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What to Know About Lung Cancer

Lung cancer originates in the lungs, but it can spread. Abnormal cells grow and can form tumors. A series of mutations in the DNA of the cell creates cancer. Each individual is unique, so survival rates, treatments and symptoms vary by patient. Here are a few basics things to know.

Who Gets Lung Cancer?

Anyone can get lung cancer at any age but some risks create red flags. Smoking is considered the highest risk factor, but non-smokers can also get lung cancer. A family history is another factor. Exposure to secondhand smoke, radon gas or asbestos has been seen as a contributing risk for lung cancer.

What Are the Symptoms?

Symptoms may not appear in the early stages of lung cancer. Some of these symptoms include coughing, hoarse voice, shortness of breath, headache and weight loss. While these symptoms can be indicators of lung cancer, they can also be indicators of other illnesses or conditions. Only a medical physician can diagnose the disease.

What Tests Are Used?

Doctors may order a series of tests before diagnosing a patient with cancer. Tests for lung cancer can include X-rays, CT scans and biopsies to analyze tissue. A sputum cytology examines mucus for abnormalities. A bronchoscopy is a tube with a camera that looks inside the body at the lungs.

Stages of Cancer

Generally speaking, stages of cancer categorize how the lung cancer has advanced. Stage one is when a tumor is less than five centimeters and is contained in the lung. Stage two is when the tumor is larger than five centimeters and has affected surrounding tissue like the diaphragm and chest wall. Stage three indicates the cancer has reached other organs. Stage four is when the cancer has affected the other lung or distant places within the body.

Treatment Options

Treatments for lung cancer include many options. There’s surgery to remove a tumor, damaged tissue or part of the affected lung. Chemotherapy uses drugs to eradicate cancer cells. Radiation therapy targets specific areas and kills cancer cells. The medical team may use a combination of treatments.


research paper on causes of lung cancer

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Lung cancer: biology and treatment options

Hassan lemjabbar-alaoui.

a Department of Surgery, Thoracic Oncology Division, University of California, San Francisco 94143, USA.

Omer Hassan

Yi-wei yang, petra buchanan.

Lung cancer remains the leading cause of cancer mortality in men and women in the U.S. and worldwide. About 90% of lung cancer cases are caused by smoking and the use of tobacco products. However, other factors such as radon gas, asbestos, air pollution exposures, and chronic infections can contribute to lung carcinogenesis. In addition, multiple inherited and acquired mechanisms of susceptibility to lung cancer have been proposed. Lung cancer is divided into two broad histologic classes, which grow and spread differently: small-cell lung carcinomas (SCLC) and non-small cell lung carcinomas (NSCLC). Treatment options for lung cancer include surgery, radiation therapy, chemotherapy, and targeted therapy. Therapeutic-modalities recommendations depend on several factors, including the type and stage of cancer. Despite the improvements in diagnosis and therapy made during the past 25 years, the prognosis for patients with lung cancer is still unsatisfactory. The responses to current standard therapies are poor except for the most localized cancers. However, a better understanding of the biology pertinent to these challenging malignancies, might lead to the development of more efficacious and perhaps more specific drugs. The purpose of this review is to summarize the recent developments in lung cancer biology and its therapeutic strategies, and discuss the latest treatment advances including therapies currently under clinical investigation.

1. Introduction

Lung cancer, a highly invasive, rapidly metastasizing and prevalent cancer, is the top killer cancer in both men and women in the United States of America (USA). During 2014, an estimated 224,210 new cases and 159,260 deaths for lung cancer were predicted in the USA [ 1 ]. It causes more deaths per year than the next four leading causes of cancer (Colon/rectal, breast, pancreas, and prostate) death combined in the United States. Its incidence and mortality patterns are consistently associated with 20 or more years of smoking history. The individual susceptibility to tobacco-induced lung cancer may be dependent on competitive gene–enzyme interactions that affect activation or detoxification of procarcinogens and levels of DNA adduct formation as well as determined by the integrity of endogenous mechanisms for repairing lesions in DNA. Lung cancer is highly heterogeneous that can arise in many different sites in the bronchial tree, therefore presenting highly variable symptoms and signs depending on its anatomic location. 70% of patients diagnosed with lung cancer present with advanced stage disease (stage III or IV) ( Figure.1 ).

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Schematic illustration of the Non-Small Lung Cancer (NSCLC) staging. Of note, Squamous cell lung carcinomas arise in the epithelial cells of main and lobar Bronchi (not shown), whereas Adenocarcinomas originate in the peripheral lung tissue and arise in the epithelial cells of segmental bronchi. For stage IV NSCLC cancers, the incidence of distant metastasis to the extrathoracic organs is depicted. For each organ, the percentages represent the incidence of metastasis for squamous cell lung carcinomas and adenocarcinomas, respectively.

Squamous cell lung cancers (SQCLC) represent about 25%–30% of all lung cancers and tend to arise in the main bronchi and advance to the carina ( Table 1 ). Adenocarcinomas (AdenoCA) account for approximately 40% of all lung cancers and consist of tumors arising in peripheral bronchi. AdenoCAs advance by producing lobar atelectasis and pneumonitis. Bronchioloalveolar cancers (BAC), now reclassified into adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), arise in alveoli and spread through the interalveolar connections. AIS and MIA describe patients with very good disease-free survival after complete resection (5-year rate nears 100%) [ 2 , 3 ]. Small cell lung cancers (SCLC) derived from the hormonal cells of the lung, are the most dedifferentiated cancers and tend to be central mediastinal tumors. SCLCs comprise 10%–15% of all lung cancers, and are extremely aggressive disseminating rapidly into submucosal lymphatic vessels and regional lymph nodes, and almost always present without a bronchial invasion. Large cell anaplastic carcinomas (LCAC), also termed NSCLC not otherwise specified (NOS), are more proximal in location and locally tend to invade the mediastinum and its structures early. NSCLC-NOS comprises about 10% of all NSCLC. and behaves similarly to small cell cancers with a rapid fatal spread. Pancoast cancer arises in superior sulcus and advances by local invasion into juxta-opposed structures. All lung cancer types can become multifocal in the lobe they arise in (T3), or spread into the lung of origin (T4), or spread to the contralateral lung (M1) ( Figure.1 ) [ 3 ]. The compression of mediastinal structures is associated invariably with advanced lymph node involvement, which can lead variously to esophageal compression and difficulty in swallowing, venous compression and congestion associated with collateral circulation, or tracheal compression. Signs of metastatic disease involving such remote sites as the liver, brain, or bone are seen before any knowledge of a primary lung lesion.

Types of Lung Cancer.

2. International Staging System for Lung Cancer

Cancer staging is a critical step in the diagnosis process, and its objectives are multifarious including 1) Helping the clinician to recommend a treatment plan; 2) Giving some indication of prognosis; 3) Aiding in the evaluation of the results of treatment; 4) Facilitating the exchange of information between treatment centers; 5) Contributing to the continuing investigation of human cancer. The international TNM-based staging system describes the anatomical extent of the disease ( Table 3 ). The T category describes the size and extent of the primary tumor. The N category describes the extent of involvement of regional lymph nodes. The M category describes the presence or absence of distant metastatic spread. The addition of numbers to these categories describes the extent of the cancer. All possible combinations of the T, N, and M categories are then used to create TNM subsets ( Table 2 ). TNM subsets with similar prognoses are then combined into stage groupings. NSCLC stages range from one to four (I through IV). The lower the stage, the less the cancer has spread. SCLC is defined using two stages: Limited (confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes) and extensive (spread beyond the supraclavicular areas) [ 4 ].

TNM stage grouping for NSCLC. TNM stand for the size and location of the T umor, the location of cancer in the lymph N odes and where the cancer has spread ( M etastases).

T = Primary tumor: T 1a (Tumor size ≤2 cm), T 1b (>2–3 cm): T 2a (>3–5 cm), T 2b (>5–7 cm); T 3 (>7 cm) and/or (Multiple tumor nodules in the same lobe); T 4 (Multiple tumor nodules (of any size) in the same lung but a different lobe).

N 0 = No regional lymph node metastasis; N 1 = Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension; N 2 = Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s); N 3 = Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s).

M = Distant metastasis: M 1a (Malignant pleural or pericardial effusions and/or Separate tumor nodules in the contralateral lung); M 2b (Distant metastasis in extrathoracic organs).

TNM-based staging system.

The term stage, without further classification, relates to the pretreatment, clinical stage or cTNM [ 3 , 5 – 7 ]. cTNM is derived using the evidence available from clinical history and examination, blood tests, imaging, endoscopic examination, biopsy material, surgical examination, and any other test considered necessary prior to making a decision as to the appropriate treatment in any individual. If this decision leads to surgical treatment, then additional information becomes available at surgery and by pathological examination allowing a more accurate assessment of disease indicated by the pathological, postsurgical stage or pTNM. pTNM does not replace the cTNM, which should remain as a record in the patient’s notes. If the patient undergoes preoperative “induction” therapy, usually with either or both chemotherapy and radiotherapy, then a reassessment is made after this treatment, prior to a final decision on surgical treatment [ 3 , 5 – 7 ]. The evidence available from this process is used to create the ycTNM, and after surgical treatment in these circumstances, the postsurgical pathological extent of disease is described as ypTNM. At various points in the patient’s journey, events may allow or demand a reassessment of disease extent. An rTNM may be established if relapse occurs after a disease-free interval. An aTNM may be formulated if the disease is first discovered at an autopsy. In each case, previous assessments of TNM are retained in the patient records [ 3 , 5 – 7 ].

3. Lung cancer biology

Lung cancer cells have defects in the regulatory circuits that govern normal cell proliferation and homeostasis. The transformation from a normal to malignant lung cancer phenotype is thought to arise in a multistep fashion, through a series of genetic and epigenetic alterations, ultimately evolving into invasive cancer by clonal expansion [ 8 , 9 ]. Following the development of the primary cancer, continued accumulation of genetic and epigenetic abnormalities, acquired during clonal expansion, influences the processes of invasion, metastasis, and resistance to cancer therapy [ 8 , 9 ]. The identification and characterization of these molecular changes are of critical importance for improving disease prevention, early detection, and treatment. The knowledge of both a patient’s tumor characteristics and genetics will significantly advance the personalized prognosis and ideal treatment selection for each patient.

3.1. Genomic alterations

Recently, the Cancer Genome Atlas Research Network reported the molecular profiling of 230 lung adenocarcinomas. High somatic mutation rates were seen from the whole-exome sequencing (mean 8.87 mutations per megabase of DNA). Eighteen genes were identified to be significantly mutated both in the abovementioned 230 AdenoCA cases as well as in 182 AdenoCA tumors previously analyzed in similar fashion. Genomic alterations include point mutations (missense and nonsense mutations, frameshift and slicing site alterations), rearrangement (transversions and transitions) as well as somatic copy number alterations [ 10 ]. The alterations of kinase protein levels or activities have also been studied. Using RNA-seq analysis in 7000 tumors (20 solid cancer types), novel and recurrent kinase gene fusion events were identified. In lung adenocarcinomas (513 samples), fusion events were found in ROS1, RET, PRKCB, NTRK, MET and ALK genes and were found in PRKCB, PRKCA, PKN1, FGR, FGFR1, FGFR2 an FGFR3 genes in lung squamous cell carcinomas (492 samples) ( Table 5 ) [ 11 ]. These findings may have significant clinical impact and new therapeutic approaches could be developed targeting these alterations. Another large systematic genomic study reclassified 12 tumor types into 11 subtypes based on the sequencing data from 3527 tumor cases (DNA copy number, DNA methylation, mRNA expression, microRNA expression, protein expression and somatic point mutation). Somatic mutations such as KEAP1 and STK11 are preferentially mutated in LUAD-enriched tumors group, containing most of the lung adenocarcinoma cases, while CDKN2A, NOTCH1, MLL2 and NFE2L2 were found mutated preferentially in squamous-like tumors group encompassing most of the lung squamous cell carcinoma cases. Squamous-like tumors also showed frequent MYC amplification and loss of CDKN2A, RB1 and TP53. The reclassification generated new prognostic information that could be used to guide therapeutic decision [ 12 ].

Kinase fusion events identified in AdenoCA and SQCLC [ 12 ]

3.2. Molecular pathology of lung cancer

Several targetable genetic alterations have been identified in lung cancer [ 13 ] ( Table 6 ), including 1) Activating mutations in a number of proto-oncogenes including KRAS, EGFR, BRAF, PI3K, MEK and HER2. Noteworthy, EGFR (Epidermal growth factor receptor) plays a critical role in regulating normal cell proliferation, apoptosis, and other cellular functions. Approximately 10% of NSCLC patients in the US and 35% in East Asia have tumor associated EGFR mutations [ 14 – 16 ]. 2) Structural rearrangements in ALK, ROS1 and possibly RET. 3) Amplification of proto-oncogenes such as MET in adenocarcinomas, FGFR1 and DDR2 in squamous cell lung carcinomas. 4) Oncogenic gene overexpression by microRNAs (miRNAs). 5) Inactivation of Tumor Suppressor Genes (TSG), including TP53, RB1, CDKN2A, FHIT, RASSF1A, and PTEN. 6) Enhanced telomerase activity, which contributes to cellular immortality by maintaining telomere length through de novo synthesis of telomeres and elongation of existing telomeres (100% of SCLCs and 80% to 85% of NSCLCs). The hTERT gene is amplified in 57% of NSCLCs.

Oncogenes and tumor suppressor genes altered in NSCLC [ 14 ].

Remarkably, scores of the aforementioned aberrations correlate with patient’s smoking history as well as with racial and gender differences, which suggest a possible role of the host’s genetic makeup as key determinants in lung carcinogenesis [ 8 , 9 ].

3.3. Clinical applications

Tremendous work has been conducted to translate the acquired information of these genetic anomalies into improvement of patient care in the clinic including early detection and treatment and prognosis prediction:

Platinum-based regimens are standard of care in advanced lung cancer. However, their clinical effectiveness is limited by cumulative haemato- and neuro-toxicities highlighting the need for alternative treatment strategies. ERCC1 functions as a key enzyme in nucleotide excision repair (NER). Low ERCC1 expression correlates with increased sensitivity to platinum-based therapy and high ERCC1 expression correlates with better overall prognosis in NSCLC [ 18 , 19 ]. Nearly 50% of NSCLC patients have low levels of ERCC1, and therefore could benefit from alternative therapies exploiting this tumor ERCC1 deficiency [ 19 ]. RRM1 is the regulatory subunit of ribonucleotide reductase essential for the deoxyribonucleotides (dNTP) synthesis.

RRM1 is the main target for the antimetabolite drug gemcitabine, which is an underpinning cancer therapy in the treatment of many malignancies including lung cancer. Gemcitabine directly binds to RRM1 and irreversibly inactivates ribonucleotide reductase [ 20 – 28 ]. High RRM1 levels are associated with tumor resistance and low RRM1 levels with tumor sensitivity to gemcitabine treatment [ 21 , 23 , 25 – 28 ].

Recent studies have suggested that low levels of the heparan sulfate 6-O-endosulfatase (SULF2) through methylation in NSCLC may be predictive of better survival and increase sensitivity to topoisomerase-1 inhibitors (TPI) [ 29 ]. SULF2 is overexpressed in many tumors including lung adenocarcinomas and lung squamous carcinomas to remove critical sulfation modifications from sulfated heparin sulfate proteoglycans (HSPGs) and thus release growth factors essential for tumor growth [ 30 – 32 ]. It was established that SULF2 methylation via induction of high expression of Ubiquitin-Like Modifier (ISG15) sensitizes lung cancer cells to TPIs via suppression of ubiquition and proteasomal degradation [ 29 ].

A number of new potentially targetable alterations were identified in NSCLC including FGFR1 amplification and DDR1 mutation found in squamous cell lung carcinomas. These alterations might be important prognostic and predictive factors for patient’s response to treatments with FGFR inhibitors or DDR1 inhibitors (e.g., Dasatinib) [ 33 , 34 ].

3.4. Tumor microenvironment

The tumor microenvironment and the complex interactions of its various cell types and their released signaling molecules are an emerging hallmark of cancer [ 46 ]. It consists of stromal cells, cancer-associated fibroblasts, stem cells and a comprehensive set of immune cells recruited into tumors. The tumor microenvironment is altered to suppress host immune responses, foster tumor growth, and help cancer cells evade immune surveillance [ 47 ]. The tumor-associated immune cells include tumor-associated macrophages (TAM), dendritic cell (DC) subsets, cytotoxic and regulatory T-cells (CTLs and Tregs), natural killer (NK) cells, and myeloid-derived suppressor cells (MDSC). The amounts of different immune cell subsets in the tumor microenvironment can vary considerably among patients and may be used as a predictor of treatment outcome and survival in certain cancers [ 48 – 50 ]. The altered tumor microenvironment is established by the cancer cells through the loss of MHC class I molecules, the loss of antigen variants, and the active secretion of several growth factors, such as vascular endothelial growth factor (VEGF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) [ 51 ]. The immune cells present in the tumor microenvironment are functionally impaired, and the newly infiltrating immune cells become alternatively activated, resulting in a perturbed phenotype [ 51 ]..

Myeloid cells including myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells (DC), can act as regulatory cells in the tumor microenvironment. MDSCs exert their pro-tumor effects through the inhibition of T-cell proliferation and activation by increasing levels of NO synthase and arginase-1 [ 52 ] [ 51 , 53 , 54 ], releasing IL-10 and overproducing reactive oxygen species (ROS) [ 55 ]. In the peripheral blood of advanced stage NSCLC patients, increased levels of MSDC were detected compared to healthy controls and were associated with lower levels of CD8+ T-cells [ 56 ].

Tumor-associated macrophages (TAM) show a higher frequency of the pro-tumor M2-phenotype, which accumulate in the tumor stroma and correlate with poor patient outcome and decreased OS [ 57 ]. These alternatively activated macrophages show impaired ability to present antigen and appropriate co-stimulation to T-cells [ 51 ]. In contrast, macrophages of the M1 phenotype accumulate intratumorally and show antitumor functions through expression of HLA-DR, inducible nitric oxide synthase (iNOS) and TNF-α [ 58 ]. Furthermore, a high intratumoral density of CD68+ macrophages correlates with increased survival in NSCLC [ 59 ].

DCs are the most important antigen-presenting cells at the border of the innate and adaptive immune system. However, in the tumor microenvironment, DCs are often in an immature state that fail to prime T-cells efficiently due to low expression levels of co-stimulatory molecules such as CD80 and CD86 and a weak antigen presenting capacity [ 60 , 61 ]. Peripheral blood lymphocytes can also be used as a prognostic marker in NSCLC: 1) the total blood count of lymphocytes was shown to be associated with a lower hazard ratio for death [ 57 , 62 ]; 2) a neutrophil to lymphocyte ratio (NLR) >3.81 was identified in the same study as a predictor of survival in patients with Stage I NSCLC; 3)Treg cells were also detected at elevated levels in the peripheral blood of NSCLC patients compared to healthy controls [ 63 , 64 ].

In early-stage NSCLC, a tertiary lymphoid structure is detected in the tumor stroma that contains mature and follicular DC, CD4+ T-cells, and CD20+ B-cells. This tertiary lymphoid structure is defined as Tumor-induced Bronchus Associated Lymphoid Tissues (Ti-BALT) [ 48 , 65 ]. A small retrospective study demonstrated that the density of mature DC (DC-LAMP +) homing in the Ti-BALT correlates with disease-free survival, disease-specific survival, and OS in early-stage NSCLC patients [ 48 ].

Chronic inflammation can also play a significant role in the tumor environment through the release of reactive oxygen and nitrogen species, as well as TNF-α. Consequently, chronic inflammation can facilitate tumor growth via activation of NF-κB and the subsequent suppression of adaptive immune responses [ 48 ]. NSCLC tumors often show hypoxic areas, which leads to the release of pro-angiogenic factors such as VEGF, thereby increasing tumor angiogenesis [ 66 , 67 ].

3.5. Racial and ethnic diversity in lung cancer

There is considerable variation in cancer incidence as well as death rates among different racial and ethnic groups [ 68 ]. Although the cause of this racial and ethnic disparity in cancer risk and outcomes remains controversial [ 69 ], there is a growing consensus that the interaction of genetic and environmental factors including diet is at least partially responsible for the ethnic differences in cancer risk and outcome [ 70 ].

Regarding lung cancer, women have lower incidence and death rates than men. African-American men have the highest incidence and death rate in the United States, followed by White, American Indian or Alaskan Natives, Asian American or Pacific Islanders, and Hispanic/Latino men. In women, the highest rates are in white women, followed by American Indian or Alaskan Natives and African Americans, Asian American or Pacific Islanders, and Hispanic/Latino groups [ 68 ]. Moreover, clinical trials have shown that Asian ethnicity is an independent favorable prognostic factor for OS in NSCLC patients regardless of their smoking history. The frequency of the activated EGFR mutations is higher in East Asian patients as compared with Caucasian patients (30 vs. 7 %, respectively). Numerous studies showed that EGFR mutation-positive patients of Asian origin have better efficacy outcomes with first-line EGFR tyrosine kinase inhibitors (TKI), especially patients with adenocarcinoma histology and never smokers [ 71 ]. In contrast, prevalence of K-ras mutations is lower in Asian patients (<10 vs. 18 %) [ 71 ]. Deciphering these racial disparities requires the identification of risk factors for lung cancer in multiracial, multiethnic groups such as genetic polymorphisms and gene-environment interactions. Moreover, inclusion of minority groups in lung cancer screening and clinical trials may be advantageous in reducing these disparities.

Environmental factors/geography as well as socioeconomic status may also affect lung cancer susceptibility, treatment outcome, and survival rates [ 72 ]. Access to treatment and adherence to treatment regimen [ 73 ] appear to be an enabling factor for racial disparities in lung cancer. It has been shown that White and African-American patients with early-stage NSCLC who were eligible and received surgical resection had comparable survival rates. In contrast, African-Americans who did not undergo surgery (due to un-insurance, limited access to health care, fear to diagnosis or beliefs) had the lowest survival rate [ 73 ]

4. Treatment of Non-Small-Cell Lung Cancer

In this section, the standard and emerging treatments for early stage, advanced, and recurrent NSCLC, as well as brain metastasis will be discussed ( Table 7 ). The various drugs and corresponding targets mentioned in this section are summarized in ( Table 8 ).

Treatment options for NSCLC.

Drugs and corresponding targets.

4.1. Treatment of early stage (stage I and Stage II) Non- Small-Cell Lung Cancer

The primary treatment for resectable and operable early stage disease (Stage I and II) is surgery [ 74 ] which provides the best option for long-term survival [ 75 ]. Five-year survival rates after surgical resection are 60%–80% for stage I NSCLC and 30%–50% for stage II NSCLC patients [ 76 ]. For patients refusing surgical resection or with unresectable tumors, primary radiotherapy can be used such as stereotactic body radiotherapy (SBRT) for high-risk patients or unresectable tumors [ 72 ]. However, post-surgery radiotherapy is not recommended for stage I and II patients [ 72 ]. To date, adjuvant platinum-based chemotherapy was shown to be beneficial for stage II NSCLC patients [ 77 ] and is the recommended treatment strategy for completely resected patients [ 72 ]. Conversely, a clear benefit has so far not been proven for adjuvant chemotherapy in stage I NSCLC patients [ 78 ].

4.2. Treatment of stage III Non- Small-Cell Lung Cancer

More than 70 % of NSCLC patients are diagnosed in advanced stages or metastatic disease [ 2 ] (stages III and IV). Stage III NSCLC is a heterogeneous disease, and varies from resectable tumors with microscopic metastases to lymph nodes to unresectable, bulky disease involving multiple nodal locations. The 5-year OS rate varies between 10% to 15% for stage IIIA-N2 disease and 2% to 5% for stage IIIA bulky disease with mediastinal involvement. In this heterogeneous population of stage III NSCLC patients, the treatment strategies, including radiotherapy, chemotherapy, and surgical resection are determined by the tumor location and whether it is resectable.

