Non-Small Cell Lung Cancer (NSCLC)
Non–small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Histologically, NSCLC is divided into adenocarcinoma, squamous cell carcinoma (SCC) (see the image below), and large cell carcinoma. Patients with NSCLC require a complete staging workup to evaluate the extent of disease, because stage plays a major role in determining the choice of treatment.
See the Critical Images slideshow Cutaneous Clues to Diagnosing Metastatic Cancer to help identify various skin lesions that are cause for concern.
NSCLC is often insidious, producing no symptoms until the disease is well advanced. Early recognition of symptoms may be beneficial to outcome.
At initial diagnosis, 20% of patients have localized disease, 25% of patients have regional metastasis, and 55% of patients have distant spread of disease. Symptoms depend on the location of cancer. 
The most common signs and symptoms of lung cancer include the following:
Metastatic signs and symptoms may include the following:
See Presentation for more detail.
After physical examination and CBC, chest x-ray is often the first test performed. Chest radiographs may show the following:
There are several methods of confirming diagnosis, with the choice determined partly by lesion location. These methods include the following:
A chest CT scan is the standard for staging lung cancer. The TNM (tumor-node-metastasis) staging system from the American Joint Committee for Cancer Staging and End Results Reporting is used for all lung carcinomas except small-cell lung cancer. The TNM takes into account the following key pieces of information:
N describes the spread of cancer to regional lymph nodes
M indicates whether the cancer has metastasized
Primary tumor (T) involvement is as follows:
Tx – Primary tumor cannot be assessed
T0 – No evidence of tumor
Tis – Carcinoma in situ
T1, T2, T3, T4: size and/or extension of the primary tumor
Lymph node (N) involvement is as follows:
Nx – Regional nodes cannot be assessed
N0 – No regional node metastasis
N1 – Metastasis in ipsilateral peribronchial and/or ipsilateral hilar nodes and intrapulmonary nodes, including involvement by direct extension
N2 – Metastasis in ipsilateral mediastinal and/or subcarinal node
N3 – Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene node, or supraclavicular node
Metastatic (M) involvement is as follows:
M0 – No metastasis
M1 – Distant metastasis
Surgery, chemotherapy, and radiation are the main treatment options for NSCLC. Because most lung cancers cannot be cured with currently available therapeutic modalities, the appropriate application of skilled palliative care is an important part of the treatment of patients with NSCLC.
Surgery is the treatment of choice for stage I and stage II NSCLC. Several different types of surgery can be used, as follows:
Lobectomy – removing a section of the lung
Pneumonectomy – removing the entire lung
Wedge resection – removing part of a lobe
Approximately 80% of all patients with lung cancer are considered for chemotherapy at some point during the course of their illness. Multiple randomized, controlled trials and large meta-analyses all confirm the superiority of combination chemotherapy regimens up front for advanced NSCLC.
The American Society for Clinical Oncology (ASCO) guidelines recommend that first-line treatment for NSCLC include a platinum combination. In younger patients, with a good performance status or in the adjuvant setting, cisplatin is preferred, but in older patients or those with significant comorbidities, carboplatin may be substituted.
In the treatment of stage I and stage II NSCLC, radiation therapy alone is considered only when surgical resection is not possible.  Radiation is a reasonable option for lung cancer treatment among those who are not candidates for surgery.  Beta blockers have been found to improve overall survival, disease-free survival, and distant metastasis–free survival, though not locoregional progession–free survival, in patients with NSCLC undergoing radiotherapy. 
See Treatment for more detail.
Lung cancers are generally divided into two main categories: small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC). NSCLC accounts for approximately 85% of all lung cancers. Histologically, NSCLC is divided further into adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma. (See Pathophysiology.)
Lung cancer was a rare entity in the early 1900s but has since become far more prevalent. The prevalence of lung cancer is second only to that of prostate cancer in men and breast cancer in women. By the end of the 1900s, lung cancer had become the leading cause of preventable death in the United States,  and recently, it surpassed heart disease as the leading cause of smoking-related mortality.
Lung cancer is the leading cause of cancer-related mortality in both men and women not only in the United States but also throughout the world. In 2016, the disease is expected to cause approximately 158,000 deaths in the United States—more than colorectal, breast, and prostate cancers combined.  The types of lung cancer in the United States, as well as in many other countries, have also changed in the past few decades: the frequency of adenocarcinoma has risen, and that of SCC has declined. (See Epidemiology.)
Most lung carcinomas are diagnosed at an advanced stage, conferring a poor prognosis. The need to diagnose lung cancer at an early and potentially curable stage is thus obvious. (See Prognosis.) In addition, most patients who develop lung cancer have been smokers and have smoking-related damage to the heart and lungs, making aggressive surgical or multimodality therapies less viable options.
Lung cancer is often insidious, producing no symptoms until the disease is well advanced. In approximately 7-10% of cases, lung cancers are diagnosed incidentally in asymptomatic patients, when a chest radiograph performed for other reasons reveals the disease. Numerous pulmonary signs may be associated with NSCLC. Systemic findings may include unexplained weight loss and low-grade fever. (See Presentation.)
Because of the importance of stage on the therapeutic decision-making process, all patients with NSCLC must be staged adequately. A complete staging workup for NSCLC should be carried out to evaluate the extent of disease. (See Workup.)
Treatment primarily involves surgery, chemotherapy, or radiation therapy. Because most lung cancers cannot be cured with currently available therapeutic modalities, the appropriate application of skilled palliative care is an important part of the treatment of patients with NSCLC. (See Treatment.)
The American College of Chest Physicians (ACCP) updated its comprehensive set of lung cancer guidelines in 2013. The guideline set includes an executive summary of current recommendations for diagnosis and treatment.  For a summary of guidelines issued by major organizations, see Non-Small Cell Lung Cancer Guidelines.
Go to Small Cell Lung Cancer for complete information on this topic.
Both exposure (environmental or occupational) to particular agents and an individual’s susceptibility to these agents are thought to contribute to one’s risk of developing lung cancer. In the United States, active smoking is responsible for approximately 90% of lung cancer cases. Occupational exposures to carcinogens account for approximately 9-15% of lung cancer cases.
Tobacco smoke contains more than 300 harmful substances with at least 40 known potent carcinogens. Polyaromatic hydrocarbons and nicotine-derived nitrosamine ketone (NNK) are known to cause DNA damage by forming DNA adducts in animal models. Benzo-A-pyrine also appears to induce molecular signaling such as AKT, as well as inducing mutations in p53 and other tumor suppressor genes.
The most common occupational risk factor for lung cancer is exposure to asbestos. Studies have shown radon exposure to be associated with 10% of lung cancer cases, while outdoor air pollution accounts for perhaps 1-2%.  In addition, preexisting nonmalignant lung diseases, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and tuberculosis have all been shown to be associated with increased lung cancer rates.
The current multiple hit theory suggests that a series of toxic cellular insults disrupts orderly genetic reproduction. Symptoms ultimately develop from the uncontrolled disorganized growth that interferes with local or distant anatomy or physiologic processes. 
A study by Ito et al assessed the shift in histologic types of lung cancer in Japan and the United States in relation to the shift from nonfiltered to filtered cigarettes.  The study determined that the shift in cigarette types only altered the most frequent type of lung cancer, which shifted from SCC to adenocarcinoma.
Advanced molecular techniques have identified amplification of oncogenes and inactivation of tumor suppressor genes in NSCLC. The most important abnormalities detected are mutations involving the ras family of oncogenes. The ras oncogene family has 3 members: H-ras, K-ras, and N-ras. These genes encode a protein on the inner surface of the cell membrane with guanosine triphosphatase activity and may be involved in signal transduction.
Studies performed on mice suggest the involvement of ras mutations in the molecular pathogenesis of NSCLC. Studies in humans suggest that ras activation contributes to tumor progression in persons with lung cancer. The ras gene mutations occur almost exclusively in adenocarcinoma and are found in 30% of such cases. These mutations were not identified in adenocarcinomas that developed in persons who do not smoke. The K-ras mutation appears to be an independent prognostic factor.
Studies are ongoing to develop management plans according to the presence or absence of ras gene mutations.
Other molecular abnormalities found in NSCLC include mutations in the oncogenes c-myc and c-raf and in the tumor suppressor genes retinoblastoma (Rb) and p53.
Two studies have documented early and extensive mutations in lung cancers that result in pronounced intratumor heterogeneity by the time these cancers manifest clinically—thus helping to explain why these cases so often fail to respond to treatment. A study by Zhang and colleagues identified 20 of 21 known cancer gene mutations in all regions of 11 localized lung adenocarcinomas. On follow-up, patients who had postsurgical relapse had significantly larger fractions of subclonal mutations in their primary tumors. 
Similarly, a study by de Bruin and colleagues in seven operable NSCLCs determined that there was a long period of tumor latency between early mutations and clinical symptoms, which appeared after new mutations triggered rapid disease growth. In some former smokers, the initial mutations dated back to when they were smoking cigarettes, two decades earlier. Over time, however, those mutations became less important, with more recent mutations resulting from a new process controlled by a protein called APOBEC. 
