC is differentiated from SCLC primarily by the larger size of the anaplastic cells, a higher cytoplasmic-to-nuclear size ratio, and a lack of "salt-and-pepper" chromatin.{{citation needed|date=November 2020}}

Many of the symptoms of NSCLC can be signs of other diseases, but having chronic or overlapping symptoms may be a signal of the presence of the disease. Some symptoms are indicators of less advanced cases, while some may signal that the cancer has spread. Some of the symptoms of less advanced cancer include chronic cough, coughing up blood, hoarseness, shortness of breath, wheezing, chest pain, weight loss, and loss of appetite.{{Cite web|url=https://www.cancer.org/cancer/non-small-cell-lung-cancer/detection-diagnosis-staging/signs-symptoms.html|title=Non-Small Cell Lung Cancer Signs and Symptoms|website=www.cancer.org|access-date=4 December 2017}} A few more symptoms associated with the early progression of the disease are feeling weak, being very tired, having trouble swallowing, swelling in the face or neck, and continuous or recurring infections such as bronchitis or pneumonia.{{Cite web|url=http://www.umm.edu/health/medical/reports/articles/nonsmall-cell-lung-cancer|title=Non-small cell lung cancer|website=University of Maryland Medical Center|language=en|access-date=4 December 2017}} Signs of more advanced cases include bone pain, nervous-system changes (headache, weakness, dizziness, balance problems, seizures), jaundice, lumps near the surface of the body, numbness of extremities due to Pancoast syndrome, and nausea, vomiting, and constipation brought on by hypercalcemia. Some more of the symptoms that indicate further progression of the cancer include shortness of breath, superior vena cava syndrome, trouble swallowing, large amounts of mucus, weakness, fatigue, and hoarseness.

The current USPSTF guidelines for lung cancer screening includes everyone aged 50 to 80 years old with a 20 pack-year history of smoking and still currently are or quit within the past 15 years.{{Cite web |title=Recommendation: Lung Cancer: Screening {{!}} United States Preventive Services Taskforce |url=https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/lung-cancer-screening |access-date=2025-03-02 |website=www.uspreventiveservicestaskforce.org |language=en}} The recommended age to commence screening was recently lowered to 50 instead of 55 along with the pack-year smoking history which was lowered from 30 to 20. The current recommended method of screening is a low-dose computed tomography (CT) annually.

Smoking is by far the leading risk factor for lung cancer.{{cite web|url=http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-risk-factors|title=Non-Small Cell Lung Cancer Risk Factors|website=www.cancer.org|access-date=23 January 2016|archive-date=7 December 2016|archive-url=https://web.archive.org/web/20161207135204/http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-risk-factors|url-status=dead}} Cigarette smoke contains more than 6,000 components, many of which lead to DNA damage{{cite journal | vauthors = Liu X, Conner H, Kobayashi T, Kim H, Wen F, Abe S, Fang Q, Wang X, Hashimoto M, Bitterman P, Rennard SI | display-authors = 6 | title = Cigarette smoke extract induces DNA damage but not apoptosis in human bronchial epithelial cells | journal = American Journal of Respiratory Cell and Molecular Biology | volume = 33 | issue = 2 | pages = 121–129 | date = August 2005 | pmid = 15845867 | doi = 10.1165/rcmb.2003-0341OC }} (see table of tobacco-related DNA damages in Tobacco smoking).

Other causes include radon, exposure to secondhand smoke, exposure to substances such as asbestos, chromium, nickel, beryllium, soot, or tar, family history of lung cancer, and air pollution.

Genetics can also play a role as a family history of lung cancer can contribute to an increased risk of developing the disease. Furthermore, research has revealed specific chromosome regions associated with increased risks of developing lung cancer.

In general, DNA damage appears to be the primary underlying cause of cancer.{{cite journal | vauthors = Kastan MB | title = DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture | journal = Molecular Cancer Research | volume = 6 | issue = 4 | pages = 517–524 | date = April 2008 | pmid = 18403632 | doi = 10.1158/1541-7786.MCR-08-0020 | doi-access = free }} Though most DNA damages are repairable, leftover unrepaired DNA damages from cigarette smoke are the likely cause of NSCLC.