The standard treatment consists of surgery followed by chemotherapy for patients with resectable stage IIIA NSCLC. It has been shown that the adjuvant chemotherapy significantly prolonged OS rate in clinical studies [ 79 – 83 ] and that adjuvant radiation therapy can improve control of resected stage IIIA-N2 disease [ 84 ]. Meta-analyses of numerous clinical studies showed that neoadjuvant chemotherapy provides a modest 5% to 6% improvement in survival at five years [ 85 ].

For unresectable stage IIIA patients, standard treatment may include either a sequential or concurrent combination of chemotherapy and radiation therapy (chemoradiation), and external radiation therapy for patients who cannot be treated with combined therapy. Meta-analyses of multiple randomized clinical studies showed that platinum based chemoradiation therapy provides a significant 10% reduction in the risk of death when compared with radiation therapy alone [ 86 – 88 ]. Several clinical investigations showed that the radical surgery in Stage IIIA patients with bulky primary tumors may provide up to 50% increase in the 5-year survival rate as compared to patients with incomplete resection [ 89 – 91 ].

Stage IIIB NSCLC represents about 17.6 % of all lung cancers [ 92 ] with a 5-year survival rate of 3% to 7% [ 93 ]. The options and sequence of treatments for stage IIIB NSCLC are determined based on the site of tumor involvement and the patient’s performance status (PS) ( Table 4 ). Generally, patients with stage IIIB NSCLC do not benefit from surgery alone. The standard therapy for these patients consists of either a sequential combination of chemotherapy or external radiation therapy. As palliative treatment, Stage IIIB NSCLC may receive external radiation therapy alone to relieve pain and other symptoms to improve the quality of life.

Eastern Cooperative Oncology Group (ECOG) Performance Status . The ECOG scale and criteria are used to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis.

4.3. Treatment of Stage IV Non-Small Cell Lung Cancer

Stage IV NSCLC accounts for 40% of the newly diagnosed NSCLC patients. The choice of treatment for stage IV NSCLC patients depends on many factors including, comorbidity, PS, histology, and molecular genetic features of the cancer [ 94 ]. Standard treatment options for stage IV NSCLC disease may include palliative external radiation therapy, combination chemotherapy, combination chemotherapy and targeted therapy, and any Laser therapy or internal endoscopic radiation therapy as needed. Similar to radiation therapy, surgery could also be used in some cases to alleviate disease-related symptoms.

4.3.1. Chemotherapy

For NSCLC, Chemotherapy is usually well tolerated by patients with PS 0 and 1 but rarely effective in patients with a PS 3 and 4 where palliative care is preferred. Use of chemotherapy is controversial in PS 2 NSCLC patients, which represent nearly 40% of advanced stage NSCLC patients. Chemotherapy is recommended only for PS 2 patients who are reasonably fit, and awake for more than 50 % of the day.

i. First-line Chemotherapy

The median OS is 4.5 months when no chemotherapy is given to advanced metastatic NSCLC or after failure of all treatments. Use of chemotherapy improves the 1-year OS rate from 10%–20% up to 30%–50% [ 74 ]. A combination of two cytotoxic drugs is the recommended first-line therapy for Stage IV NSCLC patients with a PS of 0 or 1. Platinum (Cisplatin or carboplatin)-based combination therapies yield better response and OS rates than the non-platinum combination therapies. First line platinum-based chemotherapeutics may include doublets of cisplatin or carboplatin given in combination with taxanes (paclitaxel, docetaxel, or vinorelbine), antimetabolites (gemcitabine or pemetrexed), or vinca alkaloids (vinblastine) with comparable activity [ 95 ]. Use of single cytotoxic chemotherapy is preferred in stage IV patients with a PS of 2 due to their greater risk of toxicity and drug intolerance, comparing to patients with a PS 0 to 1.

ii. First-line combination chemotherapy with targeted therapy

Currently, the addition of bevacizumab, an antibody targeting VEGF, to first-line doublet combination chemotherapy, is supported for the treatment of stage IV NSCLC patients with exception (squamous carcinoma histology, brain metastasis, significant cardiovascular disease or a PS greater than 1) due to fatal bleeding concerns. The combination of bevacizumab with carboplatin and paclitaxel doublet appeared to be superior to the combination with cisplatin and gemcitabine.

4.3.2. EGFR tyrosine kinase inhibitors (first line)

The first of the approved targeted drugs for NSCLC patients are agents that specifically block the EGFR) such as tyrosine kinase inhibitor (TKI) Erlotinib (Tarceva) and gefitinib (Iressa). Mutations of EGFRs can lead to abnormal activation of this receptor triggering uncontrolled cell growth, which may account for several subsets of cancers including NSCLC.

Evidence from several randomized clinical trials demonstrated that use of single-agent gefitinib as a first-line therapy might be recommended for patients with activating EGFR mutations, particularly for patients who have contraindications to platinum therapy. Conversely, cytotoxic chemotherapy is preferred if EGFR mutation status is negative or unknown. Three large controlled and randomized trials showed that gefitinib or erlotinib are better than platinum combination chemotherapy as first-line treatment for stage IIIB or IV lung adenocarcinomas in nonsmokers or former light smokers in East Asia [ 35 , 36 , 96 , 97 ].. Data from these trials demonstrated that gefitinib or erlotinib improved PFS but not OS and have favorable toxicity profiles compared with combination chemotherapy of patients with chemotherapy-naïve and EGFR mutations adenocarcinoma. Similar benefits of erlotinib versus platinum-based chemotherapy as first-line were reported in one European large randomized clinical trial (PFS: 9.7 vs. 5.2 months, respectively) [ 98 ]. Neither erlotinib nor gefitinib is recommended for use in combination with cytotoxic chemotherapy as first-line therapy

4.3.3. Maintenance therapy following first-line chemotherapy

Maintenance therapy is the treatment continuation until disease progression of a cancer that has not advanced following the first-line therapy. The primary goal is to improve cancer-related symptoms, and, hopefully, improve survival time beyond that provided by the first-line therapy. It has lately gained great interest in the treatment of advanced NSCLC (stage IIIB and stage IV) [ 99 ]. To date, pemetrexed (Alimta), and erlotinib (Tarceva) are the two medications that have been approved by the FDA as maintenance therapy for advanced lung cancer. Evidence from two randomized controlled clinical trials showed a statistically significant improvement of PFS (4.1 to 4.3 months vs. 2.6 to 2.8 months), with the addition of pemetrexed as maintenance therapy following standard first-line platinum-based combination chemotherapy [ 100 – 103 ]. Remarkably, pemetrexed maintenance therapy appears to be effective only in patients with adenocarcinoma and large cell carcinoma as well as in patients with EGFR mutations in their tumors, but not in patients with squamous cell lung carcinoma.

Data from a large randomized controlled clinical trial showed improved survival (both PFS and OS) with erlotinib maintenance treatment following platinum-based chemotherapy in NSCLC patients without progressive disease (PFS: 12.3 weeks vs. 11.1 weeks) [ 104 ]. Similar to pemetrexed, erlotinib maintenance therapy improved outcome primarily in non-squamous cell lung carcinoma NSCLC patients. Patients with activating EGFR mutations in their tumors showed greatest PFS benefit comparing to patients with wild type EGFR who also experienced improvement in their median PFS. This trial also demonstrated that KRAS mutation status was a significant, negative prognostic factor for maintenance erlotinib-induced PFS [ 105 ]. Moreover, never-smoking women with better PS seems to derive the utmost survival advantage from maintenance erlotinib therapy.

4.3.4. Second- and third-line therapies in the treatment of advanced NSCLC

Docetaxel (Taxotere), pemetrexed, erlotinib, and gefitinib, are currently approved as second-line therapy for patients with advanced NSCLC who have failed first-line platinum-based therapy and have an acceptable PS.

Evidence from several randomized clinical trials and meta-analyses [ 106 – 108 ] showed that docetaxel in the second-line setting leads to better survival and quality of life (QoL) when compared to best supportive care [ 107 ] or to single agent ifosfamide or vinorelbine [ 109 ]. Pemetrexed yielded similar clinical response comparing to docetaxel (a median survival of about 8 months, one-year survival of 30%, and a response rate of 10%) [ 110 ] with better toxicity profile that may benefit older patients with a PS of 3 [ 111 ]. Pemetrexed also provided better outcome in lung adenocarcinoma patients, whereas docetaxel treatment was more effective in lung squamous cell carcinoma patients [ 112 ]. Erlotinib related response was more common in women with adenocarcinoma, never-smokers, or east-Asians, which is correlated with more frequent EGFR activating mutations [ 113 ]. To date, erlotinib is approved and may be recommended as second- or third-line therapy for patients with a PS of 0 to 3 who have not received prior erlotinib or gefitinib.

Because of the scarcity of data on cytotoxic chemotherapy as third-line therapy, there are no recommendations for or against using a cytotoxic chemotherapy in the third-line setting. However, Phase III clinical trials of docetaxel, erlotinib, gefitinib, and pemetrexed allowed patients to continue chemotherapy, as tolerated, until disease progression.

4.4. Standard Treatment Options for Recurrent NSCLC

Recurrent or relapsed NSCLC is a cancer that has progressed or returned following an initial treatment with surgery, radiation therapy, and/or chemotherapy. The cancer may return in the lung, brain, or other parts of the body. For NSCLC patients who have never been treated with chemotherapy, the treatment plan is similar to that of Stage IV NSCLC. For those patients who have already been treated with chemotherapy, standard treatment options may include: 1) External palliative radiation therapy, which achieves palliation of symptoms from a localized tumor mass [ 114 ], to relieve pain and other symptoms and improve the quality of life; 2) Cytotoxic chemotherapy [ 107 , 110 , 115 ]; 3) EGFR inhibitors (TKIs) in patients with or without EGFR mutations.; 4) EML4-ALK inhibitor (Crizotinib) in patients with EML-ALK translocations.[ 116 , 117 ]; 5) Surgical resection of isolated cerebral metastases (for selected patients who have a very small amount of cancer that has spread to the brain) [ 118 ]; 6) Laser therapy or interstitial radiation therapy using an endoscope (for endobronchial lesions) [ 119 ]. 7) Stereotactic radiation surgery (for selected patients who cannot have surgery) [ 120 , 121 ].

4.4.1. Cytotoxic Chemotherapy for Recurrent NSCLC

Evidence from clinical studies showed that use of cytotoxic chemotherapy and targeted therapy may achieve objective responses, albeit with small improvement in survival for patients with recurrent NSCLC [ 122 ]. In some trials, platinum based chemotherapy has also been shown to achieve palliation of symptoms, which occurred more often than the objective response in patients with good PS [ 123 , 124 ]. Treatment options for NSCLC patients whose cancer has recurred after platinum-based chemotherapy may include either new cytotoxic chemotherapy such as docetaxel [ 107 , 114 ] and pemetrexed [ 110 ], or a targeted therapy such as erlotinib [ 113 ], gefitinib [ 115 ], and crizotinib for cancers with EML4-ALK translocations [ 116 , 117 ]. Patients with squamous lung carcinomas benefit more from docetaxel, whereas those with non-squamous NSCLC appeared to benefit more from pemetrexed [ 125 ].

4.4.2. EGFR Inhibitors for Recurrent NSCLC

A large randomized phase III trial comparing gefitinib to placebo in recurrent NSCLC patients suggested that gefitinib might be a valid treatment for recurrent NSCLC patients with improved survival compared to placebo in never-smokers (median survival 8.9 mo vs. 6.1 mo), and Asian patients (median survival 9.5 mo vs. 5.5 mo) [ 126 ], In two large randomized, placebo controlled trials, erlotinib has also been shown to improve survival and quality of life in patients with recurrent NSCLC after first-line or second-line chemotherapy compared to placebo [ 113 , 127 ]. Moreover, erlotinib treatment also induced a greater improvement in patients’ symptoms, such as cough, pain, and difficulty in breathing, compared to placebo [ 113 ]. Conversely, erlotinib did not improve survival when compared to standard second-line chemotherapy with docetaxel or pemetrexed [ 128 ], in recurrent NSCLC patients after a first-line platinum combination therapy.

4.4.3. ALK/MET Inhibitors for Recurrent NSCLC

Translocations of EML4 and ALK occur on the short arm of chromosome 2, and the fusion of EML4 and ALK (normally a dormant gene) results in a constitutive activation of the ALK kinase. The EML4-ALK fusion oncogene has been identified in approximately 4% in the NSCLC population, and is generally found in individuals who do not typically respond to EGFR TKI therapy [ 40 , 45 ]. EGFR and EML4-ALK mutations appear to be mutually exclusive with exceptions. Tumors harboring the EML4-ALK fusion oncogene are sensitive to crizotinib, a selective, ATP-competitive ALK and MET/HGF dual TKI, which is FDA approved for the treatment of patients with locally advanced or metastatic ALK positive-NSCLC [ 117 ]. Crizotinib (XALKORI @ , Pfizer) is currently approved in Switzerland for treatment of patients with previously treated ALK-positive advanced NSCLC, and in the USA for treatment of patients with locally advanced or metastatic, ALK-positive NSCLC.

Crizotinib therapy has shown improvement in survival of patients with advanced, ALK-positive NSCLC compared to standard therapies for advanced NSCLC [ 117 ] [ 129 ]. Similar to the kinase inhibitors already used in clinic, such as imatinib and EGFR inhibitors, resistance to crizotinib frequently develops in patients’ tumors [ 130 ]. These tumors might either acquire additional ALK kinase domain mutations (i.e., L1196M, C1156Y mutations) that alter drug sensitivity [ 131 ], or other ALK alterations, including amplification, gain in copy number, and loss of ALK genomic rearrangement [ 132 ]. Furthermore, signaling through other kinases, such as EGFR, might compensate for ALK inhibition, thereby mediating resistance to ALK inhibitors [ 132 ]. Mutation in the KRAS gene was also shown to play a role in resistance to crizotinib and around 8 % of ALK-positive NSCLC patients were shown to harbor either a KRAS or EGFR mutation in addition [ 130 ].

4.5. Treatment of Second Primary Tumor

A second primary cancer is a separate cancer arising in a patient who had another cancer in the past. Second or higher order primary tumors account for about 6 to 10% of all cancer diagnoses, and are the fifth most commonly diagnosed cancer in Western countries. The risk of developing a second primary cancer may increase with the use of cancer therapies, such as chemotherapy and radiation therapy. However, it is crucially important to remember that this cancer therapy-related risk is minimal when compared to the benefits of treating the original primary cancer. Patients with lung cancer are at high risk of developing second primary lung cancers. However, it may be difficult to accurately determine whether the new tumor is a secondary primary cancer or a metastasis from the original cancer. Studies have shown that in the majority of lung cancer patients the new lesion is a second primary tumor. When the original primary tumor has been surgically removed, surgical resection of second primary tumors may achieve a 5-year survival rate of 60%, with a comparable expected operative morbidity and mortality to the primary surgery. Tumors 2 cm or smaller are associated with significant positive long-term prognostic factors for survival and freedom from recurrence following resection of a the second primary cancer [ 133 – 135 ]

4.6. Treatment of Brain Metastases

Brain metastases are a common problem in lung cancer patients and a significant cause of morbidity and mortality. Brain metastases are found in about 80% of SCLC and 30% NSCLC at two years from diagnosis [ 136 , 137 ]. Among the various histologies of NSCLC, the incidence of brain metastases in patients with adenocarcinoma and large cell carcinoma is greater than in patients with squamous cell carcinoma [ 138 , 139 ]. The median survival for untreated lung cancer patients with brain metastases is 4 to 7 weeks [ 140 – 142 ]. The treatment may be for relief of symptoms or therapeutic strategies. Treatment options for lung cancer patients with brain metastases may include Whole Brain Radiotherapy (WBRT), surgical resection, Stereotactic Radiosurgery (SRS), Systemic therapy and Radiosensitization, or a combination of these various treatment modalities.

a) Whole Brain Radiotherapy (WBRT)

WBRT is the standard of care for cerebral metastasis in lung cancer patients. Several randomized trails have assessed numerous WBRT dose and fractionation schedules but showed no significant difference in either survival times, or symptomatic response rates and duration. Nevertheless, the results of these trials have suggested better palliative effects from the more prolonged schedules and the choice of dose fractionation schedule should be based on patients’ prognosis [ 143 ]. Additionally, a systematic imaging study of dose response based on tumor size and histology, following WBRT (30 Gy in 10 fractions) [ 144 ], showed an improved response rate for smaller tumors without necrosis. The complete response rate was 37% for SCLC, 25% for squamous cell carcinoma, and 14% for non-breast adenocarcinoma.

Resection of a single brain metastasis combined with WBRT is a standard treatment option of brain metastases [ 134 , 145 ]. A prospective randomized study [ 134 ], demonstrated superiority of surgical removal of the brain tumor followed by radiotherapy over needle biopsy and radiotherapy, with lower recurrence rates at the site of the original metastasis (20% vs. 52%,), and a significantly longer time to recurrence of the original brain metastasis (median >59 weeks vs. 21, p < 0.0001). Moreover, the median survival with surgery and adjuvant WBRT was much longer than with WBRT alone (40 weeks vs. 15 weeks, p < 0.01). Patient’s functional independence (KPS score of ≥70) was also preserved much longer with combined surgery and WBRT than with radiation alone (median: 38 weeks vs. 8 weeks, p < 0.005).

In patients with multiple brain metastases, surgery is typically limited to the resection of the dominant, symptomatic lesion. Various studies have shown that surgery combined with adjuvant WBRT or stereotactic radiosurgery (SRS) has similar survival outcome in patients with multiple lesions compared with patients with single brain metastasis or a single lesion [ 146 – 148 ]. About 50% of patients treated with resection and postoperative radiation therapy develop recurrence in the brain [ 118 ]. Few patients with recurrent brain metastasis and good PS, but without progressive metastases outside of the brain, may be treated with surgery or stereotactic radiation surgery [ 118 , 120 ]. However, most patients with recurrent brain metastasis may be treated with additional radiation therapy, albeit with a limited palliative benefit [ 149 ].

c) Stereotactic Radiosurgery (SRS) with and without WBRT

Stereotactic radiosurgery (SRS) is a form of non-invasive radiation therapy that focuses high-power energy on a precisely defined small target (e.g. the center of the tumor). The suggested mechanisms of SRS-induced tumor killing are radiation-induced DNA damage, endothelial cell apoptosis, microvascular dysfunction, and induction of a T-cell response against the tumor [ 150 – 152 ]. Because of the generally small size and well-defined margin of brain metastases at presentation [ 153 , 154 ], SRS may be an effective alternative to surgery for up to four small brain metastases (up to 4 cm in size) [ 154 ].

Several studies showed that SRS might achieve better prognosis and prolonged survival in lung cancer patients with good PS, no systemic disease, and longer survival time from the diagnosis of primary disease [ 155 – 160 ]. The addition of SRS to WBRT could be beneficial for patients who are not eligible for surgery due to tumor location in the brain or other medical contradictions.. A large randomized controlled Phase III trial study, showed that the local recurrence at one year decreased significantly with the combination of WBRT and SRS (18 vs. 29%, p = 0.01) [ 161 ]. A planned sub-analysis, in patients with a single brain metastasis revealed an improved median survival (6.5 vs. 4.9 months; p = 0.039) and improved quality of life with WBRT and SRS.[ 161 – 163 ]. The addition of adjuvant WBRT to SRS yielded a significant increase in the average time to deterioration in patients with one to four brain metastases (16.5 months vs. 7.6 months, p = 0.05) although no survival advantage was observed [ 164 ].

d) Systemic Therapy and Radiosensitization

In 30–70% of patients with a single brain metastasis, lung cancer is the primary disease [ 165 ]. Generally, most chemotherapeutic agents are unable to cross the blood brain barrier reach the CNS. However, the endothelium leakiness of the tumor vessels, which may disrupt the blood-brain barrier, is well documented in human cancer, particularly in case of macroscopic metastases or relapsed disease. In keeping, several small phase II studies demonstrated that chemotherapy alone yields response rates of brain metastases of 43%–100% and 0%–38% for metastases from SCLC and NSCLC, respectively [ 165 ]. However, combining chemotherapies (thalidomide, teniposide, topotecan, paclitaxel, and cisplatin) to WBRT did not demonstrate survival benefit although some showed enhanced response rates [ 166 – 175 ].

Radiosensitizing agents, such as motexafin gadolinium (Xcytrin) and efaproxyn (efaproxiral or RSR-13), may increase oxygen levels in the tumor and therefore enhance its sensitivity to radiation therapy. However, initial trials showed that the addition of radiosensitizers to WBRT may improve response rate and time to progression (TTP), but not survival. Overall, the evidence to date does not support the clinical use of chemotherapy or radiosensitizers in conjunction with WBRT in the treatment of brain metastases.

4.7. Role of Angiogenesis Inhibitors in NSCLC

Angiogenic pathways provide an important target in NSCLC treatment since they foster tumor growth through the development of new blood vessels. The complex process of angiogenesis is regulated by pro-angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), as well as angiopoietins [ 176 ]. Currently, only the monoclonal antibody bevacizumab, targeting circulating VEGF, is approved for first-line treatment of advanced NSCLC in combination with platinum-base chemotherapy [ 176 ]. Several anti-angiogenic agents are under clinical investigation, including sorafenib and sunitinib.

A randomized phase III trial (ECOG 4599) assessing the efficacy of bevacizumab in combination with first-line platinum-based chemotherapy (carboplatin/paclitaxel) showed significantly improved response rates (35 % vs. 15 %, P<0.001), PFS (6.2 vs. 4.5 months, P<0,001), and overall survival (OS) (12.3 vs. 10.3 months, P=0.003) in the antibody group, compared to chemotherapy alone [ 177 ]. Further analysis revealed that baseline tumor cavitation is the most significant risk factor for the fatal side effect after bevacizumab therapy [ 178 ]. The trial also suggested that patients with adenocarcinoma histology might benefit more from the treatment with bevacizumab [ 179 ].

However, resistance to treatment with anti-VEGF agents is a challenge and occurs in all patients eventually. This resistance might, at least partially, be caused by up-regulation of compensatory angiogenic pathways, e.g. through PDGF or FGF signaling [ 176 ]. Multi-targeted anti-angiogenesis therapies therefore represent an interesting treatment strategy for NSCLC patients. In keeping, the multiple tyrosine kinase inhibitor (TKI) sorafenib which targets VEGFR-2/3, PDGFR-β, c-Kit, Raf, and Flt-3, produced promising response rates in several phase I and II studies [ 176 ]. Although sorafenib showed activity as single agent in NSCLC patients, it did not show an added improvement when combined with the carboplatin, paclitaxel and EGFR TKI (erlotinib) [ 176 ]. Interestingly, Sorafenib treatment resulted in an increased disease control rates in NSCLC patients with K-Ras mutations [ 176 ]. Several phase II/III studies for sorafenib in NSCLC are still ongoing [ 176 ].

Another multiple TKI, sunitinib, targeting VEGFR-1/2/3, PDGFR-α/β, c-Kit, Flt-3, and RET, have also been evaluated in NSCLC patients [ 176 ]. Similar to sorafenib, sunitinib demonstrated singe-agent activity in pretreated NSCLC patients but did not show promising results when combined with paclitaxel/carboplatin alone, with bevacizumab or with erlotinib in two phase II trials [ 180 , 181 ]. Moreover, several other agents inhibiting VEGFR in combination with PDGFR are currently in clinical development, including cediranib, axitinib, motesanib, and linifinib [ 176 ].