Lung cancers are generally divided into 2 main categories: SCLC and NSCLC. NSCLC accounts for approximately 85% of all lung cancers. NSCLC is divided further into adenocarcinoma, SCC, and large cell carcinoma. All share similar treatment approaches and prognoses but have distinct histologic and clinical characteristics.
Adenocarcinoma, arising from the bronchial mucosal glands, is the most common NSCLC cancer in the United States, representing 35-40% of all lung cancers. It is the subtype observed most commonly in persons who do not smoke. It usually occurs in a peripheral location within the lung, in some cases at the site of pre-existing scars, wounds, or inflammation (ie, a “scar carcinoma”).
Bronchoalveolar carcinoma is a distinct subtype of adenocarcinoma with a classic manifestation as an interstitial lung disease on chest radiograph. Bronchoalveolar carcinoma arises from type II pneumocytes and grows along alveolar septa. This subtype may manifest as a solitary peripheral nodule, multifocal disease, or a rapidly progressing pneumonic form. A characteristic finding in persons with advanced disease is voluminous watery sputum.
Squamous cell carcinoma
SCC accounts for 25-30% of all lung cancers. Whereas adenocarcinoma tumors are peripheral in origin, SCC is found in the central parts of the lung (see the image below). The classic manifestation is a cavitary lesion in a proximal bronchus. This type is characterized histologically by the presence of keratin pearls and can be detected with cytologic studies because it has a tendency to exfoliate. It is the type most often associated with hypercalcemia.
Large-cell carcinoma accounts for 10-15% of lung cancers, typically manifesting as a large peripheral mass on chest radiograph. Histologically, this type has sheets of highly atypical cells with focal necrosis, with no evidence of keratinization (as is typical of SCC) or gland formation (as is typical of adenocarcinomas).
With improved histopathologic procedures and the use of electron microscopy, most NSCLCs that would previously have been classified as large-cell carcinomas are identified as undifferentiated adenocarcinomas or, less frequently, as SCCs.  Large-cell undifferentiated cancers have the same prognosis as do adenocarcinomas and are combined with them in clinical trials.
Causes of lung cancer include the following:
Unlike many other malignancies, whose causes are largely unknown, lung cancer is known to be caused by tobacco smoking in as many as 90% of patients. However, two recent studies have reported rising NSCLC rates in persons who have never smoked: In a United States study, rates increased from 8.9% in 1990–1995 to 19.5% in 2011–2013, while a study from the United Kingdom reported an increase from 13% to 28% during a 6-year period. 
Because not all smokers develop lung cancer and not all lung cancer patients have a history of smoking, other factors (eg, genetic susceptibility [see Pathophysiology], arsenic exposure, radiation exposure, and other environmental carcinogens  ) also play a causative role, either independently or in conjunction with smoking. Genetic factors probably contribute in all populations, but the contribution of other factors is population-specific.
A study by Bagnardi et al determined that alcohol is not an independent factor in the etiology of lung cancer. 
Smoking prevalence in the United States has gradually declined over last 4 decades. In 2012, there were an estimated 42.1 million active smokers in the United States. Overall smoking prevalence declined from 20.9% in 2005 to 18.1% in 2012.  Worldwide, the incidence of smoking in developing countries is on the rise, with almost 320 million smokers in China alone.
The development of lung cancer is directly related to number of cigarettes smoked, length of smoking history, and the tar and nicotine content of the cigarettes. Risk is highest among current smokers and lowest among nonsmokers. A large trial showed that persistent smokers had a 16-fold elevated lung cancer risk, which was further doubled in those who started smoking when younger than 16 years.  The age-adjusted incidence rates range from 4.8-20.8 per 100,000 among nonsmokers to 140-362 per 100,000 among active smokers.
Although tobacco smoking is the major cause of lung cancer, it is now believed that males and females may differ in their susceptibility to the carcinogenic effects of tobacco smoke. This difference may be due to differences in DNA repair mechanisms. Although still considered controversial, it is well known that women are more likely to develop adenocarcinomas and that, stage for stage, women live longer. In addition, differences in response to certain biologic therapies (eg, epidermal growth factor [EGF] inhibitors) and antiangiogenic agents have been observed between sexes.
The risk of lung cancer declines slowly after smoking cessation. Long-term follow-up studies show that the relative risk remains high in the first 10 years after cessation and gradually declines to 2-fold approximately 30 years after cessation. This long-term risk explains the development of almost 50% of United States lung cancer cases in past smokers.
Strong cardiorespiratory fitness might help reduce lung cancer risk in men who smoke or used to smoke, accordng to the findings from a study that assessed 1602 former smokers (40 pack-years) and 1377 current smokers (43 pack-years). All were men, aged 42 to 76 years, who were free from lung cancer at baseline. Over a follow-up period of 4.6 to 18.6 years, 46 former smokers and 53 current smokers developed lung cancer. Of this group, 40 former smokers and 39 current smokers died. Men who had higher fitness levels at baseline, measured with a maximal treadmill exercise test, had a lower incidence of lung cancer during follow-up and had better survival if they did get lung cancer. 
Cigarette smoke containing the carcinogenic N-nitrosamines and aromatic polycyclic hydrocarbons can be inhaled passively by nonsmokers (secondhand smoke); urinary levels of these carcinogens in nonsmokers are 1-5% of those found in active smokers. As many as 25% of the lung cancers in persons who do not smoke are believed to be caused by secondhand smoke. 
The US Environmental Protection Agency has recognized passive smoking as a potential carcinogen. About 3000 cases of lung cancer appear to be related to passive exposure. This awareness has led to local ordinances restricting smoking in enclosed public places, including restaurants and government buildings.
Lung cancer in never-smokers
A minority of lung cancers develop in persons who have never smoked. These lung cancers are genetically distinct from smoking-related NSCLC, and this distinction may have therapeutic implications. The observed genetic differences include a lower frequency of K-ras and a higher frequency of mutations in the EGF receptor and likely are responsible for the higher efficacy of EGF receptor inhibitors in this patient population.
The silicate type of asbestos fiber is an important carcinogen. Asbestos exposure has been shown to be strongly associated with the causation of lung cancer, malignant pleural mesothelioma, and pulmonary fibrosis. Asbestos exposure increases the risk of developing lung cancer by as much as 5 times.
Tobacco smoke and asbestos exposure act synergistically, and the risk of developing lung cancer for persons who currently smoke tobacco and have a history of asbestos exposure approaches 80-90 times that of control populations.
Radon is an inert gas produced as a result of uranium decay. Radon exposure is a well-established risk factor for lung cancer in uranium miners. Approximately 2-3% of lung cancers annually are estimated to be caused by radon exposure. Household exposure to radon, however, has never been clearly shown to cause lung cancer.
The US National Research Council’s report of the Sixth Committee on Biological Effects of Ionizing Radiation has estimated that radon exposure causes 2100 new lung cancers each year, while it contributes to lung cancer causation in approximately 9100 persons who smoke.
Persons with HIV infection have a higher lung cancer risk than those without HIV infection, with relative risk estimates ranging from 2 to 11. In persons with HIV infection, lung cancer is the most common and most fatal non-AIDS-associated malignancy, accounting for about 16% of deaths.  A majority of these cases are adenocarcinomas. In most, but not all, studies the incidence and risk of lung cancer in HIV-infected persons did not change significantly with the advent of highly active antiretroviral therapy. 
Lung cancer in HIV-infected persons develops almost exclusively in smokers, but HIV infection appears to increase lung cancer risk independent of smoking status, by a factor of at least 2.5-fold. Compared with lung cancer patients in the general population, HIV-infected patients with lung cancer are significantly younger. Most patients with HIV infection and lung cancer present with advanced-stage disease and have significantly shorter median survival. 
Beryllium, nickel, copper, chromium, and cadmium have all been implicated in causing lung cancer.
Dietary fiber and vegetables have been suggested as protective from lung cancer. Although diets rich in fruits and vegetables appear to be associated with lower rates of lung cancer, trials of supplemental beta-carotene, alone or in combination with vitamin E or retinyl palmitate, in persons at high risk for lung cancer found that this supplementation actually increased the incidence of lung cancers. 
In the United States, lung cancer is the second most common cancer, after prostate cancer in men and breast cancer in women, but the most common cause of cancer deaths. The American Cancer Society projects that 228,150 cancers of the lung and bronchus will be diagnosed in the United States in 2019, with 142,670 deaths.  Approximately 85% of those cases are expected to be NSCLC.
In US men, the incidence of lung cancer has been decreasing since the mid-1980s. In US women, however, the rate has been decreasing only since the mid-2000s. From 2004 to 2013, the incidence of lung cancer decreased by 2% per year in men and by 1% per year in women. 
Lung cancer death rates for US women are among the highest in the world. Although in the United States, death rates are higher in men than in women, rates for US men are still lower than rates for men in several other countries.  These trends in US death rates parallel trends in smoking prevalence over the past 50 years. 
Lung cancer is the most commonly diagnosed cancer worldwide, and its incidence continues to grow. In 2018, an estimated 2.1 million new cases of lung cancer were diagnosed globally, accounting for approximately 11.6% of the global cancer burden. An estimated 1.76 million lung cancer deaths occurred in 2018.  Among all cancers, lung cancer now has the highest mortality rate in most countries, with industrialized regions such as North America and Europe having the highest rates.