DNA replication past unrepaired damage can give rise to a mutation because of inaccurate translesion synthesis. In addition, during repair of DNA double-strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can lead to epigenetic gene silencing.{{cite journal | vauthors = O'Hagan HM, Mohammad HP, Baylin SB | title = Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island | journal = PLOS Genetics | volume = 4 | issue = 8 | pages = e1000155 | date = August 2008 | pmid = 18704159 | pmc = 2491723 | doi = 10.1371/journal.pgen.1000155 | veditors = Lee JT | doi-access = free }}{{cite journal | vauthors = Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV | display-authors = 6 | title = DNA damage, homology-directed repair, and DNA methylation | journal = PLOS Genetics | volume = 3 | issue = 7 | pages = e110 | date = July 2007 | pmid = 17616978 | pmc = 1913100 | doi = 10.1371/journal.pgen.0030110 | doi-access = free }}

Deficiencies in DNA repair underlie many forms of cancer.{{cite journal | vauthors = Harper JW, Elledge SJ | title = The DNA damage response: ten years after | journal = Molecular Cell | volume = 28 | issue = 5 | pages = 739–745 | date = December 2007 | pmid = 18082599 | doi = 10.1016/j.molcel.2007.11.015 | doi-access = free }} If DNA repair is deficient, the frequency of unrepaired DNA damages increases, and these tend to cause inaccurate translesion synthesis leading to mutation. Furthermore, increased damage can elevate incomplete repair, leading to epigenetic alterations.{{citation needed|date=November 2020}}

Mutations in DNA repair genes occasionally occur in cancer, but deficiencies of DNA repair due to epigenetic alterations that reduce or silence DNA repair-gene expression occur much more frequently in cancer.{{citation needed|date=November 2020}}

Epigenetic gene silencing of DNA repair genes occurs frequently in NSCLC. At least nine DNA repair genes that normally function in relatively accurate DNA repair pathways are often repressed by promoter hypermethylation in NSCLC. One DNA repair gene, FEN1, that functions in an inaccurate DNA repair pathway, is expressed at an increased level due to hypo-, rather than hyper-, methylation of its promoter region (deficiency of promoter methylation) in NSCLC.{{citation needed|date=November 2020}}

The frequent deficiencies in accurate DNA repair, and the increase in inaccurate repair, likely cause the high level of mutation in lung cancer cells of more than 100,000 mutations per genome (see Whole genome sequencing).

{{further |Lung cancer staging}}

Staging is a formal procedure to determine how developed the cancer is, which determines treatment options.

The American Joint Committee on Cancer and the International Union Against Cancer recommend TNM staging, using a uniform scheme for NSCLC, SCLC, and bronchopulmonary carcinoid tumors.{{cite book|title=AJCC Cancer Staging|year=2009|edition=7th|chapter=Cancer Staging Posters: Lung|chapter-url=http://www.cancerstaging.org/staging/posters/lung8.5x11.pdf|archive-url=https://web.archive.org/web/20110928053254/http://www.cancerstaging.org/staging/posters/lung8.5x11.pdf|archive-date=28 September 2011|url-status=dead}} With TNM staging, the cancer is classified based on the size of the primary tumor and whether it has invaded adjacent structures (T), spread to lymph nodes (N) and other organs (M). As the tumor grows in size and the areas affected become larger, the staging of the cancer becomes more advanced as well.

Several components of NSCLC staging then influence physicians' treatment strategies.{{cite web|title=National Cancer Institute Non-Small Cell Lung Cancer Treatment (PDQ)|url=http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/healthprofessional/page3#_478_toc|access-date=12 May 2015|date=1 January 1980}} The lung tumor itself is typically assessed both radiographically for overall size and by a pathologist under the microscope to identify specific genetic markers or to see if invasion into important structures within the chest (e.g., bronchus or pleural cavity) has occurred. Next, the patient's nearby lymph nodes within the chest cavity, known as the mediastinum, are checked for disease involvement. Finally, the patient is evaluated for more distant sites of metastatic disease, most typically with brain imaging and or scans of the bones.{{cite journal | vauthors = Chawla M, Kumar R, Agarwala S, Bakhshi S, Gupta DK, Malhotra A | title = Role of positron emission tomography-computed tomography in staging and early chemotherapy response evaluation in children with neuroblastoma | journal = Indian Journal of Nuclear Medicine | volume = 25 | issue = 4 | pages = 147–155 | date = October 2010 | pmid = 21713223 | pmc = 3109821 | doi = 10.4103/0972-3919.78249 | doi-access = free }}