Conversely, the angiogenesis inhibitors have not proven to increase the efficacy of standard platinum-based chemotherapy in advanced NSCLC possibly due to lower doses required to reduce toxicities [ 176 ]. In addition to dual-targeted therapies, several agents with activity against three angiogenic pathways (VEGFR, PDGFR, and FGFR) are currently under clinical investigation. An example of the aforementioned inhibitors is the small molecule inhibitor nintedanib which targets VEGFR-1/2/3, PDGFR-α/β, FGFR-1/2/3, as well as Flt-3 and Src family members [ 182 ]. Nintedanib achieved disease stabilization in 46 % of the patients, with a median PFS of 6.9 weeks and median OS of 21.9 weeks, in stage IIIB/IV advanced NSCLC patients [ 183 ]. Pazopanib is another interesting multi TKI, targeting VEGFR-1/2/3, PDGFR-α/β, and FGFR-1 and 3 [ 184 ]. In a phase II study treating naïve stage I/II resectable NSCLC patients, pazopanib showed significant activity as single agent. 86 % of the pazopanib treated patients had a reduction in tumor volume, with two patients achieving a reduction of over 50 %. Pazopanib is currently under investigation in advanced NSCLC [ 176 ].

4.8. Other Molecular Targeted Agents, under Clinical Evaluation for NSCLC Treatment

A) talactoferrin.

The glycoprotein lactoferrin was first described as an iron-binding protein in breast milk and shows immune-modulatory functions [ 185 , 186 ]. The human recombinant lactoferrin, talactoferrin, is given orally, and is able to recruit immature dendritic cells (DC) into the gut-associated lymphoid tissue, where cross-presentation of tumor antigens and subsequent DC maturation can occur [ 186 ]. Preclinical data also showed an increase in splenic NK cell activity and inhibition of NSCLC tumor growth with talactoferrin [ 187 ]. A double blind, placebo controlled phase II study using talactoferrin as monotherapy showed improved OS (median 6.1 vs, 3.7 months after a follow-up of 15.2 months). When combining with chemotherapy (carboplatin and paclitaxel) in treating advanced stage IIIB/IV NSCLC patients, talactoferrin also showed a promising trend for disease-control rates in the intention-to-treat and evaluable population [ 188 ].

b) Insulin-like Growth Factor Inhibitors

The insulin-like growth factor system (IGF system) comprises two receptors: Insulin-like growth factor 1 receptor (IGF-IR) and IGF-IIR with their respective ligands: Insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) and six high-affinity IGF binding proteins (IGFBP) that function as carrier proteins for these ligands. IGF 1 and 2 are involved in the regulation of the development and growth of somatic tissues, as well as carbohydrate metabolism [ 189 , 190 ]. The IGF signaling pathway promotes cell growth by stimulating cell proliferation and differentiation. Additionally, IGF-IR, but not IGF-IIR, signaling inhibits apoptosis [ 191 ]. These ligands bind to the extracellular domain of the IGF receptor 1 (IGF-1R), which is expressed on many normal human cells [ 192 , 193 ], and overexpressed in many cancers, including lung cancer. Furthermore, increased IGF-1 levels, and decreased IGFBP-3/4 level correlate with a higher risk of lung cancer [ 190 , 194 ].

A number of inhibitors for the IGF signaling pathway have been developed, including monoclonal antibodies and small-molecule TKIs, which target the intracellular domain of the receptor [ 190 ]. Figitumumab, a monoclonal antibody against IGF-1R, showed significantly increased overall response rates compared to chemotherapy alone (54 % vs. 42 %, P<0.0001) in a phase II trial in previously untreated locally advanced or metastatic NSCLC patients, Squamous tumors showed a response rate of 78 % and PFS (12-week) of 89 % [ 195 ]. However, two phase III trials that used Figitumumab in combination with chemotherapy in non-adenocarcinoma NSCLC were closed due to severe lethal adverse events and unmet primary endpoint [ 190 , 196 , 197 ]. Two other monoclonal antibodies against IGF ligands, cixutumumab and dalotuzumab, as well as small molecule TKIs are currently under clinical investigation [ 190 ].

c) Histone Deacetylase Inhibitors

Histones are nuclear structural enzymes and, as part of the chromatin, are involved in nucleosomal DNA organization and gene regulation. Conformational changes in DNA structure are regulated by histone acetylation and deacetylation, a mechanism that is often affected in tumor cells [ 198 ]. Histone deactylases (HDACs) are involved in chromatin condensation and repression of gene expression and are frequently overexpressed in many cancers [ 190 ]. Contrary to genetic mutations, the epigenetic modifications induced by HDACs are reversible, and therefore, HDACs are an attractive target for cancer therapy [ 198 ]. Various HDAC inhibitors have been developed and shown to modulate the acetylation status of several important cellular proteins involved in tumor cell growth and proliferation, including p53, HSP90, STAT3, subunits of NFκ-B and α-tubulin [ 190 , 199 , 200 ]. Moreover, the HDAC inhibitors can also modify the cell cycle and lower the apoptotic threshold [ 190 , 199 , 200 ]. Many HDAC inhibitors showed anticancer activity in cell culture and animal models of carcinogenesis. Two of these HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA, Vorinostat) and Romidepsin (Depsipeptide, FK228), have already been FDA approved for the treatment of cutaneous T-cell lymphoma (CTCL). The addition of vorinistat to chemotherapy was able to improve the response rate compared to the placebo addition to chemotherapy (34 vs. 12.5 %, P=0.48) in treating advanced stage IIIB/IV NSCLC patients [ 201 , 202 ]. However, a phase III trial of vorinostat in combination with carboplatin and paclitaxel was stopped due to increased adverse effects, and a lack of efficacy in the vorinostat group [ 203 ]. A number of other HDAC inhibitors including entinostat, pivanex, cI-994, panobinostat, and romidepsin, are currently under clinical investigation for treatment of NSCLC [ 204 ].

d) Pro-Apopototic Agents

Apoptosis has long been known as a hallmark of cancer, and cancer cells exploit both upregulation of antiapoptotic as well as downregulation of pro-apoptotic mechanisms [ 46 , 205 ]. Novel pro-apoptotic drugs are currently being investigated for the treatment of NSCLC. To date, both Mapatumumab, a high-affinity monoclonal antibody against the death receptor DR4/TRAIL-R1, and a pro-apoptotic agent apomab did not show clinical benefit as monotherapy or in combining with chemotherapies (carboplatin and paclitaxel) in clinical trials [ 206 , 207 ] [ 208 ] [ 190 , 209 ]. A number of other new pro-apoptotic agents, such as Conatumumab (targeting DR1) and YM155 (targeting survivin), are currently under clinical investigation for the treatment of NSCLC and have shown synergistic effects in combination with chemotherapy [ 190 , 210 , 211 ].

4.9. Immunotherapy

A) immune checkpoint inhibitors.

Tumors ascribe certain immune-checkpoint pathways as a chief mechanism of immune resistance, particularly against T cells that are specific for tumor antigens. Several of these immune checkpoints are initiated by ligand–receptor interactions, and thus are amenable to inhibition by antibodies or modulated by recombinant forms of ligands or receptors [ 186 ]. Two monoclonal antibodies, ipilimumab and tremelimumab, have been used successfully in NSCLC against the cytotoxic T-lymphocyte-associated antigen (CTLA-4), an inhibitory T-cell co-receptor found on activated T-cells and regulatory T-cell subsets [ 186 , 212 ]. A multicenter double-blind phase II trial showed that the combination of ipilimumab and chemotherapy (carboplatin or paclitaxel) significantly improved the immune-related PFS in advanced stage IIB/IV NSCLC patients with squamous cell carcinoma (without prior chemotherapy) [ 186 , 213 ]. Tremelimumab has also been tested in a randomized, phase II trial as maintenance after first-line chemotherapy, compared to best supportive care. However, the results of this trial showed no improvement in PFS [ 214 ].

2) PD-1 and PD-L1

The immune-checkpoint receptor, programmed death-1 (PD-1), is a promising target, for stimulation of antitumor immune responses by the patient's own immune system. Unlike CTLA4, the main role of PD-1 is to control the activity of T cells in peripheral tissues at the time of an inflammatory response to infection and to limit autoimmunity [ 215 – 222 ]. This translates into a major immune resistance mechanism within the tumor microenvironment [ 223 – 225 ]. Another interesting immunotherapeutic option is the direct targeting of PD-1 ligands (PD-L1), B7-H1/PD-L1 and B7-DC/PD-L2. It has been shown that B7-H1/PD-L1 is selectively upregulated in many human cancers including lung cancer [ 223 , 226 ]. An encouraging phase I study showed clinical activity of PD-L1 blocking agents in NSCLC [ 223 , 226 ].

A dose-escalation study testing a monoclonal antibody against PD-1 (MDX-1106) in the treatment of refractory-metastatic solid tumors (melanoma, renal cell cancer, colon cancer, NSCLC), showed objective responses in five of 49 NSCLC patients [ 222 ]. This result highlights the potential activity of anti-PD-1 against a non-immunogenic tumor [ 226 ]. Another study assessed the safety and antitumor activity of the anti-PD-1 monoclonal antibody BMS-936558 or nivolumab in patients with advanced tumors (NSCLC, melanoma, prostate, renal cell, and colon cancer) [ 227 ]. Durable, objective responses (partial and complete) were observed in 18 % of NSCLC patients. Significantly, the objective responses to anti-PD-1 therapy and clinical benefit correlated with PD-L1 expression by tumor cells (P=0.025 and 0.005, respectively). Although the expression of PD-L1 by infiltrating immune cells did not significantly correlate with objective response (P=0.14), marked correlation with clinical benefit was reported (P=0.038). The toxic side effects were milder with PD-1 inhibition compared to CTLA-4 inhibition, thus underlining the importance of targeting immune checkpoint-pathways with better benefit-to-toxicity ratios [ 186 , 226 ].

Several clinical trials are currently investigating immune checkpoint inhibitors, such as anti-CTLA-4 (nivolumab) and anti-PD-1 (ipilimumab), as monotherapy or in combination with chemotherapy in NSCLC [ 228 ]. Recently, results from two phase III trials (CheckMate-017 and 057) showed an OS benefit with Nivolumab compared to docetaxel in both nonsquamous and squamous NSCLC. In the phase III CheckMate-017 trial [ 229 ], there was a 41% OS improvement with nivolumab compared to docetaxel in the squamous setting. In the phase III CheckMate-057 trial [ 230 ], the OS benefit with nivolumab was 27% in patients with nonsquamous NSCLC. Based on data from CheckMate-017 trial, Nivolumab is now approved by the FDA in squamous NSCLC.

Recent publications evaluated expression of PD-1 and PD-L1 in NSCLC. Patients with KRAS mutations were shown to express higher levels of PD-1 compared to patients with wild type KRAS, whereas increased levels of PD-L1 were detected in patients with EGFR mutations or ALK translocations [ 231 ]. Interestingly, the clinical profile of PD-1 expressing patients included male smokers with adenocarcinoma more frequently, whereas PD-L1 was more frequently expressed in female non-smokers with adenocarcinoma. Both PD-1 and PD-L1 were recently shown to be upregulated through activation of EGFR, thereby leading to immune evasion [ 232 , 233 ]. Furthermore, patients with EGFR mutations and increased expression of PD-L1 showed a higher response rate to treatment with the EGFR-TKIs gefitinib or erlotinib, compared to PD-L1 negative patients, which resulted in longer TTP (11.7 vs. 5.7 months, P<0.0001) and OS (21.9 vs. 12.5 months, P=0.09) [ 231 ]. Taken together, these recent studies suggest that combination of EGFR TKIs with PD-1 inhibitors might be beneficial in treatment of NSCLC [ 231 , 232 ].

Another study analyzed the mechanism of combining immunotherapy with immune checkpoint inhibition in a B16 tumor mouse model. A TLR agonist enhanced GM-vaccine (TEGVAX) was shown to induce anti-tumor immune responses in vivo , which was associated with IFN-y dependent upregulation of PD-L1 in the tumor microenvironment. Combined treatment with TEGVAX and PD-1 inhibition led to regression of established tumors, whereas PD-1 inhibition alone did not induce anti-tumor immune responses [ 234 ]. Other antibodies against PD-1, such as pembrolizumab (MK-3475), MPDL3280A, and MEDI4736 are currently being investigated and have shown promising results in Phase 1 clinical trials [ 235 ]. A recent study used whole-exome sequencing to investigate the genomic determinants of response in two independent cohorts of NSCLC treated with this therapy [ 236 ]. This study revealed that a higher nonsynonymous mutation burden in tumors was associated with improved ORR, durable clinical benefit, and PFS. Pembrolizumab clinical efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair and replication pathway mutations (e.g., mutations in POLD1, POLE, MSH2, Rad51, Rad17, DNA-PK) [ 236 ]. Remarkably, pembrolizumab–induced neoantigen-specific T cell reactivity was also observed in the peripheral blood, thus, suggesting possible blood-based assays to monitor response during anti–PD-1 therapy.

b) Vaccine Therapy for NSCLC

Vaccination against pathogens is one of the most important developments in modern medicine and saves millions of lives each year. For advanced NSCLC patients, median OS is about one year, and only 3.5 % survive five years after diagnosis, despite the addition of new therapies to standard chemotherapy [ 186 ]. Therefore, vaccinations for solid tumors, either preventive (for tumors related to infections such as human papilloma virus-associated cervical cancer [ 237 ]) or therapeutic (breaking tolerance and achieving long lasting response in tumors such as ipilimumab (anti-CTLA-4) in advanced melanomas [ 226 , 238 ]), have long been seen as the ultimate treatment option for cancer patients.

As many other cancers, NSCLC belongs to the non-immunogenic tumors and therefore the identification of tumor specific immunogenic antigens for vaccine therapy presents a major challenge. The most promising results of vaccines for NSCLC patients have been observed in the adjuvant setting and in locally advanced NSCLC [ 190 ]. A Summary of the various vaccine therapy evaluated in NSCLC is shown in Table 9 .

Types of vaccine therapy for NSCLC.

Mucin-1 (MUC1) is a glycoprotein present on normal epithelial tissue and in various cancers, including NSCLC [ 66 , 239 ]. A mutated MUC1protein overexpressed in cancer cells shows aberrant glycosylation pattern that is antigenically different from wild-type protein expressed on normal epithelial cells [ 66 ]. L-BLP25 is a synthetic vaccine against the core peptide of MUC1 combining the peptide with cyclophosphamide as an adjuvant [ 186 , 240 ]. Recently updated data from a phase IIB randomized study treating stage IIIB/IV NSCLC patients with L-BLP25 showed significant improvement in the vaccine group comparing to the supportive group (3-year survival rates: 31 vs. 17 % [ 241 ]).

The efficacy of TG4010, a recombinant vaccinia virus that combines the human MUC1 and interleukin-2 coding sequences [ 66 ], in combination with cisplatin and vinorelbine or as monotherapy has been investigated in a randomized phase II study for advanced NSCLC patients [ 242 , 243 ]. A subgroup with a detectable CD8+ T-cell response was able to generate an immune response against MUC1 and had longer median survival [ 243 ]. Data from another phase II study comparing the vaccine plus chemotherapy with chemotherapy alone in advanced NSCLC patients with confirmed MUC1 expression showed that higher numbers of activated NK cells might suppress DC and effector T-cells and result in decreased median OS rates as well as increased adverse effects. [ 244 ] [ 243 ].

CimaVax EGF is a new vaccine that is being developed for NSCLC treatment. This vaccine is made up of a low dose cyclophosphamide and EGF. It works as an immunoadjuvant to reduce the inhibition of Tsuppressor cells and to stimulate the production of anti-EGF antibodies that may inhibit EGF binding EGFR on cancer cells, and consequently decrease cancer cells growth [ 66 , 243 , 245 , 246 ].

A phase I study showed that the production of anti-EGF antibodies and serum EGF levels after use of the EGF-based vaccine, correlate with increased survival rates in NSCLC patients [ 247 ]. A randomized phase II trial comparing the CimaVax vaccine to best supportive care in stage IIIB/IV patients [ 248 ] showed minimal toxicity and good antigen responses in 51.4% of the patients although the median OS did not improve [ 66 ]. Longer median survival rates were seen in good antigen responders than in poor antigen responders (11.7 vs. 3.6 months) [ 243 ]. In addition, longer median OS rates were seen in patients with EGF levels below 168 pg/ml (13 vs. 5.6 months) and under 60 years (11.57 vs. 5.33 months, P=0.0124) [ 243 ]. The vaccine has been approved for clinical trial development in the US stage IIIB/IV patients [ 243 ].

C. Melanoma-associated antigen (MAGE)

Melanoma-associated antigen A3 vaccine (MAGE-A3) uses a tumor specific antigen, which is expressed in 35 % of NSCLC, most frequently in squamous cell carcinomas [ 186 ]. It ranges from 16 % in stage IA to 48 % in stage IIIB and may be associated with poor prognosis [ 66 , 249 , 250 ]. The MAGE-A3 vaccine, initially developed for metastatic melanoma patients, showed a positive sign of activity after 28 months in a phase II adjuvant therapy study in early stage NSCLC [ 251 ]. Prior to treatment, the NSCLC tumors were analyzed by gene expression profiling to identify a gene signature that correlates with the clinical activity of the vaccine [ 252 ]. The identified signature of genes related to the immune system overlapped with the gene set detected in the melanoma trial. Reduction in the relative recurrence risk after treatment with the MAGE-A3 vaccine showed a 2-fold increase for tumors containing the gene signature (57%), compared to the non-selected population (25%). This result underlines the value of the stratification of patient subpopulations and suggests that gene profiling for a certain tumor microenvironment or immune cells might have a predictive value in cancer immunotherapy [ 66 , 251 – 253 ].

D. TGF beta

The allogeneic vaccine belagenpumatucel-L combines four irradiated lung cancer cell lines (two adenocarcinoma, 1 squamous cell and one large cell carcinoma) with an antisense plasmid against TGF-b (transforming growth factor beta) [ 186 ], a poor prognostic factor in NSCLC. TGF-b2 suppresses dendritic cells, NK cells, and activated cytotoxic T lymphocytes and thereby may help tumors to escape immunosurveillance [ 186 ]. The use of four tumor cell lines in the belagenpumatucel-L vaccine increases the number of tumor antigens and the suppression of TGF-b expression through the antisense plasmid removes a major source of immune suppression at the injection site [ 186 ]. Preclinical data showed that the inhibition of TGF-beta2 could help to break the tolerance and to increase the immunogenicity of tumor vaccines [ 66 , 254 , 255 ]. Patients who received a high dose of the vaccine showed a significantly improved OS compared to low dose group in a randomized, dose-variable phase II trial with 75 NSCLC patients (stages II-IV) [ 255 ] [ 186 ].

Another important tumor antigen for vaccine therapy is PRAME (preferentially expressed antigen of melanoma), which has recently been shown to contribute to carcinogenesis in NSCLC [ 256 ]. As the name suggests, it was first detected in a melanoma patient [ 67 ], and is expressed in a variety of tumors [ 66 ]. PRAME seems to function via the suppression of the retinoic acid receptor (RAR), a signaling pathway which regulates cell death and cell cycle [ 66 , 257 ].. Overexpression of PRAME might be used by tumor cells to escape suppressive RAR signaling, thereby fostering tumor-progression [ 66 ]. Clinical data suggests that poor clinical outcome of some patient subpopulations correlates with PRAME expression in neuroblastoma [ 258 ] and breast cancer [ 259 – 261 ].

A new PRAME vaccine combining the purified recombinant PRAME protein with an adjuvant (liposomal preparation with the AS15 adjuvant system) has been developed. A currently ongoing phase II study (PEARL study) is evaluating the efficacy of the PRAME vaccine in resected NSCLC. This study enrolled patients radically resected for NSCLC, stages IA (T1b), IB, II or IIIA, and whose tumors exhibit PRAME expression. The primary endpoint of the study is disease-free survival (DFS) [ 257 , 262 ].

5. Small-cell lung cancer

Small cell lung cancer (SCLC) accounts for approximately 15% of all lung carcinomas [ 4 , 263 ]. The highest risk-factor for development of SCLC is smoking, and the decrease in percentage of smokers and amount of cigarettes smoked per person in the US might explain the recent decrease in SCLC incidence rates [ 263 ]. 30% of SCLC patients are diagnosed with limited-stage disease (LS-SCLC), where the cancer is confined to the hemithorax, the mediastinum, or the supraclavicular lymph nodes. 70% of SCLC patients are diagnosed with extensive-stage disease (ES-SCLC), with tumors spreading beyond the supraclavicular areas [ 4 , 263 ]. Although SCLC is initially more responsive to chemotherapy and radiation therapy than all other lung cancer types, it is very difficult to cure, due to its aggressive growth and its wide dissemination at the time of diagnosis.

As for other lung cancers, the treatment options for SCLC patients are determined by histology, stage, and general health and comorbidities of the patient. For patients with LS-SCLC, standard treatment options include platinum based chemotherapy and radiation therapy, combination chemotherapy alone, surgery followed by chemotherapy or chemoradiation therapy, and prophylactic cranial irradiation [ 264 ]. For patients with ES-SCLC patients, current treatment recommendations include combination chemotherapy, radiation therapy and prophylactic cranial irradiation [ 264 ]. For recurrent SCLC, the treatment options are chemotherapy and palliative therapy. Although chemotherapy and radiotherapy can lead to strong initial responses in SCLC, disease recurrence is common. Notwithstanding the improvements in diagnosis and therapy made during the past two decades, the current prognosis for patients with SCLC remains substandard. Untreated SCLC is the most aggressive of all type of lung cancers, with a median survival from diagnosis of only 2 to 4 months. The 2 years DFS, following treatment of SCLC patients, remains a dismal 10% [ 265 ]. Moreover, the OS at 5 years of all population of SCLC patients is merely 5% to 10% [ 4 , 265 – 267 ], with a better prognosis for patients with LS-SCLC (5-year survivals of 14%) than for patients with ES-SCLC [ 4 , 266 , 268 , 269 ]. In patients who showed complete response to chemoradiation, prophylactic cranial radiation may avert brain metastases recurrence, and thus, increase patients’ survival [ 270 , 271 ].

Although surgery or chemotherapy alone can improve survival in patients with LS-SCLC, a greater improvement in long-term survival has been shown with combination therapy [ 269 , 272 ]. Particularly combining chemotherapy with thoracic radiation therapy (TRT) increases OS by 5% compared to chemotherapy alone [ 4 , 273 – 276 ]. Although median survival of 6 to 12 months may be achieved in patients with ES-SCLC with the currently available therapy, long-term DFS is rare in these patients [ 4 , 275 , 276 ].

Targeted therapies in SCLC

A) vegf inhibitors.

Inhibition of circulating VEGF with bevacizumab has been studied in ES-SCLC. Chemotherapy naïve patients treated with cisplatin, irinotecan, and bevacizumab, showed an ORR of 75 %, a median OS of 11.6 months, and a median PFS of 7.0 months [ 277 ]. A study investigating cisplatin, etoposide, and bevacizumab in previously untreated ES-SCLC patients showed that a higher baseline level of vascular cell adhesion molecule (VCAM) was associated with a higher risk of progression or death, compared to lower levels of VCAM, but no other biomarkers could be correlated with treatment outcome [ 278 ].

Other VEGF inhibitors, including the multi-kinase inhibitors sorafenib, sunitinib, and cediranib, are currently under clinical investigations in SCLC. [ 279 ] [ 264 ]. Aflibercept (AVE0005) is a fully humanized protein that contains immunoglobulin domains from the two VEGF receptors VEGFR1/2, fused to the constant region of IgG1. These soluble receptors work as a VEGFR-trap and inhibit binding of VEGF to its common receptors. Aflibercept is currently investigated in combination with topotecan in previously treated ES-SCLC [ 264 ].

b) EGFR inhibitors

Mutation of the EGFR is less frequent in SCLC compared to NSCLC, and only around 4% of patients were shown to harbor the mutation [ 280 ]. In a phase II study, patients were stratified according to chemosensitive or chemo-refractory relapsed SCLC and treated with gefitinib. However, the abovementioned study could not demonstrate a gefitinib benefit for SCLC patients [ 281 ].

c) Bendamustine

This cytotoxic agent causes DNA breaks through its alkylating activity. Compared with other alkylating agents, bendamustine causes more extensive and durable DNA single- and double-strand breaks [ 264 ]. Combining bendamustine with carboplatin in treating ES-SCLC [ 282 ], the ORR was 72.7 %, with a median TTP of 5.2 months and median survival time of 8.3 months.. As a single agent in second- and third-line setting in patients with relapsed/refractory SCLC, Bendamustine is well tolerated and effective agent [ 283 ].

d) Immunotherapy

To date, only few studies have evaluated immunotherapy in the treatment of SCLC [ 243 ]. The BEC2/BCG vaccine combines a monoclonal antibody that mimics the glycosphingolipid GD3, which is selectively expressed in SCLC, with the adjuvant bacillus Calmette-Guerin [ 243 ]. The BEC2/BCG vaccine has been demonstrated to develop antibodies against GD3 in Melanoma patients. In an early clinical study, although only 30% of the SCLC patients (5/15, ES/LS-SCLC=8/7) developed measureable anti-GD3 antibodies, the median OS was 20.5 months (relapse-free survival was longer in patients who developed measurable anti-GD3 antibodies) [ 243 , 284 , 285 ]..