Several differences exist in lung cancer incidence according to geographic area. The highest incidence occurs in Polynesia (38.1 cases per 100,000 population per year). The lowest incidence rate is in western Africa (approximately 1.7 cases per 100,000 population per year).  With increased smoking in developing countries, the incidence is expected to increase in the next few years, notably in China and India.
Generally, global lung cancer trends have followed the trends in smoking, with a lag time of several decades. Lung cancer incidence has been declining in several countries, including the United States, Canada, the United Kingdom, and Australia, following the decreasing rate of smoking. Lung cancer incidence among women, however, continues to increase in several parts of the globe, although it has begun to plateau in the United States. Notably, despite a very low rate of smoking, Chinese females have a higher incidence of lung cancer than European females.
Lung cancer occurs predominately in persons aged 50-70 years. The probability of developing lung cancer remains very low until age 39 years in both sexes. It then slowly starts to rise and peaks among those older than 70 years. The risk of developing lung cancer remains higher among men in all age groups after age 40 years.
Overall, lung cancer is more common in men than in women. In the United States, Northern Europe, and Western Europe, the prevalence of lung cancer has been decreasing in men. In Eastern and Southern European countries, the incidence of lung cancer has been rapidly increasing. Most Western countries have encountered a disturbing trend of increasing prevalence in women and younger patients. Women have a higher incidence of localized disease at presentation and of adenocarcinoma and typically are younger when they present with symptoms.
Over the past two decades, the incidence of lung cancer has generally decreased in both men and women 30 to 54 years of age in all races and ethnic groups. However, the incidence has declined more steeply in men. As a result, lung cancer rates in younger women have become higher than those in younger men. In non-Hispanic whites and Hispanics ages 44 to 49 years, for example, the female-to-male rate ratio for lung cancer incidence rose from 0.88 during 1995-1999 to 1.17 during 2010-2014. 
This reversal can be explained in part by increased rates of cigarette smoking in women born since 1965. However, while the difference in smoking rates in that age group has narrowed, rates in women have generally not exceeded the rates in men, so other factors may be playing a role. For example, women may be more susceptible to the oncogenic effects of smoking. 
Whereas lung cancer incidence rates are similar among African-American and white women, lung cancer occurrence is approximately 45% higher in African-American men than in white men.  This increased incidence has been attributed to differences in smoking habits; however, recent evidence suggests a slight difference in susceptibility.
From 1995-2001, the 5-year relative survival rate was 13% lower in African Americans compared with white individuals.  This racial gap persisted within each stage at diagnosis for both men and women.
Trends in 5-year survival rates in lung cancer from 1975-2003 revealed that while modest gains occurred in 5-year survival rates among whites, survival rates remained unchanged in the African-American population. Current 5-year survival rates are estimated to be 16% among whites and 13% among non-whites.
Lung cancer is highly lethal. In Europe, the 5-year overall survival rate is 12.3%. The highest recorded 5-year patient survival rates are observed in the United States. US data collected from 2009–2015 indicate that the 5-year relative survival rate for lung cancer was 19.4%, reflecting a steady but slow improvement from 12.5% in 1975. [23, 26] However, the 5-year relative survival rate varies markedly, depending on how advanced the disease is at diagnosis, as follows  :
Prognostic factors for NSCLC are summarized in the image below.
A retrospective Surveillance, Epidemiology, and End Results (SEER) data analysis suggests that the number of nodes with cancer may be predictive of survival. Mean lung cancer-specific survival decreased from 8.8 years for patients with one positive lymph node to 3.9 years for patients with more than eight positive lymph nodes. 
Patients with in situ and stage I lung cancer may respond to surgery. Their prognosis is far better than that of patients with more advanced disease. In patients with radiologically occult lung neoplasms, the 5-year survival rate is 24-26%; in those with abnormal chest radiographic findings, the rate is 12%. If the cancer is nonresectable, the prognosis is poor, with a mean survival rate of 8-14 months.
Mostertz et al found that in some patient populations, the oncogenic pathway activation profile of the tumor can have prognostic significance.  Retrospective analysis of 787 patients with predominantly early-stage NSCLC, using gene expression profiling, showed the following:
In patients younger than 70 years, high-risk patients, with the shortest recurrence-free survival, demonstrated increased activation of the Src and tumor necrosis factor (TNF) pathways.
In women, high-risk patients demonstrated increased activation of the invasiveness and signal transducer and activator of transcription 3 (STAT3) pathways.
Multivariate analyses confirmed the independent clinical relevance of the pathway-based subphenotypes in women and patients younger than 70 years.
A meta-analysis by Parsons et al suggests that smoking cessation after diagnosis of early-stage lung cancer may improve prognosis, probably by reducing cancer progression. Life table modelling on the basis of data from 9 studies gave an estimated 5-year survival rate of 33% in 65-year-old patients with early-stage NSCLC who continued to smoke compared with 70% in those who quit smoking. 
In an analysis of data on 4200 patients who participated in the National Comprehensive Cancer Network’s NSCLC Database Project, patients who were current smokers at the time of diagnosis had worse survival compared with patients who never smoked, and among younger patients with stage IV disease, current smokers had worse survival compared with former smokers who quit smoking more than 12 months before being diagnosed. 
Secondary analyses of the Women’s Health Initiative (WHI) randomized, placebo-controlled trial demonstrated an association between the use of daily conjugated equine estrogen (CEE, 0.625 mg) plus medroxyprogesterone acetate (MPA, 2.5 mg) and NSCLC. Women who used CEE plus MPA for more than 5 years were at increased risk for NSCLC, and women using CEE plus MPA who were diagnosed with NSCLC had higher mortality than women with NSCLC who do not take hormone therapy. 
The WHI analyses included 16,608 multiethnic postmenopausal women aged 50-79 years. Confirmation of lung cancers was completed by medical record review. This area deserves more attention and study to determine the risks and benefits of hormone therapy for postmenopausal women who smoke.
In contrast, a study by Bouchardy et al found that patients who had received antiestrogen treatment for breast cancer had a lower lung cancer mortality rate. However, use of antiestrogens did not significantly lower standardized incidence ratios for lung cancer. 
A review of eight trials by Rothwell et al found that allocation to daily aspirin reduced death caused by a variety of cancers, including adenocarcinoma of the lung (but no other form of lung cancer). A latent period of 5 years was observed before risk of death was decreased for lung cancer, but 20-year risk of cancer death remained lower in the aspirin groups. Benefit was unrelated to aspirin dose (75 mg or higher), sex, or smoking, but increased with age, with the absolute reduction in 20-year risk of cancer death reaching 7.08% at age 65 years and older. 
Although tumor-node-metastasis (TNM) staging is the best prognostic factor for NSCLC, a study by Hofman et al concluded that preoperative detection of circulating tumor cells (CTCs) has prognostic significance.  The results showed that the presence and level of 50 or more circulating nonhematologic cells (CNHC) were associated with worse survival among patients with resectable NSCLC. Although CTCs are potentially interesting, the significance of their presence is still being debated. 
In a 2012 retrospective review of 1402 consecutive stage I-III (N0-N1) NSCLC patients who underwent complete resection without adjuvant radiation therapy, significant risk factors for local recurrence included surgical procedure (single/multiple wedges + segmentectomy versus lobectomy + bilobectomy + pneumonectomy), visceral pleural invasion, and tumor size >2.7 cm. Significant risk factors for regional recurrence included pathologic N1 stage, lymphovascular space invasion, and visceral pleural invasion. 
In a study of 452 cases of stage I lung adenocarcinoma, thyroid transcription factor–1 (TTF-1) expression independently predicted the risk of disease recurrence. The 5-year cumulative incidence of recurrence was 40% for patients with negative TTF-1 expression, versus 15% for those with positive TTF-1 expression (P < 0.001. 
According to a 2013 retrospective analysis of 734 patients with stage I adenocarcinoma no larger than 2 cm, recurrence of small, early-stage adenocarcinoma after limited lung resection is three times more likely when the micropapillary component of the tumor is 5% or greater. In the 258 study patients who underwent wedge resection or segmentectomy, after adjustment for both vascular and lymphatic invasion, the presence of a micropapillary component of 5% or greater was independently associated with a 5-year cumulative incidence of recurrence (hazard ratio = 3.11). Micropapillary status was not significantly associated with recurrence in the 476 patients who underwent lobectomy. [38, 39]
Advise patients that smoking cessation is the most important measure for preventing lung cancer; it may also improve prognosis in patients with early-stage lung cancer.  Smoking cessation by others who share the patient’s home, car, or both is also important. According to published data, the use of nicotine alternatives (eg, gum, patch, spray) instead of cigarettes reduces the incidence of lung cancer, although it does not affect the incidence of ischemic heart disease.
Advise the patient to avoid asbestos exposure. Consider prophylactic administration of retinoids, such as beta-carotene.
Spiro SG, Gould MK, Colice GL. Initial evaluation of the patient with lung cancer: symptoms, signs, laboratory tests, and paraneoplastic syndromes: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest. 2007 Sep. 132(3 Suppl):149S-160S. [Medline].