The survival rates for stages I through IV decrease significantly due to the advancement of the disease. For stage I, the five-year survival rate is 47%, stage II is 30%, stage III is 10%, and stage IV is 1%.{{Cite web|url=https://www.cancer.org/cancer/non-small-cell-lung-cancer/detection-diagnosis-staging/survival-rates.html|title=Non-Small Cell Lung Cancer Survival Rates, by Stage|website=www.cancer.org|access-date=4 December 2017}}

{{main|Treatment of lung cancer}}

{{see also|Lung cancer surgery}}

More than one kind of treatment is often used, depending on the stage of the cancer, the individual's overall health, age, response to chemotherapy, and other factors such as the likely side effects of the treatment. After full staging, the NSCLC patient can typically be classified in one of three different categories: patients with early, nonmetastatic disease (stages I and II, and select type III tumors), patients with locally advanced disease confined to the thoracic cavity (e.g., large tumors, tumors involving critical chest structures, or patients with positive mediastinal lymph nodes), or patients with distant metastasis outside of the thoracic cavity.{{cn|date=June 2021}}

NSCLCs are usually not very sensitive to chemotherapy{{cite book | vauthors = Cotran RS, Kumar V, Fausto N, Robbins SL, Abbas AK |title=Robbins and Cotran pathologic basis of disease |publisher=Elsevier Saunders |location=St. Louis MO |year=2005 |isbn=978-0-7216-0187-8 |page=759}} and/or radiation, so surgery (lung resection to remove the tumor) remains the treatment of choice if patients are diagnosed at an early stage.{{cite web|title=NCCN Clinical Practice Guidelines for NSCLC|url=http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf|access-date=12 May 2015}}

If a person has a small but inoperable tumor, they may undergo highly targeted, high-intensity radiation therapy. New methods of giving radiation treatment allow doctors to be more accurate in treating lung cancers. This means less radiation affects nearby healthy tissues. New methods include Cyberknife and stereotactic body radiation therapy. Certain people who are deemed to be at higher risk may also receive adjuvant (ancillary) chemotherapy after initial surgery or radiation therapy. Several possible chemotherapy agents can be selected, but most involve the platinum-based chemotherapy drug called cisplatin.{{cn|date=June 2021}}

Other treatments include percutaneous ablation and chemoembolization.{{cite web |title=Chemoembolisation |publisher=Cancer Research UK |url=http://www.cancerhelp.org.uk/help/default.asp?page=4910#chemob |url-status=dead |archive-url=https://web.archive.org/web/20071009100904/http://www.cancerhelp.org.uk/help/default.asp?page=4910#chemob |archive-date=9 October 2007|date=30 August 2017 }} The most widely used ablation techniques for lung cancer are radiofrequency ablation (RFA), cryoablation, and microwave ablation.{{cite journal | vauthors = Dupuy DE, Shulman M | title = Current status of thermal ablation treatments for lung malignancies | journal = Seminars in Interventional Radiology | volume = 27 | issue = 3 | pages = 268–275 | date = September 2010 | pmid = 22550366 | pmc = 3324195 | doi = 10.1055/s-0030-1261785 }} Ablation may be an option for patients whose tumors are near the outer edge of the lungs. Nodules less than 1 cm from the trachea, main bronchi, oesophagus, and central vessels should be excluded from RFA given the high risk of complications and frequent incomplete ablation. Additionally, lesions greater than 5 cm should be excluded and lesions 3 to 5 cm should be considered with caution given the high risk of recurrence.{{cite journal | vauthors = Bargellini I, Bozzi E, Cioni R, Parentini B, Bartolozzi C | title = Radiofrequency ablation of lung tumours | journal = Insights into Imaging | volume = 2 | issue = 5 | pages = 567–576 | date = October 2011 | pmid = 22347976 | pmc = 3259330 | doi = 10.1007/s13244-011-0110-7 }} As a minimally invasive procedure, it can be a safer alternative for patients who are poor candidates for surgery due to comorbidities or limited lung function. A study comparing thermal ablation to sublobar resection as treatment for early-stage NSCLC in older people found no difference in overall survival of the patients.{{cite journal | vauthors = Kwan SW, Mortell KE, Talenfeld AD, Brunner MC | title = Thermal ablation matches sublobar resection outcomes in older patients with early-stage non-small cell lung cancer | journal = Journal of Vascular and Interventional Radiology | volume = 25 | issue = 1 | pages = 1–9.e1 | date = January 2014 | pmid = 24365502 | doi = 10.1016/j.jvir.2013.10.018 }} RFA followed by radiation therapy may have a survival benefit due to the synergism of the two mechanisms of cell destruction.{{cite journal | vauthors = Grieco CA, Simon CJ, Mayo-Smith WW, DiPetrillo TA, Ready NE, Dupuy DE | title = Percutaneous image-guided thermal ablation and radiation therapy: outcomes of combined treatment for 41 patients with inoperable stage I/II non-small-cell lung cancer | journal = Journal of Vascular and Interventional Radiology | volume = 17 | issue = 7 | pages = 1117–1124 | date = July 2006 | pmid = 16868164 | doi = 10.1097/01.RVI.0000228373.58498.6E }}