Another novel vaccine (INGN-225) targeting p53 protein was developed, and is currently under investigation for treatment of SCLC [ 243 ]. The INGN-225 vaccine is produced from patients’ autologous peripheral blood mononuclear cells (PBMCs). The autologous PBMCs are cultured in the presence of IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) prior to incubation with a viral construct containing wild-type p53 (adenovirus Ad.p53). In a preclinical study, dendritic cells transfected with Ad.p53 were able to induce cytotoxic T lymphocytes following vaccination [ 243 ]. In a recent phase I/II study.14 of the 54 enrolled ES-SCLC patients demonstrated a positive immune response and showed increased median survival (12.6 vs. 8.2 months, P=0.131) [ 243 , 286 ]. Among those responsive patients, 78.6% responded to second-line chemotherapy treatment.

6. Palliative Care for Patients with Lung Cancer

A high percentage of lung cancer patients suffers from substantial symptom burden, including fatigue, loss of appetite and weight loss, as well as dyspnea, hemoptysis, and chest pain [ 287 ]. Better quality of life, lower depressive symptoms, higher median survival and fewer needs on aggressive end-of-life care were observed in patients receiving early palliative care combined with standard oncologic care compared to standard oncologic alone for metastatic NSCLC.[ 287 ]. Megestrol acetate (MA), an appetite stimulant, is one of the supporting treatments that have shown success in treating cancer-related anorexia (CRA) and improve quality of life. Combining MA with olanzapine (OLN) for the treatment of CRA in 80 patients with either advanced gastrointestinal cancer or advanced lung cancer patients (stages III and IV) resulted in a significant improvement of mean symptom scores as measured by the MD Anderson Symptom Inventory (MDASI) [ 287 ] suggesting that combination MA and OLN may be an effective palliative therapy for patients with CRA [ 288 ]..

7. Mesothelioma

Malignant Mesothelioma (MM) is an extremely aggressive tumor affecting about 3,000 new patients in the United States annually [ 289 ]. The incidence of the disease in the US is expected to rise steadily and peak with about 85,000 new MM cases over the course of the next 20 years [ 290 , 291 ]. MM arises from the surface serosal cells of the pleura and, less frequently, from the peritoneum. Exposure to asbestos is a wellestablished cause, with occupational exposure being documented in 70–80% of MM patients [ 292 – 294 ]. MM is sub-typed into three forms according to the histological morphology: epithelial, sarcomatoid, and biphasic. Diffuse MM comprises about 75% of mesotheliomas diagnosed [ 295 ].

Treatment of MM with surgery, chemotherapy, or radiation therapy is rarely curative. Clinical trials of single modality treatment with extrapleural pneumonectomy or pleurectomy, chemotherapy or radiation therapy, have not shown significant improvement in survival compared with supportive treatment. Median survival has ranged from 10 to17 months [ 296 ]. Sugarbaker et al. reported a 15% 5-year survival with multimodal therapy and a 25% 5-year survival in patients who underwent complete surgical resection [ 297 ]. Recent trials of new-generation platinum- and pemetrexed based regimens have reported encouraging results. In particular, a phase II trial of pemetrexed plus cisplatin for MM reported a median survival of 12 months compared with nine months after treatment with cisplatin alone [ 298 ]. Despite these promising results, long-term survival with currently available treatment is rare. Therefore, novel meaningful therapies for MM are urgently needed. Recent advances have shown that tumors carrying activating mutations in some cellular proto-oncogenes are particularly sensitive to targeted therapies directed against the mutant proteins [ 14 , 16 , 299 – 307 ].

Role of immunotherapy in malignant mesothelioma

A number of immunotherapy strategies have been tested in mesothelioma patients, with varying degrees of success.

a) Mesothelin

Mesothelin is an immunogenic glycoprotein specifically overexpressed in malignant mesothelioma, NSCLC, ovarian, and pancreatic cancers [ 186 ]. CRS-207, is a genetically-engineered, double-deleted bactria Listeria monocytogenes strain expressing the human mesothelin [ 186 ]. Phagocytic cells, such as macrophages and dendritic cells, take up CRS-207, and mesothelin is subsequently expressed and processed through the MHC I presentation pathway. This process is predicted to activate T cells in order to attack mesothelin-positive mesothelioma cells. In preclinical studies, CRS-207 was shown to elicit anti-mesothelin cell-mediated immunity [ 186 ]. In a phase I dose-escalation study treating patients with advanced mesothelin expression and treatmentrefractory cancers, with CRS-207, mesothelin-specific T-cell responses were in one of five patients with mesothelioma, with 15 months or more survival after the first dose [ 186 ]. Patients who received sequential CRS-207 treatment with prior immunotherapy or subsequent local radiation therapy benefited the most. CRS-207 is currently investigated in combination with first-line chemotherapy in mesothelioma patients.

b) WT1 analogue peptide vaccine

The transcription factor Wilms’ tumor suppressor gene 1 (WT1) is frequently overexpressed in mesothelioma and other solid and hematopoietic tumors [ 186 ]. Recently, a multivalent WT1 peptide analog vaccine was developed [ 186 ]. A CD-4+ T-cell proliferation to WT1-specific peptides was seen in six of nine patients, and a CD8+ T-cell response was detected in six of six HLA-A0201 patients in an early study investigating the WT1 peptide analog vaccine in MM and NSCLC patients. Stimulated T-cells also showed cytotoxicity against WT1 positive cells [ 308 ]. A subsequent randomized phase II study is currently investigating the adjuvant WT1 analog peptide vaccine in MM patients who have completed combined modality therapy [ 309 ].

c) Dendritic cell vaccine

Dendritic cells (DCs) are the most potent antigen-producing cells, capable of sensitizing T cells to both new and recall antigens. DC-based cancer immunotherapy is aimed at using these cells to prime specific antitumor immunity through the generation of effector cells that attack and kill tumors. Dendritic cells can be matured using a standard cytokine cocktail and pulsed with autologous tumor cell lysates, which presents a source of tumor antigens for immunotherapy [ 186 ].

A phase I study has shown that the DC vaccine was well tolerated in newly diagnosed MM patients, who experienced a partial response or stable disease after previous combination chemotherapy [ 310 ]. A significant humoral response to keyhole limpet hemocyanin, a marker for immune response, was detected in serum samples from all patients. Nine patients had successful lymphocyte activation according to increased levels of granzyme B expressing CD3 and CD8 T-cells. However, no correlation between the clinical responses and the humoral or cellular immune responses was observed [ 186 ].

Another small Phase I/II study evaluated the feasibility, safety, immunogenicity, and clinical efficacy of consolidation treatment with autologous DC transfected with mRNA encoding the malignant mesothelioma-associated WT1 antigen [ 311 ]. Ten patients with unresectable MM and non-progressive disease after platinum/pemetrexed-based chemotherapy underwent leukapheresis: Isolating CD14+ monocytes to produce mature DC, followed by electroporation of WT1 mRNA and biweekly intradermal vaccinations [ 311 ].. DC vaccination was well tolerated; no systemic toxicity was recorded. The 6-, 12- and 18-month survival rates were 100%, 90%, and 75%, respectively. In vivo evidence of vaccine-elicited immunity to the DC vaccine administered was obtained in nine of the ten enrolled patients. The OS data suggest that adjuvant DC-based immunotherapy may provide a clinical benefit for patients with MM [ 311 ].

8. The future of thoracic malignancies

Despite the intensive research and development of several new targeted agents and immunotherapies, survival rates for lung cancer and mesothelioma patients remain dismal. More studies are still needed to identify the underlying genetic alterations and predispositions affecting clinical outcome. Early detection and treatment of these cancers may help dramatically in the improvement of patients’ survival. Over 60% of lung cancer patients are in fact diagnosed at late stages of the disease, where current treatment modalities are unlikely to be effective. The 5-year OS rate is less than 10 % in patients with advanced disease, and greater than 70 % in patients with stage 1 disease. Reliable biomarkers are greatly needed to predict sensitivity to each therapeutic modality in thoracic malignancies that could support optimal selection of treatment on individual patient basis as well as for early detection of lung cancer that could improve its prognosis.


This work was supported in part by The Doctors Cancer Foundation grant A118560, the American Cancer Society grant IRG-97-150-13, and The NIH/NCI U01 grant NIH Grants 5U01CA168878.


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Risk factors for lung cancer worldwide

Lung cancer is the most frequent malignant neoplasm in most countries, and the main cancer-related cause of mortality worldwide in both sexes combined.

The geographic and temporal patterns of lung cancer incidence, as well as lung cancer mortality, on a population level are chiefly determined by tobacco consumption, the main aetiological factor in lung carcinogenesis.

Other factors such as genetic susceptibility, poor diet, occupational exposures and air pollution may act independently or in concert with tobacco smoking in shaping the descriptive epidemiology of lung cancer. Moreover, novel approaches in the classification of lung cancer based on molecular techniques have started to bring new insights to its aetiology, in particular among nonsmokers. Despite the success in delineation of tobacco smoking as the major risk factor for lung cancer, this highly preventable disease remains among the most common and most lethal cancers globally.

Future preventive efforts and research need to focus on non-cigarette tobacco smoking products, as well as better understanding of risk factors underlying lung carcinogenesis in never-smokers.

Tobacco smoking is the major determinant of lung cancer risk; genetics, occupation, pollution, poor diet also contribute

Lung cancer is the most frequent malignant neoplasm among men in most countries and the main cause of cancer death in both sexes, accounting for an estimated 27% of total cancer deaths in the USA in 2015 and 20% in the European Union (EU) in 2016 [ 1 , 2 ]. According to GLOBOCAN, in 2012 lung cancer accounted for an estimated 1 242 000 new cases among men, which is 17% of all cancers excluding non-melanoma skin cancer, and 583 000 (9%) of new cancer cases among women [ 3 ]. Approximately 58% of all cases occur in middle- and low-income countries [ 4 ]. Lung cancer also accounts for 19% of all cancer deaths [ 5 ]. Among both women and men, the incidence of lung cancer is low in people aged <40 years and increases up to age 75–80 years in most populations. The decline in incidence in the older age groups can be explained, at least in part, by incomplete diagnosis or by a generation (birth-cohort) effect, as in several countries the peak of the tobacco-related lung cancer epidemic has been reached by generations born in the 1930–1940s [ 6 ].

Table 1 presents the age-standardised mortality rates from lung cancer in men and women (at all ages) in selected countries worldwide and in the EU as a whole, in 2000–2004, 2005–2009 and 2012 (or closest year available for most countries), with the corresponding percent change. These figures were obtained from official lung cancer death certification data from the World Health Organization database [ 7 ]. Between 2002 and 2012, overall lung cancer mortality increased by 17.5% in the EU in women. Increases were observed in most European countries, with the exception of Denmark, Georgia and the Russian Federation. Worldwide, similar increases were also observed in most countries except for Central American countries (Mexico and Panama) and the USA. For men, overall lung cancer mortality between 2002 and 2012 decreased by 13.5% in the EU. Declines were also noted in several countries worldwide. Figure 1 shows joinpoint analyses of the trends in age-standardised mortality rates from lung cancer between 1980 and 2012 (or the most recent available year) in men and women from 23 selected European countries and the EU at all ages. Figure 2 shows the same statistics for eight other countries worldwide. In women, overall lung cancer mortality increased up to the most recent calendar year in most European countries, as well as worldwide. In a few countries characterised by earlier peaking ( i.e. Denmark, UK and USA), mortality rates levelled off or declined over the most recent calendar year. Female lung cancer rates remain low and have not increased significantly in Russian women. Conversely, men showed a decline in lung cancer mortality in most countries except for a few, i.e. Brazil, Portugal and Bulgaria [ 8 ].

World standardised lung cancer death rates per 100 000 people (all ages) in selected countries in the periods 2000–2004, 2005–2009 and 2012 (or closest year available) and corresponding percent changes

Trends in age-standardised (world standard population) death rates for lung cancer per 100 000 people (all ages) from 1980 to 2012 (or most recent available year) in 23 European countries and the European Union (EU).

Trends in age-standardised (world standard population) death rates for lung cancer per 100 000 people (all ages) from 1980 to 2012 (or most recent available year) in eight selected countries worldwide.

Thus, the decline in lung cancer mortality rates in men have continued over recent years, and are projected to persist in the near future [ 6 ]. Overall, female lung cancer mortality has been lower than in men but has been increasing up to recent years in most countries. Trends in lung cancer mortality can be interpreted in terms of different patterns of smoking prevalence in subsequent cohorts of people in various countries [ 9 , 10 ]. An increase in tobacco consumption was paralleled a few decades later by an increase in the incidence of lung cancer, and a decrease in consumption is followed by a decrease in incidence. Similarly, the temporal lag in trends in female and male lung cancer mortality reflects historical differences in cigarette smoking between subsequent female and male cohorts [ 11 , 12 ].

Family history and high-penetrance genes

A positive family history of lung cancer has been found to be a risk factor in several registry-based studies that have reported a high familial risk for early-onset lung cancer [ 13 ]. Increased relative risks were found even after careful adjustment for smoking [ 14 ]. A linkage analysis of high-risk pedigrees identified a major susceptibility locus to chromosome 6q23–25 [ 15 ]. Lung cancer risk is also increased within the framework of the Li–Fraumeni syndrome, characterised by germline mutation in the tumour-suppressor gene p53 [ 16 ].

Genetic polymorphisms

Recent genome-wide association (GWA) studies have been able to identify multiple genetic polymorphisms underlying lung cancer risk by utilising up to a million tagging single-nucleotide polymorphisms (SNP) to identify common genetic variations. Table 2 summarises the evidence of an association between genetic variants and lung cancer. The three main susceptibility loci identified are in the 15q25, 5p15 and 6p21 regions [ 20 , 30 , 31 ], but many other common variants have also been reported, as listed in table 2 . GWA studies explain only a proportion of the overall genetic variance with lung cancer but the fact that only a minority of smokers develop cancer supports the hypothesis that genetic susceptibility might contribute to carcinogenesis.

Genetic variants identified to be associated with lung cancer risk

Three separate GWA studies of lung cancer provided strong evidence for a susceptibility region in 15q25.1 with a consistent measure of effect between the studies [ 20 , 30 , 31 ]. Both the SNPs rs1051730 and rs8034191 corresponding to the region identified in these studies map to a 100-kb region of strong linkage disequilibrium on chromosome 15 extending from 76 593 078 bp to 76 681 394 bp. The 15q25 susceptibility region contains six identified coding regions, including three cholinergic nicotine receptor genes ( CHRNA3 , CHRNA5 , and CHRNB4 ), encoding nicotinic acetylcholine receptors in neuronal and other tissues [ 30 ]. Variants on the 15q25 locus are also associated with increased vulnerability to tobacco addiction and altered smoking behaviour, including increasing the number cigarettes smoked per day [ 31 , 34 , 35 ]. In fact, a small increase in cigarette smoking leads to an association in the order of that reported for those loci. Since nicotinic acetylcholine receptors mediate sensitivity to nicotine, it has been proposed that variant receptors might increase addiction to tobacco and, therefore, exposure to tobacco carcinogens. 15q25 is the only locus which has been consistently replicated in all types of lung cancer, irrespective of lung cancer histology [ 26 ]. Another novel susceptibility locus at 9p21 reported in Caucasians is restricted to squamous cell lung cancer only [ 26 ].

The susceptibility locus in 5p15.33 represents a region that includes TERT (human telomerase reverse transcriptase gene) and CLPTM1L (cleft lip and palate transmembrane-1-like gene) [ 20 ]. Two variants in this region, rs402710 (OR 1.15; p-value: 7×10 −5 ) and rs2736100 (OR 1.09; p-value: 0.016), which are not strongly associated with each other, were both reported to be associated with lung cancer risk. TERT is the reverse transcriptase component of telomerase that is essential for telomerase enzymatic activity and maintenance of telomeres. Telomerase is responsible for telomere regeneration and up to 90% of human tumours show telomerase activity [ 36 ]. There are some variations of race and ethnicity in the association between these susceptibility loci and lung cancer risk. A GWA study in Han Chinese subjects did not replicate the findings for 15q and 6p regions but confirmed previously identified loci in 5p region [ 17 ]. In addition, a number of new loci have been reported in Asians including 3q28 [ 17 , 18 ] and 22q12.2 [ 17 ].

Some analyses have focused on pathway-based approaches to complement single SNP analysis by incorporating biological knowledge [ 37 , 38 ]. A large pooled analysis of six studies to investigate associations between 7650 genetic variants in 720 genes related to inflammation pathways and lung cancer risk identified one novel variant (rs2741354 in EPHX2 at 8q21.1; p-value: 7.4×10 −6 after correcting for multiple comparisons), and confirmed the associations between the 5p and 6p regions with lung cancer risk [ 25 ]. Another analyses used imputation to the 1000 Genomes Project using pooled GWA data in European subjects and identified large-effect associations for squamous cell lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833) and CHEK2 p.Ile157Thr (rs17879961) [ 39 ]. This demonstrated that imputation can identify rare variants associated with cancer risk using pre-existing GWA data.

Tobacco smoking is the major cause of all major histological types of lung cancer. A carcinogenic effect of tobacco smoke on the lung was demonstrated in epidemiological studies conducted since the early 1950s and has been recognised by public health and regulatory authorities since the mid-1960s [ 40 ]. The geographic and temporal patterns of the disease largely reflect tobacco consumption accumulated during previous decades [ 41 , 42 ]. The excess risk among continuous smokers relative to that among never-smokers is in the order of 20- to 50-fold. Duration of smoking should be considered the strongest determinant of lung cancer risk in smokers [ 43 ]. Newer, low-yield cigarettes caused a shift in the site of disease (from trachea and bronchus to peripheral lung), and hence in the histology of lung cancer, from predominantly squamous cell to adenocarcinoma. Their impact on overall lung cancer risk, as compared to older, higher tar cigarettes, is still open to quantification [ 44 ]. The relative risk decreases in ex-smokers, and a favourable effect of stopping is apparent even for cessation later in life. However, an excess risk throughout life probably persists even in long-term quitters [ 42 ]. The importance of tobacco smoking in the causation of lung cancer complicates the investigation of other causes because tobacco smoking may act as a powerful confounder or modifier.

Although cigarettes are the main tobacco product smoked in western countries, an exposure–response relationship with lung cancer risk has also been shown for cigars, cigarillos and pipes, indicating a carcinogenic effect of these products [ 42 ]. An increased risk of lung cancer has also been shown following consumption of local tobacco products, such as bidi and hookah in India, khii yoo in Thailand and water pipe in China [ 42 ]. The higher rate of lung cancer among African–Americans compared to other ethnic groups in the USA is probably explained by their higher tobacco consumption [ 45 ]. The lower risk of lung cancer among smokers in China and Japan compared to Europe and North America might be due to the relatively recent introduction of regular heavy smoking in Asia, although differences in the composition of traditional smoking products and in genetic susceptibility might also play a role [ 46 ].

The epidemiological evidence and biological plausibility support a causal association between second-hand exposure to cigarette smoke and lung cancer risk in nonsmokers [ 47 ] with the excess risk in the order of 20–30% for a nonsmoker married to a smoker [ 48 , 49 ]. The effect of involuntary smoking appears to be present for both household exposure, mainly from spousal and workplace exposure [ 49 , 50 ], and perhaps from involuntary childhood smoking exposure [ 51 ]. Few studies have investigated the risk of lung cancer among users of smokeless tobacco products. In two large cohorts of US volunteers, the relative risk for spit tobacco use among nonsmokers was 1.08 (95% CI 0.64–1.83) and 2.00 (95% CI 1.23–3.24), respectively [ 52 ]. Overall, the evidence of increased risk of lung cancer from use of smokeless tobacco products is weak; the apparent protective effect detected in studies including smokers might be due to uncontrolled negative confounding, or reduced smoking among users of smokeless tobacco.

There is evidence from case–control studies that a diet rich in vegetables and fruits, especially cruciferous vegetables, may exert some protective effect against lung cancer [ 53 , 54 ]. However, results of prospective studies with detailed information on dietary intake are less consistent in showing a similar effect [ 55 ]. Possible reasons for the inconsistent results include bias from retrospective dietary assessment, misclassification and limited heterogeneity of exposure in cohort studies, residual confounding by smoking, and variability in food composition. Isothiocyanates are a group of chemicals with cancer-preventive activity in experimental systems, and may be responsible for some reduced risk of lung cancer in relation to high intake of cruciferous vegetables.

High intake of meat, in particular fried or well-done red meat, may increase the risk of lung cancer [ 56 ] and this may be related to formation of nitrosamines during cooking [ 57 ]. A pooled analysis of eight cohort studies provided no evidence of an increased risk of lung cancer with a high intake of either total fat or saturated fat [ 58 ]. Many studies have addressed the risk of lung cancer according to estimated intake of either β-carotene or total carotenoids (which in most cases correspond to the sum of α- and β-carotene) [ 59 ]. The evidence of a protective effect from most observational studies has been refuted by the results of randomised intervention trials based on β-carotene supplementation [ 60 , 61 ]. In two of the studies, which included smokers or workers exposed to asbestos, a significant increase in the incidence of lung cancer was observed in the treated groups; in the remaining studies, no effect was ascertained [ 60 , 61 ]. The difference in results between observational studies and preventive trials can be explained by confounding factors in fruits and vegetables other than β-carotene, or by the fact that high, nonphysiological doses of β-carotene might cause oxidative damage, in particular among smokers [ 62 ]. There is evidence from observational studies that low levels of vitamin D are associated with lung cancer risk [ 63 ]; however, results of randomised trials do not provide supportive evidence, arguing for caution when drawing conclusions.

Coffee drinking has been associated with lung cancer in a report from the NIH-AARP study (HR (95% CI) for ≥6 cups·day −1 compared with none: 4.56 (4.08–5.10)) [ 64 ]. However, this association was substantially attenuated after adjusting for smoking (1.27 (1.14–1.42)) as coffee drinkers were more likely to be smokers than non-coffee drinkers [ 64 ]. Also, no evidence of an increased risk has been reported in studies of never-smokers [ 54 ]. There is some evidence of a chemopreventive effect of tea, notably green tea, in smokers [ 65 ]. However, the overall evidence is not consistent.

Given the strong correlation between alcohol consumption and tobacco smoking in many populations, it is difficult to elucidate the contribution of alcohol to lung carcinogenesis while properly controlling for the potential confounding effect of tobacco. Meta-analyses have indicated that the increased risk of lung cancer observed among alcoholics is mainly attributable to such residual confounding, since no consistent association was observed in never-smokers [ 66 ], but a smoking-adjusted association was suggested for high alcohol consumption [ 67 , 68 ]. This conclusion was confirmed by a pooled analysis of seven cohort studies [ 69 ].

Patients with chronic obstructive pulmonary disease are at increased risk for lung cancer, and a number of studies have suggested that this is independent of smoking [ 70 – 72 ]. However, one study has not confirmed this and concludes that it is impossible to exclude a residual effect of smoking in the published literature [ 73 ]. A meta-analysis of lung cancer studies and asthma in never-smokers reported a relative risk of 1.8 (95% CI 1.3–2.3) [ 74 ]. These results are similar to analysis restricted to studies controlling for smoking, but this is mainly based on case–control studies [ 75 ].