Rowell NP, Williams CJ. Radical radiotherapy for stage I/II non-small cell lung cancer in patients not sufficiently fit for or declining surgery (medically inoperable): a systematic review. Thorax. 2001 Aug. 56(8):628-38. [Medline].
Strand TE, Brunsvig PF, Johannessen DC, et al. Potentially curative radiotherapy for non-small-cell lung cancer in Norway: a population-based study of survival. Int J Radiat Oncol Biol Phys. 2011 May 1. 80(1):133-41. [Medline].
Wang HM, Liao ZX, Komaki R, et al. Improved survival outcomes with the incidental use of beta-blockers among patients with non-small-cell lung cancer treated with definitive radiation therapy. Ann Oncol. 2013 Jan 8. [Medline].
Rosen G. A History of Public Health: Expanded Edition. Baltimore, MD.: The Johns Hopkins University Press; 1993.
American Cancer Society. Cancer Facts & Figures 2019. American Cancer Society. Available at https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf. Accessed: April 12, 2019.
[Guideline] Detterbeck FC, Lewis SZ, Diekemper R, Addrizzo-Harris D, Alberts WM. Executive Summary: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May. 143(5 Suppl):7S-37S. [Medline]. [Full Text].
National Research Council, Committee on Health Risks of Exposure to Radon, Board on Radiation Effects Research, Commission on Life Sciences. Health effects of exposure to radon (BEIR VI). Washington, DC.: National Academy Press.; 1999.
Ito H, Matsuo K, Tanaka H, et al. Nonfilter and filter cigarette consumption and the incidence of lung cancer by histological type in Japan and the United States: analysis of 30-year data from population-based cancer registries. Int J Cancer. 2011 Apr 15. 128(8):1918-28. [Medline].
Zhang J, Fujimoto J, Zhang J, et al. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science. 2014 Oct 10. 346(6206):256-9. [Medline].
de Bruin EC, McGranahan N, Mitter R, et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science. 2014 Oct 10. 346(6206):251-6. [Medline].
Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008 May. 83(5):584-94. [Medline]. [Full Text].
Nelson R. Lung Cancer Rates Surging in Never-Smokers. Medscape Medical News. Available at http://www.medscape.com/viewarticle/850708. September 9, 2015; Accessed: September 17, 2015.
Beckett WS. Epidemiology and etiology of lung cancer. Clin Chest Med. 1993 Mar. 14(1):1-15. [Medline].
Bagnardi V, Rota M, Botteri E, et al. Alcohol consumption and lung cancer risk in never smokers: a meta-analysis. Ann Oncol. 2011 Dec. 22(12):2631-9. [Medline].
Ginsberg RJ, Vokes EE, Raben A. Non-small cell lung cancer. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven;. 1997:858-911.
Lowry F. Physical Fitness Offsets Harmful Effects of Smoking. Medscape Medical News. May 30, 2019. Available at https://www.medscape.com/viewarticle/913712.
Zhong L, Goldberg MS, Parent ME, Hanley JA. Exposure to environmental tobacco smoke and the risk of lung cancer: a meta-analysis. Lung Cancer. 2000 Jan. 27(1):3-18. [Medline].
Alberg AJ, Brock MV, Ford JG, Samet JM, Spivack SD. Epidemiology of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May. 143(5 Suppl):e1S-29S. [Medline].
Hou W, Fu J, Ge Y, Du J, Hua S. Incidence and risk of lung cancer in HIV-infected patients. J Cancer Res Clin Oncol. 2013 Nov. 139(11):1781-94. [Medline].
Cortes-Jofre M, Rueda JR, Corsini-Munoz G, Fonseca-Cortes C, Caraballoso M, Bonfill Cosp X. Drugs for preventing lung cancer in healthy people. Cochrane Database Syst Rev. 2012 Oct 17. 10:CD002141. [Medline].
Ries L, Eisner M, Kosary C. Cancer statistics review, 1975-2002. National Cancer Institute.; 2005.
World Health Organization, International Agency for Research on Cancer. Globocan 2018: Lung Cancer. International Agency for Research on Cancer. Available at http://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf. Accessed: April 12, 2019.
Jemal A, Miller KD, Ma J, Siegel RL, Fedewa SA, Islami F, et al. Higher Lung Cancer Incidence in Young Women Than Young Men in the United States. N Engl J Med. 2018 May 24. 378 (21):1999-2009. [Medline].
SEER Stat Fact Sheets: Lung and Bronchus Cancer. Surveillance, Epidemiology, and End Results Program. Available at http://seer.cancer.gov/statfacts/html/lungb.html. Accessed: April 12, 2019.
Jonnalagadda S, Smith C, Mhango G, Wisnivesky JP. The Number of Lymph Node Metastases as a Prognostic Factor in Patients With N1 Non-small Cell Lung Cancer. Chest. 2011 Aug. 140(2):433-40. [Medline]. [Full Text].
Mostertz W, Stevenson M, Acharya C, et al. Age- and sex-specific genomic profiles in non-small cell lung cancer. JAMA. 2010 Feb 10. 303(6):535-43. [Medline].
Parsons A, Daley A, Begh R, Aveyard P. Influence of smoking cessation after diagnosis of early stage lung cancer on prognosis: systematic review of observational studies with meta-analysis. BMJ. 2010 Jan 21. 340:b5569. [Medline]. [Full Text].
Ferketich AK, Niland JC, Mamet R, et al. Smoking status and survival in the national comprehensive cancer network non-small cell lung cancer cohort. Cancer. 2012 Sep 28. [Medline].
Chlebowski RT, Schwartz WH, Anderson GL, et al. Non-small cell lung cancer and estrogen plus progestin use in postmenopausal women in the Women’s Health Initiative randomized clinical trial2009 American Society of Clinical Oncology (ASCO) Annual Meeting. J Clin Oncol. 2009. 27(suppl; abstr CRA1500):18s. [Full Text].
Bouchardy C, Benhamou S, Schaffar R, et al. Lung cancer mortality risk among breast cancer patients treated with anti-estrogens. Cancer. 2011 Mar 15. 117(6):1288-95. [Medline].
Rothwell PM, Fowkes GR, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomized trials. Lancet. Dec 7/2010; Early online publication. [Full Text].
Hofman V, Bonnetaud C, Ilie MI, et al. Preoperative circulating tumor cell detection using the isolation by size of epithelial tumor cell method for patients with lung cancer is a new prognostic biomarker. Clin Cancer Res. 2011 Feb 15. 17(4):827-35. [Medline].
Wicha MS, Hayes DF. Circulating tumor cells: not all detected cells are bad and not all bad cells are detected. J Clin Oncol. 2011 Apr 20. 29(12):1508-11. [Medline].
Lopez Guerra JL, Gomez DR, Lin SH, et al. Risk factors for local and regional recurrence in patients with resected N0-N1 non-small-cell lung cancer, with implications for patient selection for adjuvant radiation therapy. Ann Oncol. 2012 Sep 20. [Medline].
Kadota K, Nitadori JI, Sarkaria IS, et al. Thyroid transcription factor-1 expression is an independent predictor of recurrence and correlates with the IASLC/ATS/ERS histologic classification in patients with stage I lung adenocarcinoma. Cancer. 2012 Oct 23. [Medline].
Nitadori J, Bograd AJ, Kadota K, et al. Impact of Micropapillary Histologic Subtype in Selecting Limited Resection vs Lobectomy for Lung Adenocarcinoma of 2cm or Smaller. J Natl Cancer Inst. 2013 Aug 21. 105(16):1212-20. [Medline]. [Full Text].
Saunders R. Histologic Subtype Predicts Recurrence of Early Lung Adenocarcinoma. Medscape [serial online]. Available at http://www.medscape.com/viewarticle/809365. August 13, 2013; Accessed: April 12, 2019.
Corner J, Hopkinson J, Fitzsimmons D, Barclay S, Muers M. Is late diagnosis of lung cancer inevitable? Interview study of patients’ recollections of symptoms before diagnosis. Thorax. 2005 Apr. 60(4):314-9. [Medline]. [Full Text].
Ejaz S, Vassilopoulou-Sellin R, Busaidy NL, et al. Cushing syndrome secondary to ectopic adrenocorticotropic hormone secretion: the University of Texas MD Anderson Cancer Center Experience. Cancer. 2011 Oct 1. 117(19):4381-9. [Medline]. [Full Text].
Fadel E, Missenard G, Court C, et al. Long-term outcomes of en bloc resection of non-small cell lung cancer invading the thoracic inlet and spine. Ann Thorac Surg. 2011 Sep. 92(3):1024-30; discussion 1030. [Medline].
Patel AM, Davila DG, Peters SG. Paraneoplastic syndromes associated with lung cancer. Mayo Clin Proc. 1993 Mar. 68(3):278-87. [Medline].
Sher T, Dy GK, Adjei AA. Small cell lung cancer. Mayo Clin Proc. 2008 Mar. 83(3):355-67. [Medline].
Annema JT, van Meerbeeck JP, Rintoul RC, et al. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. JAMA. 2010 Nov 24. 304(20):2245-52. [Medline].