The treatment scenario for patients with resectable non-small cell lung cancer has changed dramatically with the incorporation of immunotherapy. The introduction of immunotherapy into treatment algorithms has yielded improved clinical outcomes in several phase II and III trials in both adjuvant (Impower010 and PEARLS) and neoadjuvant settings (JHU/MSK, LCMC3, NEOSTAR, Columbia/MGH, NADIM,{{cite journal |last1=Provencio |first1=Mariano |last2=Nadal |first2=Ernest |last3=Insa |first3=Amelia |last4=García-Campelo |first4=María Rosario |last5=Casal-Rubio |first5=Joaquín |last6=Dómine |first6=Manuel |last7=Majem |first7=Margarita |last8=Rodríguez-Abreu |first8=Delvys |last9=Martínez-Martí |first9=Alex |last10=De Castro Carpeño |first10=Javier |last11=Cobo |first11=Manuel |last12=López Vivanco |first12=Guillermo |last13=Del Barco |first13=Edel |last14=Bernabé Caro |first14=Reyes |last15=Viñolas |first15=Nuria |last16=Barneto Aranda |first16=Isidoro |last17=Viteri |first17=Santiago |last18=Pereira |first18=Eva |last19=Royuela |first19=Ana |last20=Casarrubios |first20=Marta |last21=Salas Antón |first21=Clara |last22=Parra |first22=Edwin R |last23=Wistuba |first23=Ignacio |last24=Calvo |first24=Virginia |last25=Laza-Briviesca |first25=Raquel |last26=Romero |first26=Atocha |last27=Massuti |first27=Bartomeu |last28=Cruz-Bermúdez |first28=Alberto |title=Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial |journal=The Lancet Oncology |date=November 2020 |volume=21 |issue=11 |pages=1413–1422 |doi=10.1016/S1470-2045(20)30453-8|pmid=32979984 |s2cid=222158757 }} NADIM II{{cite journal |last1=Forde |first1=PM |last2=Spicer |first2=J |last3=Lu |first3=S |last4=Provencio |first4=M |last5=Mitsudomi |first5=T |last6=Awad |first6=MM |last7=Felip |first7=E |last8=Broderick |first8=SR |last9=Brahmer |first9=JR |last10=Swanson |first10=SJ |last11=Kerr |first11=K |last12=Wang |first12=C |last13=Ciuleanu |first13=TE |last14=Saylors |first14=GB |last15=Tanaka |first15=F |last16=Ito |first16=H |last17=Chen |first17=KN |last18=Liberman |first18=M |last19=Vokes |first19=EE |last20=Taube |first20=JM |last21=Dorange |first21=C |last22=Cai |first22=J |last23=Fiore |first23=J |last24=Jarkowski |first24=A |last25=Balli |first25=D |last26=Sausen |first26=M |last27=Pandya |first27=D |last28=Calvet |first28=CY |last29=Girard |first29=N |last30=CheckMate 816 |first30=Investigators |title=Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. |journal=The New England Journal of Medicine |date=26 May 2022 |volume=386 |issue=21 |pages=1973–1985 |doi=10.1056/NEJMoa2202170 |pmid=35403841|pmc=9844511 }}{{cite journal |last1=Provencio |first1=M |last2=Nadal |first2=E |last3=González-Larriba |first3=JL |last4=Martínez-Martí |first4=A |last5=Bernabé |first5=R |last6=Bosch-Barrera |first6=J |last7=Casal-Rubio |first7=J |last8=Calvo |first8=V |last9=Insa |first9=A |last10=Ponce |first10=S |last11=Reguart |first11=N |last12=de Castro |first12=J |last13=Mosquera |first13=J |last14=Cobo |first14=M |last15=Aguilar |first15=A |last16=López Vivanco |first16=G |last17=Camps |first17=C |last18=López-Castro |first18=R |last19=Morán |first19=T |last20=Barneto |first20=I |last21=Rodríguez-Abreu |first21=D |last22=Serna-Blasco |first22=R |last23=Benítez |first23=R |last24=Aguado de la Rosa |first24=C |last25=Palmero |first25=R |last26=Hernando-Trancho |first26=F |last27=Martín-López |first27=J |last28=Cruz-Bermúdez |first28=A |last29=Massuti |first29=B |last30=Romero |first30=A |title=Perioperative Nivolumab and Chemotherapy in Stage III Non-Small-Cell Lung Cancer. |journal=The New England Journal of Medicine |date=10 August 2023 |volume=389 |issue=6 |pages=504–513 |doi=10.1056/NEJMoa2215530 |pmid=37379158|s2cid=259283994 |hdl=10550/89125 |hdl-access=free }} and CheckMate-816), leading to new U.S. Food and Drug Administration approvals in this sense.