Patients with pulmonary tuberculosis have been found to be at increased risk of lung cancer [ 76 ]. In the most informative study, involving a large cohort of tuberculosis patients from Shanghai, China [ 77 ], the relative risk of lung cancer in the subjects with a history of tuberculosis was 1.5 and 20 years after the diagnosis of tuberculosis was 2.0; a correlation was also seen with the location of the tuberculosis lesions. Whether the excess risk is caused by the chronic inflammatory status of the lung parenchyma or by the specific action of the Mycobacterium is not clear. Six studies exploring risk of lung cancer among individuals with markers of Chlamydia pneumoniae infection consistently detected a positive association [ 78 ]. However, studies based on pre-diagnostic samples had lower risk estimates than studies based on post-diagnostic samples. No association between infection with human papilloma virus and lung cancer has been established [ 79 , 80 ].

Exposure to ionising radiation increases the risk of lung cancer [ 81 ]. This increased risk has been reported in atomic bomb survivors, as well as patients treated with radiotherapy (RR 1.5–2 for cumulative exposure in excess of 100 cGy) [ 82 ]. Underground miners exposed to radioactive radon and its decay products, which emit α-particles, have been consistently found to be at increased risk of lung cancer [ 83 ]. A pooled analysis of 11 cohorts estimated an apparently linear, ∼6% risk increase per working-level year of exposure (1 working-level year=1 working-level exposure×170 h×12 months) [ 84 ]. There was also evidence that smoking synergistically modifies the carcinogenic effect of radon [ 84 ]. Today the main concern about lung cancer risk from radon and its decay products comes from residential rather than occupational exposure. A pooled analysis of 13 European case–control studies resulted in a relative risk of 1.084 (95% CI 1.030–1.158) per 100 Bq·m −3 increase in measured indoor radon [ 85 ]. After correction for the dilution caused by measurement error, the relative risk was 1.16 (95% CI 1.05–1.31). The exposure–response relationship was linear with no evidence of a threshold. A similar analysis of North American studies came to the same conclusion [ 86 ]. The US Environment Protection Agency estimates it to be the second leading cause of lung cancer in the USA. Thus, indoor radon exposure might be an important cause of lung cancer.

Occupational exposures play a significant role in lung cancer aetiology, and the risk of lung cancer is increased among workers employed in a number of industries and occupations [ 87 ]. Two studies have reported an estimate of the proportion of lung cancer cases attributable to occupational agents in the UK to be 14.5% overall [ 88 ] and 12.5% in men in France [ 89 ]. The most important occupational lung carcinogens are reported to be asbestos, silica, radon, heavy metals and polycyclic aromatic hydrocarbons [ 90 ].

All different forms of asbestos (chrysotile and amphiboles, including crocidolite, amosite and tremolite) are carcinogenic to the human lung, although the potency of chrysotile is lower than that of other types probably due to its earlier clearance [ 91 , 92 ]. In many low- and medium-resource countries, occupational exposure remains widespread.

Metals and mixed occupation exposures

Chromium [VI] compounds increase the risk of lung cancer among chromate production workers, chromate pigment manufacturers, chromium platers and ferrochromium producers. No such risk has been detected among workers exposed only to chromium [III] compounds.

Studies of nickel miners, smelters, electrolysis workers and high-nickel alloy manufacturers showed an increased risk of lung cancer [ 93 ]. The available evidence does not allow a clear separation between different nickel salts to which workers are exposed. An increased risk of lung cancer has also been reported among workers in cadmium-based battery manufacture, copper cadmium alloy workers and cadmium smelters, but the evidence is not as strong as for other agents [ 94 ]. High-level exposure to inorganic arsenic mainly occurs among workers employed in hot smelting; other groups at increased risk are fur handlers, manufacturers of sheep-dip compounds and pesticides, and vineyard workers [ 93 ]. An increased risk of lung cancer has also been reported among people exposed to high levels of arsenic in drinking water [ 95 ]. A non-linear exposure–response relationship was observed in most of the studies showing an association between lung cancer risk and arsenic, with no apparent effect for low-dose exposure.

An increased risk of lung cancer has been consistently reported in cohorts of silicotic patients [ 96 ]. Many studies investigated crystalline silica-exposed workers in foundries, pottery making, ceramics, diatomaceous earth mining, brick making and stone cutting, some of whom might have developed silicosis. An increased risk of lung cancer was reported by some, but not all, studies and in the positive studies the increase was small, with evidence of an exposure–response relationship in the high-exposure range [ 97 ].

Polycyclic aromatic hydrocarbons

Polycyclic aromatic hydrocarbons are a complex and important group of chemicals formed during combustion of organic material. An increased risk of lung cancer has been reported in several industries and occupations involving exposure to polycyclic aromatic hydrocarbons, such as aluminium production, coal gasification, coke production, iron and steel founding, tar distillation, roofing and chimney sweeping [ 98 , 99 ]. An increase has also been suggested in a few other industries, including shale oil extraction, wood impregnation, roofing and carbon electrode manufacture, with the suggestion of an exposure–response relationship. Motor vehicle and other engine exhausts represent an important group of mixtures of polycyclic aromatic hydrocarbons, since they contribute significantly to air pollution. The available epidemiological evidence shows an excess risk among workers with high occupational exposure to diesel engine exhaust [ 100 ].

Diesel exhaust

Most studies of the association between diesel exhaust exposure and lung cancer suggest a modest, but consistent, increased risk [ 101 ]. The SYNERGY project pooled occupation and smoking information from 13 304 lung cancer cases and 16 282 controls from 11 case–control studies conducted in Europe and Canada. Cumulative diesel exposure was associated with an increased lung cancer risk with an odds ratio of 1.31 and a significant exposure–response relationship (p-value <0.01) [ 102 ].

Indoor air pollution is considered to be a major risk factor for lung cancer in never-smoking women living in several regions of Asia. This includes coal burning in poorly ventilated houses, burning of wood and other solid fuels, as well as fumes from high-temperature cooking using unrefined vegetable oils such as rapeseed oil [ 103 ]. In Europe, a positive association between various indicators of indoor air pollution and lung cancer risk has also been reported [ 104 ].

Epidemiological studies exploring association between past exposure to air pollutants and lung cancer have been mainly limited by use of proxy indicators; for example, the number of inhabitants in the community of residence and residing near a major pollution source. However, these data are inconsistent, and mainly reflect present levels or levels in the recent past. In some cohort studies, environmental measurements of fine particles are suggestive of a small increase in risk among people classified as most highly exposed to air pollution [ 105 – 108 ]. The International Agency for Research on Cancer classifies outdoor air pollution as an established lung carcinogen in humans [ 109 ].

Oestrogen and progesterone receptors are expressed in the normal lung and in lung cancer cell lines, and oestradiol has a proliferative effect on the latter type of cells [ 110 ]. A small increased risk of lung cancer has been reported in early studies, while a decreased risk was detected in the more recent studies [ 111 – 119 ]. No effect was observed in the only randomised trial [ 112 ]. While the different results might be explained by changes in the formulations used for replacement therapy, the lack of an effect in the only study with an experimental design argues towards residual confounding by smoking and hence against an effect of this type of exposure on lung cancer.

There is some evidence that a reduced body mass index is associated with an increased risk of lung cancer. However, this inverse association can be explained, at least in part, by negative confounding by smoking and tobacco-related lung disease [ 120 ], and no clear association has been demonstrated among never-smokers. Subsequent studies supported this conclusion [ 121 ].

For lung cancer prevention, control of tobacco smoking is the most important preventive measure. While the effects of tobacco control in the past few decades on the incidence and mortality of the disease can be appreciated, much remains to be done, in particular among women and in the area of lung cancer screening in smokers using low-dose computed tomography scans. Other priorities for the prevention of lung cancer include control of occupational exposures, as well as indoor and outdoor air pollution, and understanding the carcinogenic and preventive effects of dietary and other lifestyle factors.

Editorial comment in Eur Respir J 2016; 48: 626–627.

Support statement: This study was partly supported by the Italian Association for Cancer Research (AIRC; project no. 14360) Italian Foundation for Cancer Research (FIRC) and Ministero dell’ Istruzione, dell’ Università e della Ricerca (MIUR) Scientific Independence of Young Researchers (SIR) 2014 grant (project RBSI1465UH). Funding information for this article has been deposited with FundRef .

Conflict of interest: None declared.

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Descriptive epidemiology, histologic classification, disparities, risk factors, lung cancer among never smokers, screening and early detection, future directions, disclosure of potential conflicts of interest, authors' contributions, acknowledgments, cancer progress and priorities: lung cancer.

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Cancer Epidemiol Biomarkers Prev 2019;28:1563–79

Matthew B. Schabath, Michele L. Cote; Cancer Progress and Priorities: Lung Cancer. Cancer Epidemiol Biomarkers Prev 1 October 2019; 28 (10): 1563–1579.

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In the United States, lung cancer is the second most common diagnosed cancer and the leading cause of cancer-related death. Although tobacco smoking is the major risk factor accounting for 80% to 90% of all lung cancer diagnoses, there are numerous other risk factors that have been identified as casually associated with lung cancer etiology. However, there are few causally linked risk factors for lung cancer diagnosed among never smokers, which, if considered a unique reportable category, is the 11th most common cancer and the 7th leading cause of cancer-related death. Lung cancer survival has only marginally improved over the last several decades, but the availability of screening and early detection by low-dose CT and advances in targeted treatments and immunotherapy will likely decrease mortality rates and improve patient survival outcomes in the near future.

Globally, lung cancer has been the most common diagnosed cancer for the last several decades ( 1, 2 ). In 2018, there was an estimated 2.1 million new lung cancer diagnoses accounting for 12% of the global cancer burden ( 1, 2 ). Among men, lung cancer remains the most common cancer diagnosis with approximately 1.37 million diagnoses in 2018, with the highest incidence rates in Micronesia (54.1 per 100,000), Polynesia (52.0 per 100,000), Central and Eastern Europe (49.3 per 100,000), and Eastern Asia (47.2 per 100,000). Among women, incidence rates are generally lower than men with approximately over 725,000 new lung cancer diagnoses in 2018. Geographic variations in incidence rates differ for women compared with men ( Fig. 1A and B ), which are attributed to historical differences in cigarette smoking. Among women, the highest incidence rates occur in North America (30.7 per 100,000), Northern Europe (26.9 per 100,000), and Western Europe (25.7 per 100,000).

Figure 1. Age-standardized rates (ASR) for lung cancer incidence worldwide. A, Age-standardized incidence rates for lung cancer among males using data from GLOBOCAN, 2018. Lung cancer incidence among males is highest in Micronesia, Polynesia, Central and Eastern Europe, and Eastern Asia and lowest in most of Africa. B, Age-standardized incidence rates for lung cancer among females using data from GLOBOCAN, 2018. Lung cancer incidence among females is highest in North America, Northern Europe, Western Europe, and Australia/New Zealand and lowest in most of Africa. Data source: GLOBOCAN 2018. Graph production: IARC (, World Health Organization.

Age-standardized rates (ASR) for lung cancer incidence worldwide. A, Age-standardized incidence rates for lung cancer among males using data from GLOBOCAN, 2018. Lung cancer incidence among males is highest in Micronesia, Polynesia, Central and Eastern Europe, and Eastern Asia and lowest in most of Africa. B, Age-standardized incidence rates for lung cancer among females using data from GLOBOCAN, 2018. Lung cancer incidence among females is highest in North America, Northern Europe, Western Europe, and Australia/New Zealand and lowest in most of Africa. Data source: GLOBOCAN 2018. Graph production: IARC ( ), World Health Organization.

In the United States, lung cancer is the second most common cancer in men after prostate cancer and the second most common cancer in women after breast cancer ( 3, 4 ). In 2019, an estimated 228,150 new cases of lung cancer are expected. The incidence rate among men is 71.3 per 100,000 and for women it is 52.3 per 100,000. Although the incidence rate has been declining in men since the mid-1980s, incidence rates did not start declining for women until the mid-2000s because of historical sex-specific differences of smoking uptake and cessation. The decline in incidence has gained momentum in the past decade with rates decreasing from 2011 to 2015 by nearly 3% per year in men and 1.5% per year in women. Geographically, lung cancer incidence is higher in the Midwest, East, and South with the highest rates observed in the South for both men and women ( Fig. 2A and B ).

Figure 2. Age-adjusted lung cancer incidence rates in the United States. A, Age-adjusted lung cancer incidence rates for males in the United States, 2011–2015, using data from U.S. Cancer Statistics Working Group. B, Age-adjusted lung cancer incidence rates for females in the United States, 2011–2015, using data from U.S. Cancer Statistics Working Group. Among both males and females, lung cancer incidence is higher in the Midwest and East and the highest rates are observed in the South, while the lowest rates are generally found in Western states. Data source: U.S. Cancer Statistics Working Group. U.S. Cancer Statistics Data Visualizations Tool, based on November 2017 submission data (1999–2015): U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute (, June 2018.

Age-adjusted lung cancer incidence rates in the United States. A, Age-adjusted lung cancer incidence rates for males in the United States, 2011–2015, using data from U.S. Cancer Statistics Working Group. B, Age-adjusted lung cancer incidence rates for females in the United States, 2011–2015, using data from U.S. Cancer Statistics Working Group. Among both males and females, lung cancer incidence is higher in the Midwest and East and the highest rates are observed in the South, while the lowest rates are generally found in Western states. Data source: U.S. Cancer Statistics Working Group. U.S. Cancer Statistics Data Visualizations Tool, based on November 2017 submission data (1999–2015): U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute ( ), June 2018.

The global geographical patterns in lung cancer–related deaths closely follow those in incidence because of poor survival and the high fatality rate of this disease ( Fig. 3A and B ). Worldwide, lung cancer is the leading cause of cancer-related death in men and the second-leading cause in women. In 2018, an estimated 1.8 million deaths occurred (1.2 million in men and 576,100 in women), accounting for 1 in 5 cancer-related deaths worldwide ( 1, 2 ). The geographic variations by country/region between men and women are largely attributed to historic patterns in tobacco smoking and maturity of the tobacco epidemic ( 2 ).

Figure 3. Estimated age-standardized rates (ASR) for lung cancer mortality worldwide. A, Age-standardized mortality rates for lung cancer among males using data from GLOBOCAN, 2018. Lung cancer mortality among males is highest in Eastern Europe, Western Asia, Northern Africa, and specific countries in Eastern Asia and lowest in most of Africa. B, Age-standardized mortality rates for lung cancer among females using data from GLOBOCAN, 2018. Lung cancer mortality among females in North America, Northern Europe, Western Europe, and Australia/New Zealand and lowest in most of Africa. Data source: GLOBOCAN 2018. Graph production: IARC (, World Health Organization.

Estimated age-standardized rates (ASR) for lung cancer mortality worldwide. A, Age-standardized mortality rates for lung cancer among males using data from GLOBOCAN, 2018. Lung cancer mortality among males is highest in Eastern Europe, Western Asia, Northern Africa, and specific countries in Eastern Asia and lowest in most of Africa. B, Age-standardized mortality rates for lung cancer among females using data from GLOBOCAN, 2018. Lung cancer mortality among females in North America, Northern Europe, Western Europe, and Australia/New Zealand and lowest in most of Africa. Data source: GLOBOCAN 2018. Graph production: IARC ( ), World Health Organization.

In the United States, lung cancer is the leading cause of cancer-related death among both men and women ( 3, 4 ). In 2019, an estimated 142,670 deaths are expected to occur, or about 23.5% of all cancer-related deaths. The mortality rate among men is 51.6 per 100,000 and 34.4 per 100,000 for women. Because of reductions in smoking, the lung cancer–related death rate has declined 48% since 1990 in men and by 23% since 2002 in women. From 2012 to 2016, the death rate dropped by about 4% per year in men and 3% per year in women. Geographically, lung cancer mortality follows a pattern similar to incidence, including the highest rates observed in the South ( Fig. 4A and B ).

Figure 4. Age-adjusted lung cancer mortality rates in the United States. A, Age-adjusted lung cancer mortality rates for males in the United States, 2011–2015, using data from U.S. Cancer Statistics Working Group. B, Age-adjusted lung cancer mortality rates for females in the United States, 2011–2015, using data from U.S. Cancer Statistics Working Group. Among both males and females, lung cancer morality is higher in the Midwest, East, and South and lowest in most Mountain states and California. Data source: U.S. Cancer Statistics Working Group. U.S. Cancer Statistics Data Visualizations Tool, based on November 2017 submission data (1999–2015): U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute (, June 2018.

Age-adjusted lung cancer mortality rates in the United States. A, Age-adjusted lung cancer mortality rates for males in the United States, 2011–2015, using data from U.S. Cancer Statistics Working Group. B, Age-adjusted lung cancer mortality rates for females in the United States, 2011–2015, using data from U.S. Cancer Statistics Working Group. Among both males and females, lung cancer morality is higher in the Midwest, East, and South and lowest in most Mountain states and California. Data source: U.S. Cancer Statistics Working Group. U.S. Cancer Statistics Data Visualizations Tool, based on November 2017 submission data (1999–2015): U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute ( ), June 2018.

Despite substantial improvements in survival in recent years for most other cancer types in the United States, there have only been small improvements in 5-year survival among patients diagnosed with lung cancer ( Fig. 5 ). This lack of improvement is primarily because the majority of patients are diagnosed with late-stage disease where the survival rates are dismal ( Fig. 6 ). The 5-year relative survival rate for all lung cancers [non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) combined] is 19%, and the 5-year survival is higher for NSCLC (23%) than SCLC (6%; refs. 3, 4 ).

Figure 5. Temporal trends in 5-year relative percent survival for lung and bronchus cancer. Observed and modeled trends in lung and bronchus cancer 5-year survival from 1975–2015 using data from SEER 18 (

Temporal trends in 5-year relative percent survival for lung and bronchus cancer. Observed and modeled trends in lung and bronchus cancer 5-year survival from 1975–2015 using data from SEER 18 ( ).

Figure 6. Percent of lung cancer cases at diagnosis and 5-year relative survival by stage. The percentage of lung cancer cases diagnosed in the United States by stage and their respective 5-year survival rates using data from SEER 18 ( “Localized” is confined to the primary site, “regional” has spread to the regional lymph nodes, and “distant” is a cancer that has metastasized. “Unknown,” which accounts for 4% of diagnoses and has an 8.2% 5-year survival, is not shown.

Percent of lung cancer cases at diagnosis and 5-year relative survival by stage. The percentage of lung cancer cases diagnosed in the United States by stage and their respective 5-year survival rates using data from SEER 18 ( ). “Localized” is confined to the primary site, “regional” has spread to the regional lymph nodes, and “distant” is a cancer that has metastasized. “Unknown,” which accounts for 4% of diagnoses and has an 8.2% 5-year survival, is not shown.

Despite the high mortality rates and poor survival outcomes associated with a lung cancer diagnosis, the next generation of targeted therapies and the emergence of immune checkpoint inhibitors have demonstrated durable long-term survival in subsets of patients. As such, these therapies may hold the key in improving lung cancer patient outcomes leading to curable lung cancer among early-stage diagnoses and a chronic and manageable disease for patients with advanced and metastatic disease.

Lung cancer tumors are divided into two broad histologic categories: NSCLC and SCLC. NSCLC represents more than 80% to 85% of lung cancers of which approximately 40% are adenocarcinoma, 25% to 30% are squamous cell carcinoma, and 10% to 15% are large cell carcinomas ( Fig. 7 ; refs. 5–7 ). Bronchioloalveolar carcinoma (BAC) was a distinct histologic classification representing a subgroup of adenocarcinomas and has been replaced with adenocarcinoma in situ , minimally invasive adenocarcinoma, and invasive adenocarcinoma of the lung ( 8 ). Other less common histologic subtypes include adenosquamous carcinoma, pleomorphic sarcomatoid carcinoma, large-cell neuroendocrine carcinoma, and carcinoid tumor.

Figure 7. Histologic classification of lung cancer. The two major lung cancer histologic categories (NSCLC and small cell lung carcinoma) and the most common histologic subtypes among NSCLC (adenocarcinoma, squamous cell carcinoma, and large cell carcinoma).

Histologic classification of lung cancer. The two major lung cancer histologic categories (NSCLC and small cell lung carcinoma) and the most common histologic subtypes among NSCLC (adenocarcinoma, squamous cell carcinoma, and large cell carcinoma).

Among women, adenocarcinoma has been the most frequently diagnosed histologic subtype since at least the 1970s ( Fig. 8A ). Among men, the incidence rate of lung adenocarcinoma has been on the rise since the 1970s, and the incidence rate for lung adenocarcinoma surpassed squamous cell carcinoma around 1994 ( Fig. 8B ). The incidence rate for squamous cell carcinomas has been on the decline since the early 1980s. This temporal shift in histologic diagnoses is largely attributed to the widespread use of filtered cigarettes and increasing amounts of tobacco-specific nitrosamines in tobacco ( 9 ). Regarding the former, earlier in the 20th century, most mass-produced cigarettes were nonfiltered, which discouraged deep inhalation and combusted tobacco smoke exposed primarily in the trachea and bronchus, resulting in observed higher rates of squamous cell carcinoma diagnoses especially among men ( 10 ). When filtered cigarettes were introduced, combusted tobacco smoke dispersed deeper into the respiratory tree due to deeper inhalation resulting in adenocarcinomas with a more peripheral distribution ( 11 ). The introduction of so-called “light” filtered cigarettes and changing tobacco blends, which decreased nicotine but increased nitrates and N-nitrosamines, had the paradoxical effect of increasing, rather than decreasing, lung cancer risk due to promotion of deeper and more frequent inhalation of combusted tobacco smoke ( 10, 11 ).

Figure 8. Age-adjusted incidence rates (per 100,000) for lung and bronchus cancer by year of diagnosis and histology. A, Age-adjusted incidence rates among females for lung and bronchus cancer by year of diagnosis and histology using SEER 9, 1973–2015. B, Age-adjusted incidence rates among males for lung and bronchus cancer by year of diagnosis and histology using SEER 9, 1973–2015. The incidence rates are age-adjusted to the 2000 U.S. population.

Age-adjusted incidence rates (per 100,000) for lung and bronchus cancer by year of diagnosis and histology. A, Age-adjusted incidence rates among females for lung and bronchus cancer by year of diagnosis and histology using SEER 9, 1973–2015. B, Age-adjusted incidence rates among males for lung and bronchus cancer by year of diagnosis and histology using SEER 9, 1973–2015. The incidence rates are age-adjusted to the 2000 U.S. population.

Although the binary division of lung cancer into NSCLC and SCLC is still widely applied and relevant, advances in genomic profiling has resulted in a paradigm shift whereby lung cancers are also characterized and classified by tumor biomarkers and genetic alterations, such as gene expression, mutations, amplifications, and rearrangements ( Table 1 ), that are critical to tumor growth and survival and can be exploited with specific targeted agents or immune-checkpoint blockades ( 12–14 ).

Frequency of somatic mutations and alterations in NSCLC

Males versus females

Although the terms "sex" and "gender" have been historically interchangeable in medical research, their uses are distinct as sex is conventionally based on anatomy and physiology, whereas gender typically refers to identity, behavior, or socially constructed roles. As such, research in potential lung cancer disparities has not disentangled sex versus gender. Nonetheless, the established differences in lung cancer incidence and mortality rates between males and females are attributed to historic patterns in tobacco smoking as noted above. To address potential sex-specific differences in lung cancer risk, O'Keeffe and colleagues ( 15 ) conducted a systematic review and meta-analysis of prospective cohort studies on the sex-specific association of smoking with the risk of fatal and nonfatal lung cancer. By restricting the analyses to cohort studies, the goal was to minimize bias often present in case–control studies. Data from 99 cohort studies representing more than 7 million individuals and over 50,000 incident cases of lung cancer found no evidence for sex-specific differences for risk of smoking-related lung cancer. Specifically, the authors reported a pooled adjusted lung cancer relative risk of 6.99 for females and 7.33 for males and found no evidence of publication bias or differences across major predefined participant and study subtypes. The female-to-male ratio of relative risk was 0.99, 1.11, and 0.94, for light, moderate, and heavy smoking, respectively. The authors acknowledge that “… these data may yet underestimate the true relative risk of smoking-related lung cancer in women, given later uptake and lower intensity of smoking in women .”