Oken MM, Hocking WG, Kvale PA, et al. Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial. JAMA. 2011 Nov 2. 306(17):1865-73. [Medline].
[Guideline] Mazzone PJ, Silvestri GA, Patel S, Kanne JP, Kinsinger LS, Wiener RS, et al. Screening for Lung Cancer: CHEST Guideline and Expert Panel Report. Chest. 2018 Apr. 153 (4):954-985. [Medline]. [Full Text].
Foster BB, Muller NL, Miller RR, et al. Neuroendocrine carcinomas of the lung: clinical, radiologic and pathologic correlation. Radiology. 1989. 170:441-445.
Alpert JB, Fantauzzi JP, Melamud K, Greenwood H, Naidich DP, Ko JP. Clinical Significance of Lung Nodules Reported on Abdominal CT. AJR Am J Roentgenol. 2012 Apr. 198(4):793-9. [Medline].
Gould MK, Maclean CC, Kuschner WG, Rydzak CE, Owens DK. Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions: a meta-analysis. JAMA. 2001 Feb 21. 285(7):914-24. [Medline].
Deppen SA, Blume JD, Kensinger CD, et al. Accuracy of FDG-PET to diagnose lung cancer in areas with infectious lung disease: a meta-analysis. JAMA. 2014 Sep 24. 312(12):1227-36. [Medline].
Erkilic S, Ozsarac C, Kullu S. Sputum cytology for the diagnosis of lung cancer. Comparison of smear and modified cell block methods. Acta Cytol. 2003 Nov-Dec. 47(6):1023-7. [Medline].
Billah S, Stewart J, Staerkel G, et al. EGFR and KRAS mutations in lung carcinoma: molecular testing by using cytology specimens. Cancer Cytopathol. 2011 Apr 25. 119(2):111-7. [Medline].
Arroliga AC, Matthay RA. The role of bronchoscopy in lung cancer. Clin Chest Med. 1993 Mar. 14(1):87-98. [Medline].
Schreiber G, McCrory DC. Performance characteristics of different modalities for diagnosis of suspected lung cancer: summary of published evidence. Chest. 2003 Jan. 123(1 Suppl):115S-128S. [Medline].
He J, Shao W, Cao C, et al. Long-term outcome and cost-effectiveness of complete versus assisted video-assisted thoracic surgery for non-small cell lung cancer. J Surg Oncol. 2011 Aug 1. 104(2):162-8. [Medline].
Mentzer SJ, Swanson SJ, DeCamp MM, Bueno R, Sugarbaker DJ. Mediastinoscopy, thoracoscopy, and video-assisted thoracic surgery in the diagnosis and staging of lung cancer. Chest. 1997 Oct. 112(4 Suppl):239S-241S. [Medline].
[Guideline] Lindeman NI, Cagle PT, Aisner DL, Arcila ME, Beasley MB, Bernicker EH, et al. Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018 Mar. 142 (3):321-346. [Medline]. [Full Text].
Chustecka Z. FDA approves companion genetic diagnostic test for Tarceva in NSCLC. Medscape Medical News. May 14, 2013. [Full Text].
Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar. 13(3):239-46. [Medline].
Janne PA, Shaw AT, Pereira JR, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2013 Jan. 14(1):38-47. [Medline].
American Joint Committee on Cancer. Lung. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, et al, eds. AJCC Cancer Staging Handbook. 8th ed. Chicago, Ill: Springer; 2017. Chapter 25.
Tintinalli JE. Emergency complications of malignancy. Emergency Medicine: A Comprehensive Guide. 2004. 1319-1368.
Halfdanarson TR, Hogan WJ, Moynihan TJ. Oncologic emergencies: diagnosis and treatment. Mayo Clin Proc. 2006 Jun. 81(6):835-48. [Medline].
[Guideline] National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Lung Cancer Screening. Available at http://www.nccn.org/professionals/physician_gls/pdf/lung_screening.pdf. Version 1.2020 — May 14, 2019; Accessed: June 15, 2019.
[Guideline] Wender R, Fontham ET, Barrera E Jr, Colditz GA, Church TR, Ettinger DS, et al. American Cancer Society lung cancer screening guidelines. CA Cancer J Clin. 2013 Mar-Apr. 63 (2):107-17. [Medline]. [Full Text].
[Guideline] U.S. Preventive Services Task Force. Final Recommendation Statement: Lung Cancer: Screening. Available at https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/lung-cancer-screening. December 20, 2016; Accessed: June 15, 2019.
Cheung LC, Katki HA, Chaturvedi AK, Jemal A, Berg CD. Preventing Lung Cancer Mortality by Computed Tomography Screening: The Effect of Risk-Based Versus U.S. Preventive Services Task Force Eligibility Criteria, 2005–2015. Ann Intern Med. 2 January 2018. [Full Text].
Kumar V, Cohen JT, van Klaveren D, Soeteman DI, Wong JB, Neumann PJ, et al. Risk-Targeted Lung Cancer Screening: A Cost-Effectiveness Analysis. Ann Intern Med. 2 January 2018. [Full Text].
Pastorino U, Silva M, Sestini S, Sabia F, Boeri M, Cantarutti A, et al. Prolonged lung cancer screening reduced 10-year mortality in the MILD trial: new confirmation of lung cancer screening efficacy. Ann Oncol. 2019 Jun 5. [Medline]. [Full Text].
Patz EF Jr, Pinsky P, Gatsonis C, et al. Overdiagnosis in low-dose computed tomography screening for lung cancer. JAMA Intern Med. 2013 Dec 9. [Medline].
Patz EF Jr, Greco E, Gatsonis C, Pinsky P, Kramer BS, Aberle DR. Lung cancer incidence and mortality in National Lung Screening Trial participants who underwent low-dose CT prevalence screening: a retrospective cohort analysis of a randomised, multicentre, diagnostic screening trial. Lancet Oncol. 2016 Mar 18. [Medline].
Kinsinger LS, Anderson C, Kim J, Larson M, Chan SH, King HA, et al. Implementation of Lung Cancer Screening in the Veterans Health Administration. JAMA Intern Med. 2017 Jan 30. [Medline]. [Full Text].
Castellino M. Lung Cancer Screening — Benefits Few, May Harm Many. Medscape Medical News. Available at http://www.medscape.com/viewarticle/875091. January 30, 2017; Accessed: June 15, 2019.
Katki HA, Kovalchik SA, Petito LC, Cheung LC, Jacobs E, Jemal A, et al. Implications of Nine Risk Prediction Models for Selecting Ever-Smokers for Computed Tomography Lung Cancer Screening. Ann Intern Med. 15 May 2018. [Full Text].
Jenkins K. Which Smokers Should Be Screened for Lung Cancer?. Medscape Medical News. Available at https://www.medscape.com/viewarticle/896582. May 14, 2018; Accessed: June 15, 2019.
Jenkins K. Blood Test to Identify Individuals for Lung Cancer Screening. Medscape Medical News. Available at https://www.medscape.com/viewarticle/899380. July 16, 2018; Accessed: June 15, 2018.
Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium for Early Detection of Lung Cancer., Guida F, Sun N, Bantis LE, et al. Assessment of Lung Cancer Risk on the Basis of a Biomarker Panel of Circulating Proteins. JAMA Oncol. 2018 Jul 12. e182078. [Medline].
Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004 Jan 22. 350(4):351-60. [Medline].
Greer JA, Jackson VA, Meier DE, Temel JS. Early integration of palliative care services with standard oncology care for patients with advanced cancer. CA Cancer J Clin. 2013 Sep. 63(5):349-63. [Medline].
Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010 Aug 19. 363(8):733-42. [Medline].
Yang CF, Kumar A, Gulack BC, Mulvihill MS, Hartwig MG, Wang X, et al. Long-term outcomes after lobectomy for non-small cell lung cancer when unsuspected pN2 disease is found: A National Cancer Data Base analysis. J Thorac Cardiovasc Surg. 2016 May. 151 (5):1380-8. [Medline].
Okada M, Nakayama H, Okumura S, et al. Multicenter analysis of high-resolution computed tomography and positron emission tomography/computed tomography findings to choose therapeutic strategies for clinical stage IA lung adenocarcinoma. J Thorac Cardiovasc Surg. 2011 Jun. 141(6):1384-91. [Medline].
Ma Z, Dong A, Fan J, Cheng H. Does sleeve lobectomy concomitant with or without pulmonary artery reconstruction (double sleeve) have favorable results for non-small cell lung cancer compared with pneumonectomy? A meta-analysis. Eur J Cardiothorac Surg. 2007 Jul. 32(1):20-8. [Medline].
Kates M, Swanson S, Wisnivesky JP. Survival following lobectomy and limited resection for the treatment of stage I non-small cell lung cancer<=1 cm in size: a review of SEER data. Chest. 2011 Mar. 139(3):491-6. [Medline].
Comparison of Different Types of Surgery in Treating Patients With Stage IA Non-Small Cell Lung Cancer. National Cancer Institute. Available at https://clinicaltrials.gov/ct2/show/NCT00499330. May 28, 2018; Accessed: June 15, 2019.