The treatment approach for people who have advanced NSCLC is first aimed at relieving pain and distress (palliative), but a wide variety of chemotherapy options exists.{{cite web|url=http://www.lungcanceronline.org/treatment-nsclc/chemo.html|title=Lung Cancer online|website=lungcanceronline.org|access-date=13 December 2008|archive-url=https://web.archive.org/web/20080617213618/http://www.lungcanceronline.org/treatment-nsclc/chemo.html|archive-date=17 June 2008|url-status=dead}}{{cite journal | vauthors = Vasconcellos VF, Marta GN, da Silva EM, Gois AF, de Castria TB, Riera R | title = Cisplatin versus carboplatin in combination with third-generation drugs for advanced non-small cell lung cancer | journal = The Cochrane Database of Systematic Reviews | volume = 1 | issue = 1 | pages = CD009256 | date = January 2020 | pmid = 31930743 | pmc = 6956680 | doi = 10.1002/14651858.CD009256.pub3 }} These agents include both traditional chemotherapies, such as cisplatin, which indiscriminately target all rapidly dividing cells, and newer targeted agents, which are more tailored to specific genetic aberrations found within a person's tumor. When choosing an appropriate chemotherapy approach, the toxicity profile (side effects of the drug) should be taken into account and balanced with the person's comorbidities (other conditions or side effects that the person is experiencing).{{cite journal | vauthors = Gijtenbeek RG, de Jong K, Venmans BJ, van Vollenhoven FH, Ten Brinke A, Van der Wekken AJ, van Geffen WH | title = Best first-line therapy for people with advanced non-small cell lung cancer, performance status 2 without a targetable mutation or with an unknown mutation status | journal = The Cochrane Database of Systematic Reviews | volume = 2023 | issue = 7 | pages = CD013382 | date = July 2023 | pmid = 37419867 | pmc = 10327404 | doi = 10.1002/14651858.CD013382.pub2 | collaboration = Cochrane Lung Cancer Group }} Carboplatin is a chemotherapy agent that has a similar effect on a person's survival when compared to cisplatin, and has a different toxicity profile from cisplatin. Carboplatin may be associated with a higher risk of thrombocytopenia. Cisplatin may cause more nausea or vomiting when compared to carboplatin treatment. PD‐L1 inhibitors are more effective and lead to longer survival with fewer side effects compared to platinum-based chemotherapy.{{cite journal | vauthors = Ferrara R, Imbimbo M, Malouf R, Paget-Bailly S, Calais F, Marchal C, Westeel V | title = Single or combined immune checkpoint inhibitors compared to first-line platinum-based chemotherapy with or without bevacizumab for people with advanced non-small cell lung cancer | journal = The Cochrane Database of Systematic Reviews | volume = 2021 | issue = 4 | pages = CD013257 | date = April 2021 | pmid = 33930176 | pmc = 8092423 | doi = 10.1002/14651858.CD013257.pub3 }} Because PD-L1 inhibitors often face acquired resistance (AR) with extensive regions of tumor hypoxia, research is being conducted on the potential to combine those PD-L1 inhibitors with hypoxia-activated prodrugs, such as evofosfamide or CP-506.{{Cite journal |last=Robles-Oteíza |first=Camila |last2=Hastings |first2=Katherine |last3=Choi |first3=Jungmin |last4=Sirois |first4=Isabelle |last5=Ravi |first5=Arvind |last6=Expósito |first6=Francisco |last7=de Miguel |first7=Fernando |last8=Knight |first8=James R. |last9=López-Giráldez |first9=Francesc |last10=Choi |first10=Hyejin |last11=Socci |first11=Nicholas D. |last12=Merghoub |first12=Taha |last13=Awad |first13=Mark |last14=Getz |first14=Gad |last15=Gainor |first15=Justin |date=2024-11-25 |title=Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer |url=https://rupress.org/jem/article/222/1/e20231106/277112/Hypoxia-is-linked-to-acquired-resistance-to-immune |journal=Journal of Experimental Medicine |volume=222 |issue=1 |pages=e20231106 |doi=10.1084/jem.20231106 |issn=0022-1007}}{{Cite web |title=Clinical Trials Register |url=https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-000423-12/NL |access-date=2025-01-26 |website=www.clinicaltrialsregister.eu}}