Regarding sex-specific lung cancer among never smokers, there is compelling historic evidence ( 16–18 ) that suggests a higher risk, incidence, and mortality among never-smoking females versus never-smoking males. Conversely, a multi-institutional registry-based study ( 19 ) of over 12,000 patients with lung cancer found that the proportion of patients with lung cancer who reported themselves as never smokers increased over time, but the observed increase was independent of sex.

Race and ethnicity

Racial and ethnic differences in lung cancer incidence, mortality, and survival outcomes are well-documented and are largely attributed to inequalities in wealth (i.e., socioeconomic status) leading to differences in risk factor exposures and barriers to high-quality prevention, early detection, and treatment ( 4 ). Analyses from the American Cancer Society ( 4 ) revealed that lung cancer incidence for non-Hispanic Black men (85.4 per 100,000) is higher than non-Hispanic White men (74.3 per 100,000) and Hispanic men (39.2 per 100,000). However, the incidence for non-Hispanic Black women (49.2 per 100,000) and Hispanic women (24.6 per 100,000) is lower than non-Hispanic White women (57.4 per 100,000). Similar trends were noted for lung cancer mortality. Black patients with lung cancer (16%) have overall lower 5-year relative survival rate than Whites (19%), which is consistent for localized (52% vs. 56%) and regional disease (27% vs. 30%), but not for distant disease (5% vs. 5%). Black patients with lung cancer are more frequently diagnosed with distant disease compared with White patients (61% vs. 57%) and less frequently diagnosed with localized disease (13% vs. 17%).

Socioeconomic status

Socioeconomic status (SES) is a broad term for the social standing or “class” of an individual or group of people and is often measured based on highest attained education, income, and occupation. SES is associated with health and disease through multiple interacting pathways in terms of resources, physical and psychosocial stressors, and health-related behaviors and risk factors. SES is strongly associated with some lung cancer risk factors, including tobacco smoking behavior, whereby uptake may be higher among those with low SES and quit attempts are less likely to be successful ( 20 ). Results from the American Cancer Society found that cancer mortality is 28% higher overall in poor counties than affluent counties in the United States and >40% higher among men in poor counties ( 4 ). A pooled analysis of 17,021 cases and 20,885 controls found that, after adjusting for smoking, low SES based on International Socio-Economic Index was associated with an 84% increased risk of lung cancer among men and a 54% increased risk among women ( 21 ). Lung cancer risk was still elevated but somewhat attenuated when SES was assessed using the European Socio-economic Classification. The authors concluded that the strong associations emphasizes the need for further exploration of the pathways from SES to lung cancer and “ clarifying these pathways could then contribute to further understanding of lung cancer etiology and shape prevention approaches .”

LGBTQ individuals

The lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ) community, also referred to as sexual and gender minorities, is a diverse and medically underserved population that has been historically marginalized ( 22–25 ). The sparse but growing body of evidence demonstrates the LGBTQ population may be an ignored epidemic ( 26 ) associated with increased risk and poorer outcomes for certain cancers, including lung cancer ( 27–32 ). Prior studies linking Surveillance, Epidemiology and End Results (SEER) data with the United States Census ( 31 ) and California Cancer Registry with the California Health Interview Survey ( 30 ) provided evidence that gay men have higher incidence and mortality rates for lung cancer, and lesbian females have lower incidence and mortality rates from lung cancer compared with the general population. In the bisexual community, men have a lower incidence of lung cancer, whereas bisexual women have higher incidence of lung cancer. The lung cancer disparities among LGBTQ individuals may be attributed, in part, to higher prevalence of tobacco smoking among this population ( 33–35 ). To date, there are no published risk estimates for the association between tobacco smoking and lung cancer among LGBTQ individuals. Another potential risk modifier is human immunodeficiency virus (HIV) infection, in which gay and bisexual individuals account for over 67% of all HIV diagnoses ( 36 ) and incidence of lung cancer among HIV-infected patients is significantly higher than the general population ( 37 ). HIV and lung cancer are discussed below.

Causative and putative lung cancer risk factors that are discussed below are summarized in Table 2 .

Established and putative risk lung cancer risk factors

Abbreviation: COPD, chronic obstructive pulmonary disease.

Tobacco smoking

Unequivocally, tobacco smoking is the most important and prevalent lung cancer risk factor. A rare disease at the beginning of the 20th century, lung cancer was one of the first diseases to be causally linked to tobacco smoking ( 38 ). Throughout most of the 20th century in the United States, lung cancer incidence and mortality increased as the per capita in cigarette consumption increased ( Fig. 9 ) and as successive generations of first male and then female smokers began smoking at earlier ages. Men predominantly began smoking manufactured cigarettes earlier in the 20th century, during and after World War II. Although few women smoked regularly before World War II, average age at initiation continued to decrease and per capita in cigarette consumption increased through the 1960s ( 39 ). Tobacco consumption fell drastically in the United States following publication of the landmark 1964 U.S. Surgeon General's Report that concluded cigarette smoking is causally related to lung cancer in men ( 10 ).

Figure 9. Trends in cigarette and lung cancer–related death rates. The temporal trends in cigarette use versus lung cancer death rates for both males and females in the United States using data from the Centers for Disease Control and Prevention. Data sources from National Center for Health Statistics (NCHS), Centers for Disease Control and Prevention, 2017, and CDC Report on Consumption of Combustible and Smokeless Tobacco — United States, 2000–2015, page 1359.

Trends in cigarette and lung cancer–related death rates. The temporal trends in cigarette use versus lung cancer death rates for both males and females in the United States using data from the Centers for Disease Control and Prevention. Data sources from National Center for Health Statistics (NCHS), Centers for Disease Control and Prevention, 2017, and CDC Report on Consumption of Combustible and Smokeless Tobacco — United States, 2000–2015, page 1359.

Tobacco smoke contains more than 4,000 chemicals, including at least 69 established carcinogens and other toxicants associated with major diseases ( 40 ). Although only around 15% of smokers develop lung cancer, 80% to 90% of lung cancer diagnoses are attributed to tobacco smoking in the United States ( 3 ). The relative risk of lung cancer is estimated to be about 20-fold higher than that of a lifetime never smoker, and the magnitude of lung cancer risk is related to smoking intensity (i.e., cigarettes smoked per day and number of years smoked; refs. 40–42 ). Numerous lung cancer risk models ( 43–48 ) are available as web-based tools ( 49 ) that provide risk assessment based on demographic information, including smoking history and intensity.

Exposure to secondhand smoke

Secondhand smoke, or side-stream smoke, is an indirect carcinogenic exposure resulting from the burning of tobacco products. From 1988 to 2014, secondhand smoke exposure among never smokers in the United States significantly declined from 87.5% to 25.2%, attributed to tobacco control efforts and smoke-free laws and policies in workplaces and public places ( 50 ). However, there has been no change in secondhand smoke exposure between 2011 to 2012 and between 2013 to 2014 with an estimated 1 in 4 never smokers, or about 58 million people, exposed to secondhand smoke from 2013 to 2014 ( 50 ). Carcinogens that have been measured in secondhand smoke include polycyclic aromatic hydrocarbons, nitrosamines, and aromatic amines. Studies have shown that nicotine and its metabolite cotinine as well as DNA adducts from tobacco carcinogens are present in the urine of never smokers who are exposed to secondhand smoke ( 51 ). A 2006 report from the U.S. Surgeon General on The Health Consequences of Involuntary Exposure to Tobacco Smoke ( 52 ) concluded there is no safe level of exposure to secondhand tobacco smoke and stated, “ The evidence is sufficient to infer a causal relationship between secondhand smoke exposure and lung cancer among lifetime nonsmokers. This conclusion extends to all secondhand smoke exposure, regardless of location .” A meta-analysis published in 2018 of 12 studies found that secondhand smoke exposure compared with never smokers without such exposure was associated with a 25% increased risk of lung cancer ( 53 ). A separate meta-analysis that assessed the association between secondhand smoke and lung cancer in Japanese nonsmokers found a 28% increased risk ( 54 ).

Electronic cigarettes

Electronic nicotine delivery systems, also referred to as electronic cigarettes and e-cigarettes, allow for the delivery of nicotine to the lung epithelium via an electronic device. Although a patent for this type of device was first issued in 1965, mass production of e-cigarettes did not occur until 2003 and became widely available in 2005 in the United States. Today in the United States, there are over 460 different brands on the market with over 7,700 flavors ( 55, 56 ), and prevalence of e-cigarette use among adults is estimated to be between 2.6% and 4.5% ( 57–61 ). Of particular concern is the uptake of e-cigarette use among youth ages 12 to 18 years, with the 2017 National Youth Tobacco Survey reporting 11.7% of high school students and 3.3% of middle school students using e-cigarettes within the last month. One year later, 20.8% of high school students and 4.9% of middle school students reported using e-cigarettes within the last month, representing increases of 78% and 48%, respectively ( 62 ). In addition, e-cigarette use among U.S. youths is associated with increased risk of initiation of traditional cigarette use ( 63, 64 ). Within the next 10 years, it is anticipated that total sales of e-cigarettes are to exceed tobacco products ( 65 ). Although there are various configurations, these devices typically include a mouthpiece and a battery-operated heating element to heat fluid contained in a replaceable cartridge or reservoir that contains a mixture of liquid nicotine, flavorings, and other chemical solvents ( 66 ). Propylene glycol and vegetable glycerin are the two major solvents in e-cigarettes and studies have shown that vapors from these solvents contain toxic and carcinogenic carbonyl compounds, including formaldehyde, acetaldehyde, acetone, and acrolein ( 62, 67 ). Studies have also shown that e-cigarette use is associated with increased oxidative stress, which seems to mediate the adverse effects of e-cigarettes. Oxidative stress develops in e-cigarette–exposed human bronchial and lung epithelial cells that can result in adverse intermediate events, including inflammation, cytotoxicity, and increased endothelial cell permeability ( 68, 69 ). A model has been proposed for the role of oxidative stress in mediating adverse effects of e-cigarettes leading to cancer, cardiopulmonary pathogenesis, and neurodegenerative disorders ( 65 ). Furthermore, studies have demonstrated that e-cigarettes generate acute deleterious effects on lung function ( 70, 71 ). Cumulatively, data suggest that vapor produced from e-cigarettes contains potentially harmful compounds and may lead to adverse effects on human health. Although data suggest that e-cigarettes may be a less harmful alternative to conventional cigarettes, at present, there are no data regarding the long-term cancer risk associated with low-level exposure to the detected carcinogens ( 72 ).

Other tobacco use

Although cigarettes remain the most prevalent form of tobacco use in the United States, other tobacco products, including pipes, cigars, and water pipes (e.g., hookah), are still common and have been associated with increased risk and mortality of lung cancer. Christensen and colleagues ( 73 ) identified 357,420 individuals who were never, current, or former users of cigars, pipes, and cigarettes by linking data from the National Longitudinal Mortality Study and the Tobacco Use Supplement of the Current Population Survey. After excluding nearly 49,000 individuals who reported multiple tobacco product use, risk of lung cancer–related death among daily users was highest among cigarette users (12.7-fold increased risk), followed by daily cigar use (4.2-fold increased risk), and then daily pipe users (1.7-fold increased risk). A meta-analysis ( 74 ) of 287 epidemiologic studies of lung cancer found that pipe use only was associated with a 3.3-fold increased risk of lung cancer and cigar use only was associated with a 2.95-fold increased risk. A recent pooled analysis ( 75 ) of five prospective cohort studies from the U.S. National Cancer Institute (NCI) Cohort Consortium that had collected data on cigar and pipe smoking found a 2.7-fold increased risk of lung cancer cigar use only and a 1.9-fold increased risk for pipe use only. A meta-analysis ( 76 ) of 13 case–control studies reported a 4.6-fold increased risk of lung cancer among those using water pipes only. While the risk of lung cancer and death is lower for individuals using these products compared with those who smoke cigarettes, it should be noted that these are not safer alternatives to cigarette smoking as the lower point estimates are likely attributed to lower smoking intensity and perhaps lesser degrees of inhalation of these products.

Although the terms cannabis and marijuana are frequently used interchangeably, cannabis is the generic term that includes cannabinoids, hemp, and marijuana derived from the Cannabis sativa plant ( 77 ). In the United States, smoked cannabis is estimated to be the most commonly inhaled drug after tobacco with an estimated 7,000 new users a day ( 78 ). As of early 2019, 30 states, the District of Columbia, Guam, and Puerto Rico have legalized marijuana use for medical purposes and 20 states and the District of Columbia have decriminalized the possession of small amounts of marijuana for personal use ( 79 ). However, smoked cannabis contains many of the same chemical toxins and carcinogens as tobacco smoke, including acetaldehyde, acrolein, ammonia, carbon monoxide, formaldehyde, phenols, nitrosamines, and polycyclic aromatic hydrocarbons ( 80 ). In addition, regular smoking of marijuana alone is associated with adverse effects on the respiratory system similar to that of cigarette smoking ( 81, 82 ). However, despite the evidence of adverse biological effects, to date there is no conclusive evidence that suggests cannabis smoking is associated with an increased incidence of lung cancer. A pooled analysis from the International Lung Cancer Consortium of 2,159 lung cancer cases and 2,985 controls found little evidence for an increased risk of lung cancer among habitual or long-term cannabis smokers ( 83 ). However, it should be noted that studies to date have been limited by sample size, self-report, and confounding (e.g., many marijuana users also report tobacco use). Marijuana use is prevalent among youth in the United States, as data from the National Survey on Drug Use and Health reported that prevalence of past-year use was between 12% and 16% for adolescents ages 12 to 17 years between 2002 and 2014 ( 84 ). In addition, over the last decade, fewer adolescents perceive “moderate” or “regular” use of marijuana as a health risk ( 85, 86 ). As the association between smoked cannabis and lung cancer is still undefined and marijuana use is prevalent, more research will be required in the future to characterize the association between smoked cannabis and risk of lung cancer and for other diseases.

Because tobacco smoking is a potent and prevalent risk factor, secondary causes of lung cancer are often diminished in perceived importance. However, there are numerous other exposures that are causally linked to lung cancer risk. Radon is an invisible, odorless, tasteless radioactive gas that is found in soil and produced naturally during the radioactive decay of thorium and uranium. All humans are exposed to radon gas and there are substantial geographic variations globally and throughout the United States. Worldwide, 3% to 14% of lung cancers are attributed to radon exposure and the variance is attributed to geographic differences in radon concentration and on the method of calculation ( 87 ). In the United States, radon exposure is estimated to be the second leading cause of lung cancer and responsible for over 21,000 or 13% of lung cancer–related deaths each year ( 87, 88 ). Published meta-analyses have reported that indoor radon exposure is associated with a 14% to 29% increased risk of lung cancer ( 89–91 ).

Occupational exposures

Occupational exposure to carcinogens is estimated to account for 5% to 10% of lung cancers ( 41, 88, 92 ), of which asbestos exposure is historically the most common. Asbestos is a commercial term for a group of naturally occurring mineral silicate fibers, including amphiboles (crocidolite, amosite, tremolite, anthophyllite, and actinolite) and chrysotile (the sole serpentine fiber). Asbestos is found on all continents, has been used commercially since the 19th century, and is still used in some countries today in numerous applications, including insulation, textile, cement, and roofing ( 93 ). Although the mechanisms involved in asbestos-associated diseases are complex and the molecular pathways involved are not fully established, direct and indirect cellular and molecular effects likely contribute to lung cancer etiology, including oxidative stress, chronic inflammation, genetic and epigenetic alterations, and cellular toxicity and fibrosis ( 94 ). A meta-analysis of 14 case–control studies conducted in Europe and Canada that included 17,705 lung cancer cases and 21,813 controls found ever-exposure to asbestos was associated with a 24% increased risk in men and 12% increased risk in women ( 95 ). There are substantial synergistic effects ( 96 ) between asbestos exposure and tobacco smoking on lung cancer risk and morality ( 95, 97, 98 ).

The International Agency for Research on Cancer (IARC) evaluates carcinogenicity for a wide range of human exposures. Agents classified as “carcinogenic to humans” (Group 1; ref. 99 ) that have sufficient evidence of causing lung cancer in humans include numerous occupational-related exposures, including arsenic, beryllium, cadmium, chromium, and diesel exhaust, and specific occupations, including aluminum production, coal gasification, coke production, underground hematite mining, iron and steel founding, painting, and rubber production (reviewed in ref. 100 ).

History of noninfectious-related respiratory diseases

Chronic obstructive pulmonary disease (COPD), which includes emphysema and chronic bronchitis, is an irreversible chronic inflammatory condition that leads to fixed narrowing of small airways and alveolar wall destruction. The long-standing inflammatory reaction in the bronchi is accompanied by a continual cycle of injury and repair and therefore could play a key role in lung carcinogenesis. In the United States, over 15 million people reported ever receiving a diagnosis of COPD in 2015 and is the third leading cause of death after heart disease and cancer ( 101 ). Tobacco smoking is the major risk factor for COPD ( 102 ), so it is expected to find a positive association between COPD and lung cancer. Published meta-analyses have reported a 2- to 3-fold risk of lung cancer associated with a history of COPD, emphysema, or chronic bronchitis ( 103–105 ). A pooled analysis from the International Lung Cancer Consortium found that a history of emphysema conferred a 2.44-fold increased risk of lung cancer ( 106 ).

Asthma is a common childhood disease affecting approximately 300 million people worldwide ( 107 ). Asthma is characterized by chronic inflammation of the lungs and presents with airway hyper-reactivity, excessive mucous formation, and respiratory obstruction. Asthma has been suspected as a potential risk factor for lung cancer because inflammation also plays a pivotal role in the lung cancer pathogenesis. A pooled analysis published in 2012 of 16 studies in the International Lung Cancer Consortium concluded that increased risk between asthma and lung cancer may not reflect a causal effect because the increased incidence was largely observed in small cell and squamous cell lung carcinomas, primarily within 2 years of asthma diagnosis, and the association was weak among never smokers ( 108 ). However, a meta-analysis published in 2017 that included 18 studies with over 16 million individuals ( 109 ) found that asthma was significantly associated with a 44% increased risk of lung cancer and a 28% increased risk among never smokers. Subgroup analyses also demonstrated significant increases for non-Hispanic Whites, Asians, males, and females.

History of infectious-related respiratory diseases

Pneumococcal disease is an umbrella term for a group of syndromes caused by a variety of organisms resulting in varied manifestations and sequelae ( 110, 111 ). Most commonly, pneumococcal disease is an infection caused by the Streptococcus pneumoniae bacterium that can infect the lungs (pneumonia), bloodstream (bacteremia), and tissues and fluids surrounding the brain and spinal cord (meningitis). In the United States, approximately 400,000 hospitalizations from pneumococcal pneumonia occur annually ( 112 ). Pneumonia is a putative lung cancer risk factor through several possible mechanisms from mediators of chronic local inflammation, including elevated reactive oxygen species that can cause DNA damage and somatic mutations, antiapoptotic signaling, and increased angiogenesis ( 112 ). Published meta-analyses have reported a history of pneumonia was associated with a 30% to 40% increased risk of lung cancer risk ( 104, 113 ) and a pooled analysis from the International Lung Cancer Consortium reported a 57% increased risk ( 106 ). However, such findings should be interpreted with caution because reverse causality cannot be ruled out as pulmonary infections can be a result of a weakened immune system due to lung cancer ( 104 ). Furthermore, the timing of a pneumonia diagnosis can coincide with or confound the diagnosis of lung cancer, and pneumonia may be a complication of lung cancer such as postobstructive pneumonia ( 114 ).

Chlamydia pneumonia ( C. pneumoniae ) is the most commonly occurring intracellular bacterial pathogen and is responsible for sinusitis, pharyngitis, and pneumonia ( 115 ). Its transmission occurs via respiratory secretions and may increase risk of lung cancer through mediators of inflammation similar to those speculated for pneumonia ( 116 ) as described above. A meta-analysis ( 117 ) of 12 studies, including 2,595 lung cancer cases and 2,585 controls, reported that C. pneumoniae infection was associated with a 1.5-fold increased risk of lung cancer. C. pneumoniae infection was significantly associated with a 1.2-fold increased risk of lung cancer in prospective studies and a 2.2-fold increased risk in retrospective studies. When the definition of chronic infection was defined by antibody titer, the IgA ≥ 16 cutoff group was associated with a 1.2-fold increased risk and the IgA ≥ 64 cutoff group was associated with a 2.4-fold increased risk. Tuberculosis is a communicable infectious disease transmitted by cough aerosol and is caused by the Mycobacterium tuberculosis bacterium. Although tuberculosis primarily affects the lungs, it can affect other parts of the body. Worldwide incidence of tuberculosis has slowly declined over the past decade; in 2013, an estimated 9 million incident cases of tuberculosis (126 cases per 100,000) were reported with more than 60% of the burden concentrated in the 22 high-burden countries ( 118 ). The United States is a low-incidence country with an annual incidence of 30 tuberculosis cases per 1 million ( 119 ). Tuberculosis can induce chronic inflammation and pulmonary fibrosis, leading to higher rates of genetic alterations and mutations, and may be the factors responsible for the role of tuberculosis on lung cancer risk ( 120 ). A pooled analysis from the International Lung Cancer Consortium and a meta-analysis reported that previous history of tuberculosis was associated with a 48% and 76% increased risk of lung cancer, respectively ( 104, 106 ).

Individuals who are infected with HIV are at increased risk for many cancers, attributed to many factors, including HIV-related immunosuppression, which impairs control of oncogenic viral infections, mediators of inflammation, and coinfection with oncogenic viruses such as hepatitis B and C ( 121–123 ). Lung cancer is a leading non-acquired immunity deficiency syndrome (AIDS) defining cancer (NADC) and is the most frequent cause of cancer-related death among persons infected with HIV ( 124 ). Although adults with HIV are more likely to smoke cigarettes than the general adult population ( 125 ), when accounting for smoking, elevated incidence of lung cancer among HIV-infected persons has been observed ( 126 ). The HIV/AIDS Cancer Match (HACM) Study used linked data collected by U.S. HIV and cancer registries to describe cancer risk in HIV-infected people in the United States relative to the general population ( 127 ). Standardized incidence ratios (SIR) were used to test for differences by AIDS status and over time. Among 448,258 HIV-infected people, lung cancer was the second common individual cancer type (11.6%), and lung cancer risk was elevated 2-fold.

Other lifestyle factors

There is also compelling evidence that other factors may be associated with an increased risk of lung cancer for both smokers and never smokers, including poor diet and low body mass index ( 128–136 ).

Inherited genetics

In 2004, the Genetic Epidemiology of Lung Cancer Consortium revealed the first evidence for a major susceptibility locus influencing lung cancer risk to a region on 6q23–25 ( 137 ). With the arrival of genome-wide association (GWA) studies about 17 years ago, it is now possible to interrogate the human genome more comprehensively for associations between inherited single-nucleotide polymorphisms (SNP) and human disease. GWA studies have successfully identified genetic factors significantly associated with lung cancer susceptibility with varying strengths of association evidence and some loci have been refined to specific subgroups, including sex, ethnicity, smoking status, and histologic subtypes ( 138, 139 ). Data from these large GWA studies could be leveraged toward development of risk models based on polygenic risk scores defined by the combination of SNPs that yield the best predictive model ( 140 ).