Yendamuri S, Sharma R, Demmy M, et al. Temporal trends in outcomes following sublobar and lobar resections for small (= 2 cm) non-small cell lung cancers–a Surveillance Epidemiology End Results database analysis. J Surg Res. 2013 Jul. 183(1):27-32. [Medline].
Okami J, Ito Y, Higashiyama M, et al. Sublobar resection provides an equivalent survival after lobectomy in elderly patients with early lung cancer. Ann Thorac Surg. 2010 Nov. 90(5):1651-6. [Medline].
Wolf AS, Richards WG, Jaklitsch MT, et al. Lobectomy versus sublobar resection for small (2 cm or less) non-small cell lung cancers. Ann Thorac Surg. 2011 Nov. 92(5):1819-23; discussion 1824-5. [Medline].
Cattaneo SM, Park BJ, Wilton AS, et al. Use of video-assisted thoracic surgery for lobectomy in the elderly results in fewer complications. Ann Thorac Surg. 2008 Jan. 85(1):231-5; discussion 235-6. [Medline].
[Guideline] National Comprehensive Cancer Network. National Comprehensive Cancer Network. Non-Small Cell Lung Cancer. NCCN. Available at https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Version 5.2019 — June 7, 2019; Accessed: June 15, 2019.
Swanson SJ, Herndon JE 2nd, D’Amico TA, et al. Video-assisted thoracic surgery lobectomy: report of CALGB 39802–a prospective, multi-institution feasibility study. J Clin Oncol. 2007 Nov 1. 25(31):4993-7. [Medline].
Darling GE, Allen MS, Decker PA, et al. Number of lymph nodes harvested from a mediastinal lymphadenectomy: results of the randomized, prospective American College of Surgeons Oncology Group Z0030 trial. Chest. 2011 May. 139(5):1124-9. [Medline]. [Full Text].
Allen JW, Farooq A, O’Brien TF, Osarogiagbon RU. Quality of surgical resection for nonsmall cell lung cancer in a US metropolitan area. Cancer. 2011 Jan 1. 117(1):134-42. [Medline].
Yun YH, Kim YA, Min YH, et al. Health-Related Quality of Life in Disease-Free Survivors of Surgically Treated Lung Cancer Compared With the General Population. Ann Surg. 2012 Mar 30. [Medline].
Dosoretz DE, Katin MJ, Blitzer PH, et al. Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies. Int J Radiat Oncol Biol Phys. 1992. 24(1):3-9. [Medline].
Jeremic B, Milicic B, Milisavljevic S. Clinical prognostic factors in patients with locally advanced (stage III) nonsmall cell lung cancer treated with hyperfractionated radiation therapy with and without concurrent chemotherapy: single-Institution Experience in 600 Patients. Cancer. 2011 Jan 10. [Medline].
Sigel K, Lurslurchachai L, Bonomi M, et al. Effectiveness of radiation therapy alone for elderly patients with unresected stage III non-small cell lung cancer. Lung Cancer. 2013 Sep 4. [Medline].
Onishi H, Shirato H, Nagata Y, Hiraoka M, Fujino M, Gomi K. Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study. J Thorac Oncol. 2007 Jul. 2(7 Suppl 3):S94-100. [Medline].
Grills IS, Mangona VS, Welsh R, et al. Outcomes after stereotactic lung radiotherapy or wedge resection for stage I non-small-cell lung cancer. J Clin Oncol. 2010 Feb 20. 28(6):928-35. [Medline].
Lencioni R, Crocetti L, Cioni R, Suh R, Glenn D, Regge D. Response to radiofrequency ablation of pulmonary tumours: a prospective, intention-to-treat, multicentre clinical trial (the RAPTURE study). Lancet Oncol. 2008 Jul. 9(7):621-8. [Medline].
Muirhead R, van der Weide L, van Sornsen de Koste JR, Cover KS, Senan S. Use of megavoltage cine-images for studying intra-thoracic motion during radiotherapy for locally advanced lung cancer. Radiother Oncol. 2011 May. 99(2):155-60. [Medline].
PORT Meta-analysis Trialists Group. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. Lancet. 1998 Jul 25. 352(9124):257-63. [Medline].
Rusch VW, Albain KS, Crowley JJ, et al. Surgical resection of stage IIIA and stage IIIB non-small-cell lung cancer after concurrent induction chemoradiotherapy. A Southwest Oncology Group trial. J Thorac Cardiovasc Surg. 1993 Jan. 105(1):97-104; discussion 104-6. [Medline].
Azzoli CG, Temin S, Aliff T, et al. 2011 Focused Update of 2009 American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer. J Clin Oncol. 2011 Oct 1. 29(28):3825-31. [Medline]. [Full Text].
Rosell R, Gomez-Codina J, Camps C, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med. 1994. 330:153-158. [Medline].
Roth JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst. 1994. 86:673-680. [Medline].
Sigel K, Mhango G, Cohen J, et al. Outcomes After Adjuvant Platinum-based Chemotherapy in Elderly NSCLC Patients with T4 Disease. Ann Surg Oncol. 2012 Nov 1. [Medline].
NSCLC Meta-Analyses collaborative Group. Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol. 2008 Oct 1. 26(28):4617-25. [Medline].
Marino P, Pampallona S, Preatoni A, et al. Chemotherapy vs supportive care in advanced non-small-cell lung cancer. Results of a meta-analysis of the literature. Chest. 1994 Sep. 106(3):861-5. [Medline].
Wanders R, Steevens J, Botterweck A, et al. Treatment with curative intent of stage III non-small cell lung cancer patients of 75 years: a prospective population-based study. Eur J Cancer. 2011 Dec. 47(18):2691-7. [Medline].
Wisnivesky JP, Smith CB, Packer S, et al. Survival and risk of adverse events in older patients receiving postoperative adjuvant chemotherapy for resected stages II-IIIA lung cancer: observational cohort study. BMJ. 2011 Jul 14. 343:d4013. [Medline]. [Full Text].
Weick JK, Crowley J, Natale RB, et al. A randomized trial of five cisplatin-containing treatments in patients with metastatic non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol. 1991 Jul. 9(7):1157-62. [Medline].
Rajeswaran A, Trojan A, Burnand B, Giannelli M. Efficacy and side effects of cisplatin- and carboplatin-based doublet chemotherapeutic regimens versus non-platinum-based doublet chemotherapeutic regimens as first line treatment of metastatic non-small cell lung carcinoma: a systematic review of randomized controlled trials. Lung Cancer. 2008 Jan. 59(1):1-11. [Medline].
Socinski MA, Bondarenko I, Karaseva NA, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012 Jun 10. 30(17):2055-62. [Medline].
Le Chevalier T, Scagliotti G, Natale R, et al. Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes. Lung Cancer. 2005 Jan. 47(1):69-80. [Medline].
Quoix E, Zalcman G, Oster JP, et al. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17. 378(9796):1079-88. [Medline].
Pallis AG, Karampeazis A, Vamvakas L, et al. Efficacy and treatment tolerance in older patients with NSCLC: a meta-analysis of five phase III randomized trials conducted by the Hellenic Oncology Research Group. Ann Oncol. 2011 Nov. 22(11):2448-55. [Medline].
Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20. 26(21):3543-51. [Medline].
Holm B, Mellemgaard A, Skov T, Skov BG. Different impact of excision repair cross-complementation group 1 on survival in male and female patients with inoperable non-small-cell lung cancer treated with carboplatin and gemcitabine. J Clin Oncol. 2009 Sep 10. 27(26):4254-9. [Medline].
Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014 Aug 23. 384(9944):665-73. [Medline].
Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Feb 1. 27(4):591-8. [Medline].
Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004 May 1. 22(9):1589-97. [Medline].
Ramlau R, Gorbunova V, Ciuleanu TE, et al. Aflibercept and Docetaxel versus Docetaxel alone after platinum failure in patients with advanced or metastatic non-small-cell lung cancer: a randomized, controlled phase III trial. J Clin Oncol. 2012 Oct 10. 30(29):3640-7. [Medline].
Dillman RO, Seagren SL, Propert KJ, et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med. 1990 Oct 4. 323(14):940-5. [Medline].
Le Chevalier T, Arriagada R, Quoix E, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Natl Cancer Inst. 1991 Mar 20. 83(6):417-23. [Medline].
Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol. 1995 Aug. 13(8):1880-92. [Medline].
Schaake-Koning C, van den Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non- small-cell lung cancer. N Engl J Med. 1992 Feb 20. 326(8):524-30. [Medline].
Albain KS, Swann RS, Rusch VR, et al. Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 9309). J Clin Oncol. 2005. 23:624s.
Curran WJ, Scott C, Langer C, et al. Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with unresected stage III non small cell lung cancer: RTOG 9410 (abstract). Proc Am Soc Clin Oncol. 2003. 22:621a.
Curran WJ, Scott C, Langer C, et al. Phase III Comparison of Sequential vs Concurrent Chemoradiation for Patients (Pts) with Unresected Stage III Non-Small Cell Lung Cancer (NSCLC): Initial Report of Radiation Therapy Oncology Group (RTOG) 9410. Proc Am Soc Clin Oncol. 2000. 19:484a.
Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol. 2005 Sep 1. 23(25):5883-91. [Medline].