At present, two genetic markers are routinely profiled in NSCLC tumors to guide further treatment decision-making - mutations within epidermal growth factor (EGFR) and anaplastic lymphoma kinase.{{cite web|title=Molecular Profiling of Lung Cancer|url=http://www.mycancergenome.org/content/disease/lung-cancer/|access-date=12 May 2015}} Also, several additional genetic markers are known to be mutated within NSCLC and may impact treatment in the future, including BRAF, HER2/neu, and KRAS. For advanced NSCLC, a combined chemotherapy treatment approach that includes cetuximab, an antibody that targets the EGFR signalling pathway, is more effective at improving a person's overall survival when compared to standard chemotherapy alone.{{cite journal | vauthors = Yang ZY, Liu L, Mao C, Wu XY, Huang YF, Hu XF, Tang JL | title = Chemotherapy with cetuximab versus chemotherapy alone for chemotherapy-naive advanced non-small cell lung cancer | journal = The Cochrane Database of Systematic Reviews | volume = 2014 | issue = 11 | pages = CD009948 | date = November 2014 | pmid = 25400254 | pmc = 10639006 | doi = 10.1002/14651858.CD009948.pub2 }}

Thermal ablations, i.e. RFA, cryoablation, and microwave ablation, are appropriate for palliative treatment of tumor-related symptoms or recurrences within treatment fields. People with severe pulmonary fibrosis and severe emphysema with a life expectancy of less than a year should be considered poor candidates for this treatment.

Roughly 10–35% of people who have NSCLC will have drug-sensitizing mutations of the EGFR. The distribution of these mutations is race-dependent, with one study estimating that 10% of Caucasians, but 50% of Asians, will be found to have such tumor markers.{{cite journal | vauthors = Hirsch FR, Bunn PA | title = EGFR testing in lung cancer is ready for prime time | journal = The Lancet. Oncology | volume = 10 | issue = 5 | pages = 432–433 | date = May 2009 | pmid = 19410185 | doi = 10.1016/s1470-2045(09)70110-x }} Many different EGFR mutations have been discovered, but certain aberrations result in hyperactive forms of the protein. People with these mutations are more likely to have adenocarcinoma histology and be nonsmokers or light smokers. These people are sensitized to certain medications that block the EGFR protein known as tyrosine kinase inhibitors specifically, erlotinib, gefitinib, afatinib, or osimertinib.{{cite journal | vauthors = Kris MG | title = How today's developments in the treatment of non-small cell lung cancer will change tomorrow's standards of care | journal = The Oncologist | volume = 10 | issue = Suppl 2 | pages = 23–29 | date = October 2005 | pmid = 16272456 | doi = 10.1634/theoncologist.10-90002-23 | doi-access = free }}