Globally, approximately 25% of lung cancer diagnoses are among never smokers ( 141 ), and approximately 60% to 80% of women diagnosed with NSCLC are never smokers. In East and South Asia, a high proportion of female lung cancers occur among never smokers ( 142 ). In the United States, although smoking rates and the incidence of lung cancer have declined over the last several decades, the incidence of lung cancer among never smokers (LCANS) has been on the rise. Approximately 10% to 20% of all lung cancer diagnoses occur in never smokers in the United States, and if considered a separate reportable category, LCANS is the 11th most common cancer and the 7th leading cause of cancer-related deaths.

Many of the exposures associated with lung cancer risk have been found to be risk factors for both smokers and never smokers. Nonetheless, risk factors found to be associated with LCANS include secondhand smoke, cooking fumes, ionizing radiation, radon gas, inherited genetic susceptibility, occupational exposures, preexisting lung disease, and oncogenic viruses (reviewed in ref. 143 ). Among all risk factors, advanced age is the most significant contributor to LCANS. Even if the incidence of LCANS remains constant over time, the number of lung cancer–related deaths among never smokers is expected to increase significantly in the following decades as the prevalence of smoking continues to decline as the population age structure continues to shift to older ages ( 143 ). Thus, lung cancer will continue to be a substantial public health burden in the United States in spite of the significant improvements in tobacco control and early detection.

The histology of LCANS is most likely to be adenocarcinoma, and molecular profiling studies have found that the tumor genome of LCANS is significantly different from the genome of lung cancers arising in smokers. Mutations in TP53 , KRAS , and STK11 are more frequent in tobacco smokers with lung cancer, whereas EGFR and HER2 mutations and the ALK-ELM4 fusion are more common among LCANS ( 144 ). Revealing and understanding differences at the molecular level among LCANS may identify the etiologic processes involved in tumorigenesis and reveal important therapeutic strategies for targeting key oncogenic events. As such, the National Cancer Institute has launched “ Sherlock Lung: A Molecular Epidemiologic Study of Lung Cancer in Never Smokers ” ( 145 ), with the goal of tracing lung cancer etiology in never smokers by analyzing molecular data in conjunction with histologic features to develop an integrated molecular, histologic, and radiologic classification of LCANS.

Most lung cancers are preventable and could be mitigated by reducing smoking initiation among adolescents and increasing smoking cessation among adults. Fortunately, smoking rates have steadily declined in the United States since the 1960s ( 10 ). In 2016, the prevalence of current cigarette smoking among adults was 15.5%, which was substantially declined from 20.9% in 2005 ( 146 ). Although primary prevention (smoking prevention and cessation) mitigates risk and mortality, former smokers remain at significant risk of dying from lung cancer ( Fig. 10 ; ref. 147 ). As such, early detection is currently the only option for those who have already quit smoking and among those individuals who are at high risk. Lung cancer will likely remain a major public health burden globally throughout the 21st century and advances in risk assessment, early detection, diagnosis, and treatment will be imperative in improving outcomes of this disease ( 148 ).

Figure 10. Lung cancer mortality by smoking status. Lung cancer mortality (per 100,000) among current smokers, former smokers, and never smokers based on published figures that were adapted from Halpern and colleagues (ref. 147; J Natl Cancer Inst 1993;85:457–464). Former smokers are presented by age-at-quit.

Lung cancer mortality by smoking status. Lung cancer mortality (per 100,000) among current smokers, former smokers, and never smokers based on published figures that were adapted from Halpern and colleagues (ref. 147 ; J Natl Cancer Inst 1993;85:457–464). Former smokers are presented by age-at-quit.

As described earlier, the majority of patients with lung cancer are diagnosed with advanced stage disease, where the prospects for cure are limited. However, local therapy for early-stage disease is associated with substantially improved overall survival. Until recently, a modality for the successful detection of early-stage lung cancer has been elusive. In 2011, results from the National Lung Screening Trial (NLST) demonstrated a 20% relative reduction in lung cancer mortality for individuals screened by low-dose helical CT (LDCT) compared with standard chest radiography in a high-risk population of 53,454 current and former smokers ages 55 to 74 years ( 149 ). Screen-detected incidence lung cancers diagnosed following a positive screen at 1 or 2 years after the baseline screen accounted for 58% of all LDCT-detected lung cancers in the NLST, were 2.7-fold higher in the LDCT arm versus the chest radiography arm, and were associated with a favorable stage shift from advanced to more early-stage lung cancers ( 149 ). In addition, in the LDCT arm, a subset of screen-detected incidence lung cancers where their antecedent screens were positive prior to the screen of the cancer diagnosis were associated with improved 5-year survival compared with prevalent lung cancers ( 150 ) that are usually diagnosed when patients develop symptoms in a “real world setting.” Following publication of the NLST results, the United States Preventive Services Task Force (USPSTF) in December 2013 and the Centers for Medicare and Medicaid (CMS) in February 2015 issued recommendations for annual LDCT screening for eligible high-risk individuals ( 151, 152 ). Both the USPSTF and CMS guidelines recommend smoking cessation interventions for individuals who enter a lung cancer screening program. Novel smoking cessation strategies tailored to the lung cancer screening setting will likely amplify the survivorship gains expected from screening alone ( 153 ).

Despite the conclusive benefits shown by the NLST and the recommendations and implementation of lung cancer screening in the United States, European nations have not yet issued similar recommendations because of the absence of proven benefit in randomized clinical trials conducted in Europe ( 154 ). However, in 2018 the initial results of the Nederlands-Leuvens Longkanker Screenings ONderzo ek (NELSON) trial ( 155 ) were presented at the 19th World Conference on Lung Cancer of the International Association for the Study of Lung Cancer and indicated significant reductions in lung cancer mortality. Moreover, two additional randomized trials conducted in Italy ( 156 ) and Germany ( 157 ) were published in 2019 providing additional confirmation of lung cancer screening efficacy. The Multicentric Italian Lung Detection (MILD) trial ( 156 ), in which 4,099 participants ages 49 to 75 years with a smoking history of ≥ 20 pack-years were prospectively randomized to undergo LDCT screening for a median period of 6 years ( n = 2,376) or to a control arm with no screening intervention ( n = 1,723). Landmark analysis that considered only individuals alive with no lung cancer diagnosis after 5 years from randomization revealed a 58% reduction in lung cancer mortality and a 32% reduction in all-cause mortality after the fifth year of screening. The German Lung cancer Screening Intervention (LUSI), a randomized trial ( 157 ) of 4,052 long-term smokers ages 50 to 69 years comparing five annual rounds of LDCT screening ( n = 2,029) versus a control arm without screening ( n = 2,023), found a 26% reduction in lung cancer mortality over an average observation time of 8.8 years after randomization. The cumulative evidence based on the results of the NLST, the MILD trial, the LUSI trial, and anticipated publication of the NELSON trial has demonstrated substantial beneficial mortality reductions associated with LDCT screening.

Over the last several decades, substantial progress has been made across the cancer control continuum in terms of etiology, prevention, early detection, diagnosis, treatment, survivorship, and end of life; however, lung cancer is still a major public health burden globally and in the United States. Etiologically, concerted efforts are needed to identify causal risk factors for lung cancer among never smokers and to identify never smokers at the greatest risk for lung cancer who perhaps can benefit from a lung cancer screening program. In addition, the impact of marijuana and e-cigarettes on lung cancer risk needs to be clarified. From a prevention standpoint, additional research is needed to identify potential agents that can reduce lung cancer risk especially among former smokers. Precision-based risk and screening should be explored to identify individuals who would benefit most from entering a lung cancer screening program. Advancements in screening technology and biomarkers in the screening setting could reduce false positives and overdiagnosis and improve nodule management. Further research is needed on the feasibility and efficacy of providing smoking cessation treatment in the lung cancer screening setting. Biomarkers that are highly predictive of negative responses to targeted therapies and immunotherapy are a significant unmet clinical need because there are subgroups of patients who may not respond to these specific treatments. This is particularly salient in the subsets of patients that may experience treatment-induced rapid disease progression, which can be rapid and lethal. Finally, more research is needed to personalize treatment plans that minimize adverse survivorship issues and lead to improved quality of life for lung cancer survivors.

No potential conflicts of interest were disclosed.

Conception and design: M.B. Schabath, M.L. Cote

Writing, review, and/or revision of the manuscript: M.B. Schabath, M.L. Cote

Study supervision: M.B. Schabath

This manuscript is dedicated to the memory of Grace C. Schabath (1941–2019). This work was funded in part by the National Institutes of Health (NIH) grant U01 CA200464 (to M.B. Schabath).

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What Causes Lung Cancer?

We don’t know what causes each case of lung cancer. But we do know many of the risk factors for these cancers (see Lung Cancer Risk Factors ) and how some of them cause cells to become cancer.

Smoking tobacco is by far the leading cause of lung cancer. About 80% of lung cancer deaths are caused by smoking, and many others are caused by exposure to secondhand smoke.

Smoking is clearly the strongest risk factor for lung cancer, but it often interacts with other factors. People who smoke and are exposed to other known risk factors such as radon and asbestos are at an even higher risk. Not everyone who smokes gets lung cancer, so other factors like genetics probably play a role as well (see below).

Causes in people who don't smoke

Not all people who get lung cancer smoke. Many people with lung cancer formerly smoked, but many others never smoked at all. And it is rare for someone who has never smoked to be diagnosed with small cell lung cancer (SCLC), but it can happen. 

Lung cancer in people who don't smoke can be caused by exposure to radon, secondhand smoke , air pollution, or other factors. Workplace exposures to asbestos, diesel exhaust or certain other chemicals can also cause lung cancers in some people who don’t smoke.

A small portion of lung cancers develop in people with no known risk factors for the disease. Some of these might just be random events that don’t have an outside cause, but others might be due to factors that we don’t yet know about.

Lung cancers in people who don't smoke are often different from those that occur in people who do. They tend to develop in younger people and often have certain gene changes that are different from those in tumors found in people who smoke. In some cases, these gene changes can be used to guide treatment.

Gene changes that may lead to lung cancer

Scientists know how some of the risk factors for lung cancer can cause certain changes in the DNA of lung cells. These changes can lead to abnormal cell growth and, sometimes, cancer. DNA is the chemical in our cells that makes up our genes, which control how our cells function. DNA, which comes from both our parents, affects more than just how we look. It also can influence our risk for developing certain diseases, including some kinds of cancer.

Some genes help control when cells grow, divide to make new cells, and die:

Cancers can be caused by DNA changes that turn on oncogenes or turn off tumor suppressor genes. Changes in many different genes are usually needed to cause lung cancer.

Inherited gene changes

Some people inherit DNA mutations (changes) from their parents that greatly increase their risk for developing certain cancers. But inherited mutations alone are not thought to cause very many lung cancers.

Still, genes do seem to play a role in some families with a history of lung cancer. For example, people who inherit certain DNA changes in a particular chromosome (chromosome 6) are more likely to develop lung cancer, even if they don’t smoke or only smoke a little.

Some people seem to inherit a reduced ability to break down or get rid of certain types of cancer-causing chemicals in the body, such as those found in tobacco smoke. This could put them at higher risk for lung cancer.

Other people inherit faulty DNA repair mechanisms that make it more likely they will end up with DNA changes. People with DNA repair enzymes that don’t work normally might be especially vulnerable to cancer-causing chemicals and radiation.

Some non-small cell lung cancers (NSCLCs) make too much EGFR protein (which comes from an abnormal EGFR gene). This specific gene change is seen more often with adenocarcinoma of the lung in young, non-smoking, Asian women, but the excess EGFR protein has also been seen in more than 60% of metastatic NSCLCs.

Researchers are developing tests that may help identify such people, but these tests are not yet used routinely. For now, doctors recommend that all people avoid tobacco smoke and other exposures that might increase their cancer risk.

Acquired gene changes

Gene changes related to lung cancer are usually acquired during a person's lifetime rather than inherited. Acquired mutations in lung cells often result from exposure to factors in the environment, such as cancer-causing chemicals in tobacco smoke. But some gene changes may just be random events that sometimes happen inside a cell, without having an outside cause.

Acquired changes in certain genes, such as the RB1 tumor suppressor gene, are thought to be important in the development of SCLC. Acquired changes in genes such as the p16 tumor suppressor gene and the K-RAS oncogene, are thought to be important in the development of NSCLC. Changes in the TP53 tumor suppression gene and to chromosome 3 can be seen in both NSCLC and SCLC. Not all lung cancers share the same gene changes, so there are undoubtedly changes in other genes that have not yet been found.

The American Cancer Society medical and editorial content team

Our team is made up of doctors and oncology certified nurses with deep knowledge of cancer care as well as journalists, editors, and translators with extensive experience in medical writing.

Amos CI, Pinney SM, Li Y, et al. A susceptibility locus on chromosome 6q greatly increases lung cancer risk among light and never smokers. Cancer Res . 2010;70:2359–2367.

Araujo LH, Horn L, Merritt RE, Shilo K, Xu-Welliver M, Carbone DP. Ch. 69 - Cancer of the Lung: Non-small cell lung cancer and small cell lung cancer. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds. Abeloff’s Clinical Oncology . 6th ed. Philadelphia, Pa: Elsevier; 2020. 

Chiang A, Detterbeck FC, Stewart T, Decker RH, Tanoue L. Chapter 48: Non-small cell lung cancer. In: DeVita VT, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology . 11th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2019.

Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene . 2009;28 Suppl 1(Suppl 1):S24–S31. 

Hann CL, Wu A, Rekhtman N, Rudin CM. Chapter 49: Small cell and Neuroendocrine Tumors of the Lung. In: DeVita VT, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology . 11th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2019.

National Cancer Institute. Physician Data Query (PDQ). Patient Version. Non-Small Cell Lung Cancer Treatment. 2019. Accessed at on May 22, 2019.

Varella-Garcia M. Chromosomal and genomic changes in lung cancer. Cell Adh Migr . 2010;4(1):100–106. 

Last Revised: October 1, 2019

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More In Lung Cancer

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Journal of Thoracic Oncology

Original article translational oncology the state of lung cancer research: a global analysis, introduction.

Lung cancer is the leading cause of years of life lost because of cancer and is associated with the highest economic burden relative to other tumor types. Research remains at the cornerstone of achieving improved outcomes of lung cancer. We present the results of a comprehensive analysis of global lung cancer research between 2004 and 2013 (10 years).

The study used bibliometrics to undertake a quantitative analysis of research output in the 24 leading countries in cancer research internationally on the basis of articles and reviews in the Web of Science (WoS) database.

A total of 32,161 lung cancer research articles from 2085 different journals were analyzed. Lung cancer research represented only 5.6% of overall cancer research in 2013, a 1.2% increase since 2004. The commitment to lung cancer research has fallen in most countries apart from China and shows no correlation with lung cancer burden. A review of key research types demonstrated that diagnostics, screening, and quality of life research represent 4.3%, 1.8%, and 0.3% of total lung cancer research, respectively. The leading research types were genetics (20%), systemic therapies (17%), and prognostic biomarkers (16%). Research output is increasingly basic science, with a decrease in clinical translational research output during this period.


Our findings have established that relative to the huge health, social, and economic burden associated with lung cancer, the level of world research output lags significantly behind that of research on other malignancies. Commitment to diagnostics, screening, and quality of life research is much lower than to basic science and medical research. The study findings are expected to provide the requisite knowledge to guide future cancer research programs in lung cancer.

Cited by (0)

Drs. Aggarwal and Lewison contributed equally to this article.

Disclosure: Dr. Boyle was the scientific advisor to the commission for the development of the European Tobacco Directive and has been involved in radical legislation that banned smoking in bars, restaurants, and other public places. Dr. Sethi is vice president of the Respiratory, Inflammatory, and Autoimmune Diseases Translational Medicine Unit of AstraZeneca and a cofounder of Galecto Biotec. Dr. Lewison is a shareholder in GlaxoSmithKline, AstraZeneca, and Shire. Roy Castle Lung Cancer Foundation receives unrestricted grants for the work of the Global Lung Cancer Coalition from AstraZeneca, Boehringer Ingelheim, Bristol-Meyers Squibb, GlaxoSmithKline, Lilly, Novartis, Pfizer, and Roche. The remaining authors declare no conflict of interest.

Lung Cancer Causes & Risk Factors

What causes lung cancer.

Anyone can get lung cancer. Lung cancer happens when cells in the lung mutate or change. Various factors can cause this mutation (a permanent change in the DNA sequence of a gene) to happen. Most often, this change in lung cells happens when people breathe in dangerous, toxic substances. Even if you were exposed to these substances many years ago, you are still at risk for lung cancer. Talk to your doctor if you have been exposed to any of the substances listed below and take steps to reduce your risk and protect your lungs.

Smoking is the number one cause of lung cancer. It causes about 90 percent of lung cancer cases. Tobacco smoke contains many chemicals that are known to cause lung cancer. If you still smoke, quitting smoking is the single best thing you can do for your lung health. 

Smokers are not the only ones affected by cigarette smoke. If you are a former smoker, your risk is decreased, but has not gone away completely—you can still get lung cancer. Nonsmokers also can be affected by smoking. Breathing in secondhand smoke puts you at risk for lung cancer or other illnesses.

Reduce Your Risk

Learn more about how to stop smoking or how to help a loved one quit.

Radon exposure is the second-leading cause of lung cancer. Radon is a colorless, odorless radioactive gas that exists naturally in soil. It comes up through the soil and enters buildings through small gaps and cracks. One out of every 15 homes in the U.S. is subject to radon exposure. Exposure to radon combined with cigarette smoking seriously increases your lung cancer risk.

Test your home for radon . You can do this with inexpensive, easy-to-use test kits sold at hardware stores.

Hazardous Chemicals

Exposure to certain hazardous chemicals poses a lung cancer risk. Working with materials such as asbestos, uranium, arsenic, cadmium, chromium, nickel and some petroleum products is especially dangerous. If you think you may be breathing in hazardous chemicals at your job , talk to your employer and your doctor to find out to protect yourself. 

If you are exposed to dust and fumes at work , ask your health and safety advisor how you are being protected.

Particle Pollution

Particle pollution refers to a mix of very tiny solid and liquid particles that are in the air we breathe. Evidence shows that particle pollution—like that coming from that exhaust smoke—increases the risk of lung cancer.

Help fight pollution . Work with others in your community to clean up the air you and your family breathe.

Genetic factors also may play a role in one's chances of developing lung cancer. A family history of lung cancer may mean you are at a higher risk of getting the disease. If others in your family have or ever had lung cancer, it's important to mention this to your doctor.

Take Action

Protecting your lungs is one of the best ways to stay healthy and reduce your risk of lung cancer. Take steps to protect your lungs from lung cancer all of the time.

Reviewed and approved by the American Lung Association Scientific and Medical Editorial Review Panel.

Page last updated: November 17, 2022

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research paper on causes of lung cancer

The epidemiology of lung cancer

Patricia M. de Groot 1 , Carol C. Wu 1 , Brett W. Carter 1 , Reginald F. Munden 2

1 Department of Diagnostic Radiology at The UT MD Anderson Cancer Center , Houston, TX , USA ; 2 Department of Radiology, Wake Forest Baptist Hospital , Winston-Salem, NC , USA

Contributions: (I) Conception and design: PM de Groot, RF Munden; (II) Administrative support: All authors; (III) Provision of study materials or patients: PM de Groot, CC Wu, RF Munden; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Abstract: The incidence and mortality from lung cancer is decreasing in the US due to decades of public education and tobacco control policies, but are increasing elsewhere in the world related to the commencement of the tobacco epidemic in various countries and populations in the developing world. Individual cigarette smoking is by far the most common risk factor for lung carcinoma; other risks include passive smoke inhalation, residential radon, occupational exposures, infection and genetic susceptibility. The predominant disease burden currently falls on minority populations and socioeconomically disadvantaged people. In the US, the recent legalization of marijuana for recreational use in many states and the rapid growth of commercially available electronic nicotine delivery systems (ENDS) present challenges to public health for which little short term and no long term safety data is available.

Keywords: Lung cancer; epidemiology; smoking; e-cigarettes

Submitted Jan 25, 2018. Accepted for publication May 07, 2018.

doi: 10.21037/tlcr.2018.05.06


In the last century carcinoma of the lung has progressed from an uncommon and obscure disease to the most common cancer in the world and the most common cause of death from cancer. In the late 1840s, the British author Hasse could find no more than 22 ever-published cases of lung cancer ( 1 , 2 ). In 1912, Adler identified only 374 published cases ( 3 , 4 ). In the current era, the most recent global statistical analysis estimates 1.8 million new cases were diagnosed worldwide in 2012, with 1.6 million deaths in the same year ( 5 ). This is increased from 1.6 million new diagnoses and 1.4 million lung cancer deaths in 2008 ( 6 ). Incidence trends and geographical patterns are different for men and women and primarily reflect historical, cultural and regional differences in tobacco smoking ( 5 ). In the United States, an estimated 234,030 persons, a little less than a quarter of a million, will be newly diagnosed with lung cancer in 2018 ( 7 ). The known risk factors for lung cancer include behavioral, environmental and genetic risk factors, all of which play a part in tumor development and also affect individual patients’ capacity for response. The low overall 5-year survival rate for lung cancer has changed only minimally in decades ( 7 - 9 ).

Lung cancer statistics

The estimated new cases of lung cancer in the US for 2018 are 121,680 for men and 112,350 for women, for a total of 234,030 ( 7 ), the equivalent of 641 lung cancers diagnosed per day. Lung carcinoma is the 2 nd most common cancer diagnosis by gender, behind prostate cancer for men and breast cancer for women ( 7 ). In 2018, lung cancer accounts for 14% of new cancers in men and 13% of new cancers in women in the US ( 7 ).

Age-adjusted lung cancer incidence rates for men in the US have declined per 100,000 population since 1982 ( 7 ), reflecting changes in risk behaviors following the promulgation of information about the risks of tobacco smoking in the 1950s and 1960s and later governmental tobacco control measures. In the last few decades, the incidence rate in men has decreased at twice the decline of incidence in women, due to differences in smoking uptake and cessation ( 7 , 10 ). The incidence rates for US women did not plateau until the early to mid-2000s, and saw a modest decline between 2006 and 2014 ( 7 ). It should be noted that while the incidence rates for new lung cancer diagnoses per 100,000 population have trended down, the actual number of incident cases of lung cancer has increased: there were 161,000 new lung cancer cases in 1991 ( 3 , 11 ), compared with an estimated 234,101 new diagnoses in 2018 ( 7 ).

Mortality and survival

In the US, a hard-won decline in lung cancer deaths follows decades of tobacco control initiatives. There was a 45% decrease in male lung cancer deaths between 1990 and 2015 and lung cancer deaths in women declined 19% from 2002–2015 ( 7 ). Estimates of mortality in 2018 are 83,550 deaths for men and 70,500 for women, around 25% of annual cancer fatalities ( 7 ). Lung cancer has one of the lowest survival rates, along with liver and pancreatic cancer. The 5-year relative survival rate for all stages combined was 12% for lung cancers diagnosed from 1975–1977. It is now 18% for new cancer diagnoses between 2003 and 2009 ( 9 , 12 ). Lung cancer is often not diagnosed until advanced stage disease is present, even more so in black Americans compared with white Americans ( 7 , 13 ). Advanced lung cancer has extremely poor prognosis, with a 5-year survival of only 5% ( 7 ).

Global trends in lung cancer epidemiology

Lung cancer rates vary around the world, reflecting geographical differences in tobacco use and air quality ( 12 ). Worldwide, lung cancer incidence is increasing ( 5 , 14 ). Rates of lung cancer in men are considerably higher in developed countries than in less-developed ones, predominantly related to smoking habits, but overall incidence is decreasing in men from developed countries due to tobacco control policies ( 12 , 14 ). Lung cancer in women is also more prevalent in the developed world and linked with cigarette smoking ( 12 ). Worldwide, rates of female lung cancer are increasing ( 14 ). For instance, female lung cancer incidence in Europe has been rising for most of the 21 st century and in 2017 exceeded breast cancer mortality rates for the first time, 14.6 lung cancer deaths per 100,000 compared with 14 per 100,000 for breast cancer ( 15 ). In some regions, particularly Asia, indoor air pollution and occupational exposures play a greater role in female lung cancer ( 12 ). Similar to the US, there is significant geographical and ethnic variation in lung cancer incidence and mortality within regions. Higher income countries have comparatively improved survival rates than low income countries ( 12 ). Of particular concern for the future is the recent rise of cigarette consumption in countries like China, where 65% of men initiate smoking by their mid-20s, presaging an epidemic of lung cancer in the next few decades ( 16 ).