Johnson DH, Paul DM, Hande KR, et al. Paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a phase II trial. J Clin Oncol. 1996 Jul. 14(7):2054-60. [Medline].
Langer CJ, Leighton JC, Comis RL, et al. Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer: a phase II toxicity, response, and survival analysis. J Clin Oncol. 1995 Aug. 13(8):1860-70. [Medline].
Hanna N, Neubauer M, Yiannoutsos C, et al. Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol. 2008 Dec 10. 26(35):5755-60. [Medline].
Curran WJ Jr, Paulus R, Langer CJ, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5. 103(19):1452-60. [Medline]. [Full Text].
Antonia SJ, et al; PACIFIC Investigators. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Nov 16. 377 (20):1919-1929. [Medline].
Schumacher A, Riesenbeck D, Braunheim M, et al. Combined modality treatment for locally advanced non-small cell lung cancer: preoperative chemoradiation does not result in a poorer quality of life. Lung Cancer. 2004 Apr. 44(1):89-97. [Medline].
van Meerbeeck JP, Kramer GW, Van Schil PE, Legrand C, Smit EF, Schramel F, et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst. 2007 Mar 21. 99 (6):442-50. [Medline].
Daly BD, Ebright MI, Walkey AJ, et al. Impact of neoadjuvant chemoradiotherapy followed by surgical resection on node-negative T3 and T4 non-small cell lung cancer. J Thorac Cardiovasc Surg. 2011 Jun. 141(6):1392-7. [Medline].
Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009 Sep 3. 361(10):958-67. [Medline].
Sequist LV, Yang JC, Yamamoto N, et al. Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. J Clin Oncol. 2013 Jul 1. [Medline].
Gilotrif (afatinib [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. January, 2018. Available at [Full Text].
Soria JC, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015 Aug. 16 (8):897-907. [Medline].
Lynch TJ, Bell DW, Sordella R. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004 May 20. 350(21):2129-39. [Medline].
Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005 Oct 29-Nov 4. 366(9496):1527-37. [Medline].
Douillard JY, Ostoros G, Cobo M, Ciuleanu T, McCormack R, Webster A, et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer. 2014 Jan 7. 110 (1):55-62. [Medline]. [Full Text].
Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010 Jun 24. 362 (25):2380-8. [Medline]. [Full Text].
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3. 361(10):947-57. [Medline].
Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker Analyses and Final Overall Survival Results From a Phase III, Randomized, Open-Label, First-Line Study of Gefitinib Versus Carboplatin/Paclitaxel in Clinically Selected Patients With Advanced Non-Small-Cell Lung Cancer in Asia (IPASS). J Clin Oncol. 2011 Jul 20. 29(21):2866-74. [Medline].
Shepherd FA, Pereira J, Ciuleanu TE, et al. A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial. J Clin Oncol. 2004. Vol 22, No 14S (July 15 Supplement):Abstract 7022.
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005 Jul 14. 353(2):123-32. [Medline].
Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011 Aug. 12(8):735-42. [Medline].
Gridelli C, Ciardiello F, Gallo C, et al. First-Line Erlotinib Followed by Second-Line Cisplatin-Gemcitabine Chemotherapy in Advanced Non-Small-Cell Lung Cancer: The TORCH Randomized Trial. J Clin Oncol. 2012 Aug 20. 30(24):3002-11. [Medline].
Herbst RS, Ansari R, Bustin F, et al. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet. 2011 May 28. 377(9780):1846-54. [Medline].
Hirsch FR, Kabbinavar F, Eisen T, et al. A randomized, phase II, biomarker-selected study comparing erlotinib to erlotinib intercalated with chemotherapy in first-line therapy for advanced non-small-cell lung cancer. J Clin Oncol. 2011 Sep 10. 29(26):3567-73. [Medline]. [Full Text].
Tagrisso (osimertinib) [package insert]. Wilmington, DE 19850: AstraZeneca Pharmaceuticals LP. April 2018. Available at [Full Text].
Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Nov. 18 (11):1454-1466. [Medline].
Mok TS, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, et al. Improvement in Overall Survival in a Randomized Study That Compared Dacomitinib With Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations. J Clin Oncol. 2018 Aug 1. 36 (22):2244-2250. [Medline].
Pirker R, Szczesna A, von Pawel J, et al. FLEX: A randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2008. 26:1006s (Abstract).
Pirker R, Pereira JR, von Pawel J, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol. 2012 Jan. 13(1):33-42. [Medline].
Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015 Jul. 16 (7):763-74. [Medline].
Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Nov 22. 379 (21):2040-2051. [Medline].
de Boer RH, Arrieta O, Yang CH, et al. Vandetanib Plus Pemetrexed for the Second-Line Treatment of Advanced Non-Small-Cell Lung Cancer: A Randomized, Double-Blind Phase III Trial. J Clin Oncol. 2011 Mar 10. 29(8):1067-74. [Medline].
Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14. 355(24):2542-50. [Medline].
Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10. 27(8):1227-34. [Medline].
Soria JC, Mauguen A, Reck M, et al. Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol. 2012 Nov 23. [Medline].
Stark, Angela. FDA approves first biosimilar for the treatment of cancer. FDA News Release. 09/14/2017. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm576112.htm.
Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014 Aug 23. 384 (9944):665-73. [Medline].
Crizotinib now standard of care for ALK+ NSCLC. Medscape Medical News. Available at http://www.medscape.com/viewarticle/771853. Accessed: Oct 16 2012.
Barclay L. Crizotinib Beats Chemo in ALK-Positive Advanced NSCLC. Medscape [serial online]. Available at http://www.medscape.com/viewarticle/805209. Accessed: June 24, 2013.
Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013 Jun 20. 368(25):2385-94. [Medline].
Kim DW, Tiseo M, Ahn MJ, Reckamp KL, Hansen KH, Kim SW, et al. Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial. J Clin Oncol. 2017 May 5. JCO2016715904. [Medline].
Soria JC, Tan DS, Chiari R, Wu YL, Paz-Ares L, Wolf J, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017 Mar 4. 389 (10072):917-929. [Medline].
Cho BC, et al. ASCEND-8: A Randomized Phase 1 Study of Ceritinib, 450 mg or 600 mg, Taken with a Low-Fat Meal versus 750 mg in Fasted State in Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Metastatic Non-Small Cell Lung Cancer (NSCLC). J Thorac Oncol. 2017 Sep. 12 (9):1357-1367. [Medline]. [Full Text].
Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Aug 31. 377 (9):829-838. [Medline]. [Full Text].
Hida T, Nokihara H, Kondo M, Kim YH, Azuma K, Seto T, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017 Jul 1. 390 (10089):29-39. [Medline]. [Full Text].
Solomon BJ, Besse B, Bauer TM, Felip E, Soo RA, Camidge DR, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018 Nov 6. [Medline].
Steuer CE, Khuri FR, Ramalingam SS. The next generation of epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of lung cancer. Cancer. 2014 Dec 17. [Medline].
Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015 Apr 30. 372 (18):1689-99. [Medline]. [Full Text].
Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Jan 11. 378 (2):113-125. [Medline].
ClinicalTrials.gov. Study of BMS-936558 (Nivolumab) Compared to Docetaxel in Previously Treated Advanced or Metastatic Squamous Cell Non-small Cell Lung Cancer (NSCLC) (CheckMate 017). NCT01642004.
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015 May 21. 372 (21):2018-28. [Medline].
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016 Oct 8. [Medline]. [Full Text].
Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 Apr 4. [Medline].
Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov. 17 (11):1497-1508. [Medline].
Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9. 387 (10027):1540-50. [Medline].
Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016 Apr 30. 387 (10030):1837-46. [Medline].
Barlesi F, Park K, Ciardiello F, von Pawel J, Gadgeel S, Hida T, et al. A randomized phase 3 study of atezolizumab (an engineered anti-PDL1 antibody) compared to docetaxel in patients with locally advanced or metastatic non-small cell lung cancer who have failed platinum therapy – “OAK”. ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT02008227. January 9, 2019; Accessed: June 15, 2019.
Karp DD, Paz-Ares LG, Novello S, et al. Phase II study of the anti-insulin-like growth factor type 1 receptor antibody CP-751,871 in combination with paclitaxel and carboplatin in previously untreated, locally advanced, or metastatic non-small-cell lung cancer. J Clin Oncol. 2009 May 20. 27(15):2516-22. [Medline].
FDA grants regular approval to dabrafenib and trametinib combination for metastatic NSCLC with BRAF V600E mutation. FDA.gov. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm564331.htm. June 22, 2017; Accessed: June 15, 2019.
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016 Nov 10. 375 (19):1823-1833. [Medline]. [Full Text].
Berner F, Bomze D, Diem S, et al. Association of Checkpoint Inhibitor-Induced Toxic Effects With Shared Cancer and Tissue Antigens in Non-Small Cell Lung Cancer. JAMA Oncol. 2019 Apr 25. [Medline]. [Full Text].
[Guideline] National Comprehensive Cancer Network. Management of Immunotherapy-Related Toxicities. NCCN. Available at https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Version 2.2019 — April 8, 2019; Accessed: August 1, 2019.
Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008 Jul 20. 26(21):3552-9. [Medline].