Reliable identification of mutations in lung cancer needs careful consideration due to the variable sensitivity of diagnostic techniques.{{cite journal | vauthors = Sherwood J, Dearden S, Ratcliffe M, Walker J | title = Mutation status concordance between primary lesions and metastatic sites of advanced non-small-cell lung cancer and the impact of mutation testing methodologies: a literature review | journal = Journal of Experimental & Clinical Cancer Research | volume = 34 | issue = 1 | pages = 92 | date = September 2015 | pmid = 26338018 | pmc = 4559261 | doi = 10.1186/s13046-015-0207-9 | doi-access = free }}

Lazertinib was approved for medical use in the United States in August 2024.{{cite web | title=FDA approves lazertinib with amivantamab-vmjw for non-small lung cancer | website=U.S. Food and Drug Administration (FDA) | date=19 August 2024 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lazertinib-amivantamab-vmjw-non-small-lung-cancer | access-date=21 August 2024}}

Up to 7% of NSCLC patients have EML4-ALK translocations or mutations in the ROS1 gene; these patients may benefit from ALK inhibitors, which are now approved for this subset of patients.{{cite web |url=http://www.genengnews.com/gen-articles/treatment-paradigm-shifting-for-nsclc/3423?page=1 |title=Non-Small-Cell Lung Cancer Standards of Care Challenged by a Cornucopia of New Drugs |author=Farmer |year=2010 }} Crizotinib, which gained FDA approval in August 2011, is an inhibitor of several kinases, specifically ALK, ROS1, and MET. Crizotinib has been shown in clinical studies to have response rates around 60% if patients are shown to have ALK-positive disease. Several studies have also shown that ALK mutations and EGFR activating mutations are typically mutually exclusive. Thus, patients who fail crizotinib are not recommended to be switched to an EGFR-targeted drug such as erlotinib.

Image:PD-L1_positive_lung_adenocarcinoma_--_intermed_mag.jpg showing a PD-L1-positive NSCLC, PD-L1 immunostain]]

NSCLC patients with advanced disease who are not found to have either EGFR or ALK mutations may receive bevacizumab, which is a monoclonal antibody medication targeted against the vascular endothelial growth factor (VEGF). This is based on an Eastern Cooperative Oncology Group study that found that adding bevacizumab to carboplatin and paclitaxel chemotherapy for certain patients with recurrent or advanced NSCLC (stage IIIB or IV) may increase both overall survival and progression-free survival.{{cite journal | vauthors = Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH | display-authors = 6 | title = Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer | journal = The New England Journal of Medicine | volume = 355 | issue = 24 | pages = 2542–2550 | date = December 2006 | pmid = 17167137 | doi = 10.1056/nejmoa061884 | doi-access = free }}

File:Pharmaceuticals-13-00373-g002-550.jpg Text was copied from this source, which is available under a [https://creativecommons.org/licenses/by/4.0/ Creative Commons Attribution 4.0 International License].]]

File:Monoclonal antibodies used in the treatment of non small cell lung cancer and their mechanism of action.webp (PD-1) expressed on the surface of T cells, and result in decreased tumor cell kill by the immune system. 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 (VEGF) in the circulation and functions as an angiogenesis inhibitor.]]

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. 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 the Vascular Endothelial Growth Factor (VEGF) in the circulation and functions as an angiogenesis inhibitor. 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.

In 2015, the US Food and Drug Administration (FDA) approved the anti-PD-1 agent nivolumab for advanced or metastatic SCC.{{Cite web |date=24 March 2015 |title=FDA Approves First Immunotherapy Treatment for Lung Cancer - NCI |url=https://www.cancer.gov/news-events/cancer-currents-blog/2015/fda-opdivo |access-date=22 September 2023 |website=www.cancer.gov |language=en}}

In 2015, FDA also approved the anti-EGFR drug necitumumab for metastatic SCC.{{Cite web |date=28 December 2015 |title=Approvals Increase Lung Cancer Treatment Options - NCI |url=https://www.cancer.gov/news-events/cancer-currents-blog/2015/fda-osimertinib-necitumumab |access-date=22 September 2023 |website=www.cancer.gov |language=en}}

2 October 2015, the FDA approved pembrolizumab for the treatment of metastatic NSCLC in patients whose tumors express PD-L1 and who have failed treatment with other chemotherapeutic agents.{{Cite web |date=18 November 2015 |title=FDA Approves Pembrolizumab to Treat Non-Small Cell Lung Cancer - NCI |url=https://www.cancer.gov/news-events/cancer-currents-blog/2015/pembrolizumab-nsclc |access-date=22 September 2023 |website=www.cancer.gov |language=en}}

In October 2016, pembrolizumab became the first immunotherapy to be used first line in the treatment of NSCLC if the cancer overexpresses PDL1 and the cancer has no mutations in EGFR or in ALK; if chemotherapy has already been administered, then pembrolizumab can be used as a second-line treatment, but if the cancer has EGFR or ALK mutations, agents targeting those mutations should be used first. Assessment of PDL1 must be conducted with a validated and approved companion diagnostic.{{cn|date=June 2021}}

File:Overall survival in non-small lung cancer patients treated with modern immunotherapy in the first line for advanced or metastatic disease.jpg

The prognosis of patients with non-small-cell lung cancer improved significantly with the introduction of immunotherapy. People with tumor PDL-1 expressed over half or more of the tumor cells achieved a median overall survival of 30 months with pembrolizumab.{{cite journal | vauthors = Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR | display-authors = 6 | title = Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer | journal = The New England Journal of Medicine | volume = 375 | issue = 19 | pages = 1823–1833 | date = November 2016 | pmid = 27718847 | doi = 10.1056/NEJMoa1606774 | doi-access = free }}{{cite journal | vauthors = Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR | display-authors = 6 | title = Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater | journal = Journal of Clinical Oncology | volume = 37 | issue = 7 | pages = 537–546 | date = March 2019 | pmid = 30620668 | doi = 10.1200/JCO.18.00149 | s2cid = 58640902 | url = https://ro.uow.edu.au/smhpapers1/660 }}

Mobocertinib (Exkivity) was approved for medical use in the United States in September 2021, and it is indicated for adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.{{cite web | title=FDA grants accelerated approval to mobocertinib for metastatic non-sma | website=U.S. Food and Drug Administration (FDA) | date=16 September 2021 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-mobocertinib-metastatic-non-small-cell-lung-cancer-egfr-exon-20 | access-date=16 September 2021}} {{PD-notice}}{{cite press release | title=Takeda's Exkivity (mobocertinib) Approved by U.S. FDA as the First Oral Therapy Specifically Designed for Patients with EGFR Exon20 Insertion+ NSCLC | publisher=Takeda | via=Business Wire | date=15 September 2021 | url=https://www.businesswire.com/news/home/20210915006101/en/ | access-date=16 September 2021}} In October 2023, the manufacturer, Takeda, voluntarily withdrew Mobocertinib from use in the United States. In phase 3 clinical trials, the drug failed to show a significant effect on progression-free survival (PFS).{{cite web | url=https://www.medicalnewstoday.com/articles/mobocertinib-withdrawal-what-it-means-for-people-with-egfr-lung-cancer | title=Lung cancer in nonsmokers: Removal of drug may impact care | date=13 February 2024 }}

{{reflist}}

{{Medical resources

| DiseasesDB =

| ICD10 = C34.90

| ICD9 = 162

| ICDO =

| OMIM =

| MedlinePlus = 007194

| eMedicineSubj = med

| eMedicineTopic = 1333

| MeshID = D002289

| Scholia = Q3658562

}}

• {{MedlinePlusEncyclopedia|007194|Lung cancer — non-small cell}}

{{Respiratory and intrathoracic neoplasia}}

Category:Lung cancer