Strauss GM, Herndon JE 2nd, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol. 2008 Nov 1. 26(31):5043-51. [Medline]. [Full Text].
Gore EM, Bae K, Wong SJ, et al. Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small-cell lung cancer: primary analysis of radiation therapy oncology group study RTOG 0214. J Clin Oncol. 2011 Jan 20. 29(3):272-8. [Medline].
Sun A, Bae K, Gore EM, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: neurocognitive and quality-of-life analysis. J Clin Oncol. 2011 Jan 20. 29(3):279-86. [Medline].
Lynch TJ, Patel T, Dreisbach L, et al. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol. 2010 Feb 20. 28(6):911-7. [Medline].
Biesma B, Wymenga AN, Vincent A, et al. Quality of life, geriatric assessment and survival in elderly patients with non-small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study. Ann Oncol. 2011 Jul. 22(7):1520-7. [Medline].
Raz DJ, Lanuti M, Gaissert HC, et al. Outcomes of patients with isolated adrenal metastasis from non-small cell lung carcinoma. Ann Thorac Surg. 2011 Nov. 92(5):1788-92; discussion 1793. [Medline].
Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009 Oct 24. 374(9699):1432-40. [Medline].
Belani CP, Brodowicz T, Ciuleanu TE, et al. Quality of life in patients with advanced non-small-cell lung cancer given maintenance treatment with pemetrexed versus placebo (H3E-MC-JMEN): results from a randomised, double-blind, phase 3 study. Lancet Oncol. 2012 Mar. 13(3):292-9. [Medline].
Paz-Ares L, de Marinis F, Dediu M, et al. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012 Mar. 13(3):247-55. [Medline].
[Guideline] Masters GA, Temin S, Azzoli CG, Giaccone G, Baker S Jr, Brahmer JR, et al. Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015 Oct 20. 33 (30):3488-515. [Medline]. [Full Text].
Jorenby DE, Leischow SJ, Nides MA, et al. A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med. 1999 Mar 4. 340(9):685-91. [Medline].
Mallin R. Smoking cessation: integration of behavioral and drug therapies. Am Fam Physician. 2002 Mar 15. 65(6):1107-14. [Medline].
Jaklitsch MT, Jacobson FL, Austin JH, Field JK, Jett JR, Keshavjee S, et al. The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups. J Thorac Cardiovasc Surg. 2012 Jul. 144 (1):33-8. [Medline].
[Guideline] Kalemkerian GP, Narula N, Kennedy EB, Biermann WA, Donington J, Leighl NB, et al. Molecular Testing Guideline for the Selection of Patients With Lung Cancer for Treatment With Targeted Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline Update. J Clin Oncol. 2018 Mar 20. 36 (9):911-919. [Medline]. [Full Text].
[Guideline] Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018 Oct 1. 29 (Supplement_4):iv192-iv237. [Medline]. [Full Text].
Hanna N, Johnson D, Temin S, Baker S Jr, Brahmer J, Ellis PM, et al. Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2017 Aug 14. JCO2017746065. [Medline]. [Full Text].
[Guideline] Rodrigues G, Choy H, Bradley J, Rosenzweig KE, Bogart J, Curran WJ Jr, et al. Adjuvant radiation therapy in locally advanced non-small cell lung cancer: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based clinical practice guideline. Pract Radiat Oncol. 2015 May-Jun. 5 (3):149-55. [Medline]. [Full Text].
[Guideline] Rodrigues G, Choy H, Bradley J, Rosenzweig KE, Bogart J, Curran WJ Jr, et al. Definitive radiation therapy in locally advanced non-small cell lung cancer: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based clinical practice guideline. Pract Radiat Oncol. 2015 May-Jun. 5 (3):141-8. [Medline]. [Full Text].
[Guideline] Bezjak A, Temin S, Franklin G, Giaccone G, Govindan R, Johnson ML, et al. Definitive and Adjuvant Radiotherapy in Locally Advanced Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline. J Clin Oncol. 2015 Jun 20. 33 (18):2100-5. [Medline]. [Full Text].
Planchard D, Kim TM, Mazieres J, Quoix E, Riely G, Barlesi F, et al. Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016 May. 17 (5):642-50. [Medline]. [Full Text].
D’Addario G, Fruh M, Reck M, Baumann P, Klepetko W, Felip E. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010 May. 21 Suppl 5:v116-9. [Medline]. [Full Text].
Alecensa (alectinib) [package insert]. South San Francisco, CA: Genentech USA, Inc. December, 2015. Available at [Full Text].
Ou SI, Ahn JS, De Petris L, Govindan R, Yang JC, Hughes B, et al. Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. J Clin Oncol. 2015 Nov 23. [Medline].
Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening. N Engl J Med. 2011 Jun 29. [Medline].
Gohagan J, Marcus P, Fagerstrom R, Pinsky P, Kramer B, Prorok P. Baseline findings of a randomized feasibility trial of lung cancer screening with spiral CT scan vs chest radiograph: the Lung Screening Study of the National Cancer Institute. Chest. 2004 Jul. 126(1):114-21. [Medline].
Nelson R. USPSTF finalizes recommendations for lung cancer screening. Medscape Medical News. December 30, 2013. [Full Text].
Mekinist (trametinib) [package insert]. East Hanover, New Jersey 07936: Novartis Pharmaceuticals Corporation. 06/2017. Available at [Full Text].
Tafinlar (dabrafenib) [package insert]. East Hanover, New Jersey 07936: Novartis Pharmaceuticals Corporation. June 2017. Available at [Full Text].
Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Nov 16. 377 (20):1919-1929. [Medline].
Winston W Tan, MD, FACP Associate Professor of Medicine, Mayo Medical School; Consultant and Person-in-Charge of Genitourinary Oncology-Medical Oncology, Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic Jacksonville; Vice Chairman, Division of Hematology/Oncology Education, Chair, Cancer Survivorship Program, Associate Chair, Department of Medicine Faculty Development, Mayo Clinic Florida; Vice President, Florida Society of Clinical Oncology
Winston W Tan, MD, FACP is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, American Society of Hematology, Philippine Medical Association, Texas Medical Association
Disclosure: Nothing to disclose.
Syed Huq, MD Fellow, Division of Hematology-Oncology, Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Ellis Fischel Cancer Center
Disclosure: Nothing to disclose.
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Nagla Abdel Karim, MD, PhD Associate Professor of Medicine, Associate Director of Experimental Therapeutics, Division of Hematology/Oncology, University of Cincinnati Cancer Institute, Department of Internal Medicine, University of Cincinnati College of Medicine
Nagla Abdel Karim, MD, PhD is a member of the following medical societies: American Medical Association, American Society of Clinical Oncology, Egyptian American Medical Association, Egyptian Cancer Society, International Association for the Study of Lung Cancer
Disclosure: Nothing to disclose.
Jeffrey L Arnold, MD, FACEP Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center
Disclosure: Nothing to disclose.
Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine, Professor of Internal Medicine, Program Director for Emergency Medicine, Case Medical Center, University Hospitals, Case Western Reserve University School of Medicine
Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency Physicians, American College of Physicians, American Heart Association, American Thoracic Society, Arkansas Medical Society, New York Academy of Medicine, New York Academy of Sciences, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Gino A Farina, MD, FACEP, FAAEM Associate Professor of Emergency Medicine, Hofstra North Shore LIJ School of Medicine and Albert Einstein College of Medicine; Program Director, Department of Emergency Medicine, Long Island Jewish Medical Center
Gino A Farina, MD, FACEP, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Edmond A Hooker II, MD, DrPH, FAAEM Associate Professor, Department of Health Services Administration, Xavier University, Cincinnati, Ohio; Assistant Professor, Department of Emergency Medicine, University of Cincinnati College of Medicine
Edmond A Hooker II, MD, DrPH, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American Public Health Association, Society for Academic Emergency Medicine, and Southern Medical Association
Disclosure: Nothing to disclose.
Irfan Maghfoor, MD Consulting Oncologist, Department of Oncology, King Faisal Specialist Hospital and Research Center, Saudi Arabia
Irfan Maghfoor, MD is a member of the following medical societies: American Society of Hematology
Disclosure: Nothing to disclose.
Tamas Peredy, MD Assistant Professor, Department of Emergency Medicine, Maine Medical Center
Disclosure: Nothing to disclose.
Michael Perry, MD, MS, MACP Nellie B Smith Chair of Oncology Emeritus, Director, Division of Hematology and Medical Oncology, Deputy Director, Ellis Fischel Cancer Center, University of Missouri-Columbia School of Medicine
Michael Perry, MD, MS, MACP is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, International Association for the Study of Lung Cancer, and Missouri State Medical Association
Disclosure: Nothing to disclose.
Peter T Porrello, MD, FACEP Clinical Instructor, Department of Emergency Medicine, Yale University School of Medicine; Chief Medical Informatics Officer, Consulting Staff, Waterbury Hospital
Disclosure: Nothing to disclose.
Mityanand Ramnarine, MD Chief Resident Physician, Department of Emergency Medicine, Albert Einstein College of Medicine at Long Island Jewish Medical Center
Mityanand Ramnarine, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians, Emergency Medicine Residents Association, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
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