Demographic factors in US lung cancer

Lung cancer incidence and mortality in the US have racial and ethnic disparities as well as geographical differences. They are inversely proportional to the level of education attained by segments of the population. Education levels correlate with socioeconomic factors, including employment opportunities and income. As a result of this entwined set of factors, the burden of lung cancer in the 21 st century is disproportionately borne by minorities and those living in poverty. Age and gender also influence patterns of disease.


Non-Hispanic black (NHB) men have the highest incidence at 87.9 per 100,000. Non-Hispanic white (NHW) men and American Indian/Alaska native (AI/AN) have incidences of 75.9 and 71.9, respectively. These are considerably higher than 45.2 per 100,000 for Asian/Pacific Islanders (A/PI) and 40.6 for Hispanic men ( 7 ). In US women, incidence rates are highest in NHW, 57.6 per 100,000, and AI/AN, 55.9 per 100,000. Lung cancer is diagnosed in NHB women at a somewhat lower rate, 50.1, which is nevertheless almost twice that of A/PI women, 27.9, and Hispanic women, 25.2 (7).

Nevertheless, substantial variation exists within these broad categories. For instance, lung cancer incidence rates within the Asian population from 2004–2008 are significantly different for Indian and Pakistani men, 30.1 per 100,000, than for Vietnamese men at 73.4 per 100,000 ( 12 ). Hawaiian men have an incidence of lung cancer similar to NHW men, even though A/PI rates overall are lower. Within the NHB population, foreign born immigrants have a lower cancer incidence than native African Americans due to divergent smoking habits ( 7 ). Cuban Hispanic men have almost twice the lung cancer mortality of Mexican men, also related to cultural smoking trends ( 17 ).

Geographic patterns in lung cancer diagnosis are also evident, attributable to differences in the percentage of smokers in the population. The incidence of lung cancer in men in the state of Kentucky is 116.3 per 100,000, compared with 73 for the US overall and 32.7 for the lowest state, Utah. The same is true for women; the incidence rate of 79.7 per 100,000 in Kentucky is more than 3 times that in Utah, 24.1. Other states with higher incidence and mortality rates from lung cancer are Mississippi, Arkansas, West Virginia, Tennessee, Alabama and Louisiana ( 7 ). The lung cancer mortality rates for women in some Southern and Midwestern states have been reported to be unchanged or even increased despite the overall national trends ( 18 ). So far 18 states have declined to expand Medicaid, which is a joint federal and state program for low income individual and families to help with medical expenses; this is leading to reduced access to health care ( 19 ).


Cigarette smoking is much more prevalent in individuals with less than a high school education, 32.1%, compared with 9.1% in college graduates ( 7 ). Lung cancer incidence is similarly disproportionate by education level. Incidence rates range from 166.6 per 100,000 in men who didn’t graduate from high school to 57.6 in college graduates ( 12 ). Individuals with more education are less likely to start smoking and more amendable to quitting ( 12 ). Smokers with low educations levels are less likely to even attempt to quit ( 12 ). Better educated people also have more resources with greater access to healthcare, leading to disparities in mortality and survival ( 7 ).

Smoking prevalence is 24% in the active military, and 29% of male veterans are smokers ( 20 , 21 ). Cigarette use in the military is linked with young Caucasian men without college education. Career enlisted individuals are more likely to be heavy smokers than officers ( 21 ). Tobacco use is highest in the Army, 37.3%, and Marine Corps, 35.7%. The Air Force has the lowest rate at 23.2% ( 21 ). The military services have been specifically targeted by tobacco company advertising ( 20 , 22 ).

Approximately 27.9% of people below the poverty threshold smoke ( 12 ). Although there is a strong association between lower income and cigarette smoking, some studies have shown a correlation between lower socioeconomic status and lung cancer incidence regardless of smoking status, suggesting contribution of other environmental factors including housing accommodations and occupational exposures ( 23 , 24 ).

Older age is associated with cancer development due to biologic factors that include DNA damage over time and shortening telomeres. Accordingly, the median age of lung cancer diagnosis is 70 years for both men and women ( 12 ). Approximately 53% of cases occur in individuals 55 to 74 years old and 37% occur over 75 years old. The highest incidence of lung cancer in men is 585.9 per 100,000 in 85–89 years old, while the highest incidence in women is 365.8 per 100,000 in 75–79 years old ( 12 ). Lung cancer is the leading cause of death by any means in men over 40 years and in women over 59 years of age ( 7 ).

Nevertheless, lung cancer is seen in very young adults. Ten percent of cases occur in patients less than 55 years. Studies of non-small cell lung cancer (NSCLC) in patients 20–46 years of age have reported that young lung cancer patients are more likely to be female, to have adenocarcinoma histology, to be non-smokers, and to present at a more advanced stage of disease ( 25 ). Young patients usually have few co-morbidities and genetic factors are thought to play a large role in this patient population. Younger patients are more likely to receive more aggressive treatment at all stages of the disease and to have improved survival at every stage, although this margin is very small for advanced disease ( 25 ).

Historically more men than women smoke tobacco and have higher rates of incidence and mortality. Women took up smoking at a later period, mostly after the Second World War, and their rates of cessation have lagged behind those of men, leading to a much later peak in lung cancer incidence in women ( 7 ). Height at maturity has been reported to be linked with invasive cancer diagnosis and may be a factor in gender disparity ( 26 ).

There are conflicting data regarding the possibility that women may be more susceptible to developing lung cancer ( 27 ). There is a higher rate of lung cancer in non-smoking women compared with non-smoking men, a higher proportion of epidermal growth factor receptor (EGFR) mutations in female NSCLC, and a higher incidence of adenocarcinoma with lepidic features in women ( 28 , 29 ). Some genetic mutations found to be more common in female smokers may predispose toward lung cancer development in women, including over-expression of the CYP1A1 gene, mutation of the glutathione S-transferase M1 enzyme, mutations of the p53 tumor suppressor gene, and over-expression of X-linked gastrin-releasing peptide receptor ( 27 - 29 ). Women also have a higher family risk of lung cancer, even adjusting for smoking status ( 30 ).

The question of hormonal influence is also debated. Estrogen receptor (ER)α, which is not present in normal lung tissue, has been shown to be overexpressed in lung adenocarcinoma of women, but some studies also demonstrate overexpression in cancers of men ( 27 ). One study has found that estradiol promoted growth of female but not male adenocarcinoma cells in vitro ( 31 ). Anti-estrogen compounds have been shown in vitro to have anti-tumor effects ( 30 ). Other variables studied include parity, age at menarche, length of menstrual cycle, age at menopause, and exogenous hormone replacement therapy, in some cases with conflicting results ( 30 , 32 ).

Overall, women have some unique risk factors for lung cancer compared with men, and lung tumors in women have different pathologic behavior, outcomes and prognosis in comparison with lung cancer in men ( 30 ).

Lung cancer incidence in transgender men and women has not yet been addressed. Transgender adults have higher prevalence of cigarette smoking than the general population, 35.5% ( 33 , 34 ). Lesbian, Gay, Bisexual, Transgender, Queer or Questioning (LGBTQ) adolescents are reported to have equally high smoking rates as well as earlier smoking initiation ( 35 ). Questions about the role of endogenous and exogenous hormones in lung cancer in cisgender women will also need to be examined for this population group.

Behavioral risk factors for lung cancer

Tobacco and smoking: historical perspective.

The use of tobacco cigarettes is the single greatest risk factor in the development of lung cancer, with up to 90% of lung cancers attributed to smoking. An understanding of this causal relationship developed only slowly and gradually, not least because of the decades-long latency period between smoking initiation and lung cancer occurrence ( 16 ). Prior to the 20 th century, tobacco had been used for centuries without significant disease burden ( 16 ). In the pre-Columbian Americas, tobacco was used primarily for medicinal and ritual purposes ( 36 , 37 ). Tobacco was brought to Europe at the end of the 15 th century and utilized in various forms including snuff, pipes and cigars. Cigarettes were, until the late 19 th century, expensive, hand-rolled, and not considered acceptable in polite society or around women ( 16 , 38 , 39 ).

Several technological developments in the mid to late 1800s precipitated the increased popularity and wide use of cigarettes. Flue curing of tobacco, which was introduced in the 1840s, produced a higher sugar content in dried tobacco with a smoother smoke that was easier to inhale. The safety match was invented in 1844, creating a quick and convenient method of lighting a cigarette. The automated cigarette rolling machine was invented in 1880 and the improved capacity for production led to a decline in prices and mass availability ( 16 , 40 ).

Cigarette smoking increased dramatically in the US and Europe during the world wars, first in men and then in women. Soldiers were given free cigarettes and developed a nicotine habit, subsequently bringing the practice back home at the end of the war ( 16 ). At that time, there was no detailed knowledge of harmful effects from tobacco smoking or understanding of nicotine addiction, and many healthcare professionals smoked. Some authors suggested a link between cigarette smoking and the increasing cases of lung cancer in the 1920s and 1930s, but these reports did not have a tangible effect on consumption ( 2 , 41 - 47 ). Major epidemiological studies published in 1950 by Doll and Hill ( 48 ) and Wynder and Graham ( 49 ) definitively established that cigarette smoking causes lung cancer; additional confirmatory studies followed. Subsequently, reports were issued by the Royal College of Physicians in Great Britain in 1962 and the US Surgeon General in 1964 to warn the public about the dangers of smoking ( 50 , 51 ). Concerted efforts since the 1960s to decrease tobacco consumption have had success in reducing the percentage of smokers in the US population, from 42.4% of the adult population in 1965 to 15% in 2015 ( 52 , 53 ). The absolute number of tobacco users in the US was 48.1 million in 1970 ( 54 ), 42.1 million in 2012 ( 55 ), and 37.5 million in 2015 ( 53 ). An estimated 6.8 million people in the US meet eligibility criteria for lung cancer screening, although only 4% of them have pursued it ( 7 , 56 ). This may be at least partly because of the concentration of current smokers within groups of lower socioeconomic status ( 7 ) and the inverse relationship between socioeconomic standing and participation in medical screening programs ( 57 , 58 ).

Tobacco and smoking: carcinogenesis

The addictive component of tobacco is nicotine, a natural alkaloid that acts as an acetylcholine agonist and binds to nicotinic acetylcholine receptors (nAChR) in the nervous system, causing release of neurotransmitters into the blood stream, including dopamine, serotonin, norepinephrine, endorphins, and gamma-aminobutyric acid (GABA). While nicotine itself is not a carcinogen, it upregulates nicotinic receptors and produces alterations in gene expression that foster tobacco dependence and is associated with progression of existing lung tumors ( 59 - 61 ).

Tobacco combustion produces at least 60 known carcinogens. The most significant are polycyclic aromatic hydrocarbons (PAH), including benzo[a]pyrene; nitrates; and tobacco-specific N-nitrosamines (TSNAs), such as 4-(methylnitrosamino)-1-(13-pyridyl-1-butanone) (NNK) ( 62 , 63 ). Tobacco smoke has a vapor phase and a particulate phase, which respectively produce 10 15 and 10 17 free radicals per gram ( 61 ). The mechanisms of carcinogenesis from tobacco include formation of DNA adducts by carcinogens and their metabolites as well as free radical damage ( 64 ). While tar emissions and the amount of benzo[a]pyrene have decreased in cigarette smoke over several decades, there is no convincing evidence that lower tar cigarettes have improved safety ( 65 ). Meanwhile, the concentration of nitrates and TSNAs in cigarettes has increased since 1978 ( 62 ). Laboratory studies have demonstrated the relationship of NNK to lung cancers, specifically adenocarcinomas ( 66 ). The amplified concentration of NNK in tobacco smoke likely correlates with the increase in lung adenocarcinomas relative to squamous non-small cell lung cancer in recent decades.

Menthol as a cigarette additive has been in use since the 1920s. Menthol cigarette advertising in the US has been directed particularly toward women, African Americans and youth ( 67 , 68 ). Menthol, a derivative of the peppermint plant, has the effect of decreasing irritation of mucosal tissues in the hypopharynx and lung as well as producing a minty flavor ( 69 ). In addition to making cigarette smoke more palatable, it affects nicotine binding to nicotinic acetylcholine receptors and it upregulates expression of nicotinic cholinergic receptors, producing increased addiction and reduced ability to quit ( 70 , 71 ). Up to 90% of the tobacco merchandise currently on the market contains some percentage of menthol, even if not marketed as a menthol-containing product ( 67 , 68 ).

Other smoking products

Cannabis sativa.

In 2013, marijuana was the most commonly used illegal substance in the US, with up to 12% of adolescents and adults admitting use ( 72 ). The number of users is likely to increase as states legalize personal recreational use of the drug. At this moment, the states of Maine, Massachusetts, Colorado, Washington, Oregon, Nevada, California, Alaska and Vermont and the District of Columbia permit recreational marijuana use. Medical marijuana is legal in up to 30 states. Studies on the health effects of marijuana, including risk for lung cancer, have been limited due to previous illegal status and the confounding effects of frequent combined use with tobacco ( 73 , 74 ).

The main psychoactive ingredient in cannabis, Δ 9 -tetrahydrocannabinol (THC), is not known to be carcinogenic but like nicotine, produces addiction. Up to 17% of people who initiate marijuana in their teens will become dependent, and an estimated 25–50% of daily smokers are addicted ( 72 , 75 ). Also similar to nicotine, there is evidence that THC has a deleterious effect on adolescent brain development ( 72 ). The constituent percentage of THC in marijuana products has been increasing over the last 20 years ( 72 ). There is an association between marijuana smoking and initiation of tobacco use in young people ( 76 - 78 ).

The combustion of organic material while smoking marijuana does produce carcinogenic substances. The tar levels in marijuana smoke are much higher than those in tobacco, as are the concentrations of polyaromatic hydrocarbons ( 73 , 79 - 81 ). Inhalation of marijuana smoke causes inflammation of the distal airways with subsequent release of cytokines. There is evidence that marijuana produces molecular histologic changes to the bronchial epithelium that mimic those of tobacco use and are known to be premalignant ( 80 , 82 , 83 ).

Some case controlled studies in 3 North African countries have suggested a 2.4-fold increased risk for lung cancer in men after adjusting for tobacco smoking and occupational exposures ( 73 ). A case control study in New Zealand found a 5.7-fold increased risk of lung cancer in the highest one-third of marijuana consumers, after adjustment for confounding variables ( 80 ). Epidemiologic studies to date have not found a strong association between cannabis use and lung cancer ( 84 , 85 ). However, it has been noted that the relatively low prevalence of marijuana use pre-legalization is similar to that of tobacco prior to the 20 th century and that impending industrialization of marijuana in the US may have unforeseen consequences ( 86 ).

Electronic nicotine delivery systems (ENDS)

Electronic technology for delivery of nicotine to the lung epithelium via an electronic device became available for sale in 2007. The basic mechanism consists of a battery-operated heating coil that heats fluid contained in a replaceable cartridge, usually a mixture of flavorings, a solvent, and liquid nicotine ( 87 ). When evaporated, this produces an aerosol vapor that is inhaled by the smoker, or vaper. Nicotine-containing aerosols can achieve peak serum nicotine levels in under 5 minutes ( 87 ). ENDS, also called electronic cigarettes or e-cigarettes, have evolved at a rapid rate in the last decade, with 466 brands and thousands of flavorings available as of 2014 ( 87 , 88 ). The diversity of available products as well as individual variations in vaping practices have made it difficult to effectively evaluate the safety of these devices and their use. The disparity in content and quality of the cartridges, especially, is substantial ( 89 , 90 ).

ENDS products are currently unregulated in the US except with respect to mandatory age and photo ID checks to prevent sales to minors. In 2016, the US Food and Drug Administration (FDA) claimed jurisdiction and regulatory authority over the manufacture, promotion, sale and distribution of ENDS and associated merchandise as newly deemed tobacco products. However, in 2017 the compliance dates for these regulations were extended to 2021–2022, and the registration of entities that manufacture, prepare, compound, or process a newly deemed finished tobacco product now applies only to those corporations that commence those activities on or after August 8, 2016 ( 91 , 92 ).

The prevalence of ENDS usage is 3.2% of adults in 2016. ENDS users fall into three categories: current smokers who use them as an intentionally transitory cigarette smoking cessation device, current smokers who practice continued use and dual use, and previous non- smokers of traditional tobacco ( 87 ). The last category is particularly prevalent in young adults; 40% of e-cigarette users between the ages of 18–24 were not previous smokers ( 93 ).

Randomized controlled trials have found that e-cigarettes containing nicotine are more effective for smoking cessation than e-cigarettes that do not contain nicotine ( 94 ). However, there is no proven benefit over other cessation aids with nicotine ( 87 , 95 ). Dual use is defined as the continued smoking of traditional tobacco cigarettes and electronic cigarettes; there is no evidence of health benefit ( 87 , 95 ). Smokers who converted to exclusive ENDS use were evaluated in a 2-year study that reported no significant adverse events within a 24-month period after switching to an electronic cigarette with nicotine ( 96 ). However, there is a lack of short- or long-term safety data. The particles in e-cigarette vapor are different from those in traditional tobacco cigarettes, but available data suggests that formaldehyde, acetaldehyde and reactive oxygen species are present in sufficient concentrations to cause inflammatory damage to the airway and lung epithelium. Microscopic particles from e-cigarettes can deposit in the distal bronchioles or alveoli ( 87 ). E-cigarette aerosol can also contain polycyclic aromatic hydrocarbons, nitrosamines, and trace metals, although concentrations vary ( 97 ). Further, nicotine is present in e-cigarette vapor and can cause new addictions in users who are not already smokers ( 98 ).

The rise of ENDS use in previous non-smokers is predicated on consumer understanding of the devices as “safer”. Television and magazine advertisements for e-cigarettes utilize traditional marketing ploys of the tobacco industry, such as appeals to freedom, courage and individuality ( 99 ). Most troubling is the 900% increase in e-cigarette use in high school students between 2011 and 2015, with over 2 million middle and high school students using ENDS in 2016 ( 93 , 100 , 101 ). There is evidence that nicotine can damage brain development in adolescents ( 98 ). People with depression and anxiety are reported to have higher rates of ENDS usage and may also be a vulnerable population ( 87 ). Other at risk populations include rural, low income and LGBTQ individuals ( 100 ). Recent studies have shown that use of ENDS and other tobacco products by adolescents and young adults is independently associated with smoking of traditional tobacco cigarettes within a year ( 102 , 103 ).

The recommendations of the CDC at this time with regard to electronic cigarettes are that non-pregnant adult smokers may benefit from ENDS use when completely substituted for previous tobacco habits. E-cigarettes are considered not safe for adolescents, young adults, pregnant women and non-smokers ( 93 ).

Environmental risk factors for lung cancer

An association between mining and lung disease has been known in Europe since the 15 th century, when miners in the Erzgebirge mountain range along the Germany-Czech border suffered high incidence and mortality from what was then known as bergkrankheit , or mountain disease. Mines in that part of the world produced copper, iron, silver, cobalt, arsenic, bismuth, and, in the 20 th century, radium. We now know that the German and Czech mining population had extremely high rates of lung cancer, mostly squamous cell carcinoma ( 3 ). In the modern medical era, epidemiologic studies of underground workers in uranium mines have provided the framework for our understanding of radon exposure as a cause of lung cancer ( 104 - 106 ).

Residential radon from soil accounts for the second most common risk factor for lung cancer, estimated 10% of cases ( 106 ). Radon is a naturally occurring radioactive gas produced by uranium decay in the earth’s crust. It emits alpha particles, decaying to polonium and then bismuth. The average environmental concentration of radon is 0.2pCi/L ( 107 ), but indoor levels can be quite variable depending on soil composition, building foundations and ventilation. Radon can accumulate to unsafe levels in basements and lower building levels ( 106 , 108 ). The US Environmental Protection Agency provides resources for assessing and reducing radon levels in homes. Radon exposure in underground workplaces is regulated in the US ( 107 ). Concurrent tobacco smoking increases the relative risk of lung cancer from radon ( 106 , 109 ).

Occupational exposure to carcinogens is estimated to account for 5–10% of lung cancers ( 69 , 110 - 112 ). Of these, asbestos is the most common. A naturally occurring silicate mineral, asbestos has amphibole (amosite, crocidolite, trenolite) and serpentine (chrysotile) subtypes, and the use of asbestos in construction has been ongoing since the 19 th century. Chrysotile fibers have the greatest association with thoracic malignancies ( 107 ). Occupational exposure to asbestos correlates with a 5-fold excess risk of lung cancer ( 69 ). Asbestos exposure and tobacco smoking have a synergistic effect on the risk for lung cancer ( 107 ).

Pollution and air quality

Ambient air quality was suggested as a potential risk factor for lung cancer as early as the 1920s ( 41 ). There are two main areas of concern for both outdoor and indoor air quality: carcinogens produced by combustion of fossil fuels and particulate matter in the air ( 69 ). Atmospheric carcinogens in the outdoor environment can include PAH, sulfur dioxide and trace metals ( 69 , 113 ). The risk of lung cancer is elevated in occupations that have prolonged exposure to these elements. In this regard, occupational exposures in the trucking industry, for instance, are associated with up to 50% increase in the relative risk of lung cancer ( 107 ).

Particular matter in the air increased with industrialization and it began to be regulated in the 1950s ( 107 ). The US Environmental Protection Agency in 1997 increased the legal limits on fine particles less than 2.5 µm in diameter (PM 2.5 ) due to evidence of adverse health effects at even low levels of particulate concentration in the air ( 114 ). A study of large urban environments in the US found a 40% increased risk of lung cancer in the 6 US cities with the highest levels of particulate matter ( 69 ). The risk of lung cancer from fine particulate pollution is increased regardless of smoking status, and the association is greatest in nonsmokers. These is also a correlation with lower levels of education which may influence housing options ( 114 ). Particulate matter has been designated a Group I carcinogen by the International Agency for Research on Cancer (IARC) ( 115 ). The risk of lung cancer from pollution is potentiated with tobacco smoking.

Indoor air pollution from the use of unprocessed fossil fuels such as soft coal and biomass fuels, which include wood, other plant-based materials and solid waste, for heating and cooking is implicated in lung cancer risk, primarily in the developing world. In some parts of Asia it is linked with lung cancer in never smokers ( 69 , 116 , 117 ). Studies have shown that proper ventilation of previously unvented cooking areas can reduce the risk of lung cancer by 50% ( 69 ).

Second hand, or side-stream, tobacco smoke is also an environmental pollutant with a dose response relationship between exposure and lung cancer risk ( 118 ). The carcinogens in side-stream smoke include PAH, nitrosamines and aromatic amines. Benzo[a]pyrene concentrations are 4 times higher in side-stream smoke compared with filtered mainstream cigarette smoke ( 119 ). Studies have shown the presence of nicotine and its metabolite cotinine as well as DNA adducts from tobacco carcinogens in the urine of nonsmokers with passive exposure to tobacco smoke ( 119 ). Nonsmoking spouses of smokers have a 20–30% increased risk for developing lung cancer ( 119 - 121 ). The US Surgeon General has declared that there is no safe level of exposure to second hand tobacco smoke ( 118 ).

More recently, questions of second hand exposure to e-cigarette vapor have arisen. While some studies of simulated indoor air quality with ENDS have found no significant levels of chemicals in the environment ( 122 ), a non-simulated real life evaluation of indoor air quality at a vaping convention found high levels of air nicotine, particulate matter, total volatile organic compounds (TVOCs), and carbon dioxide in the air that raises concerns for workers and others exposed to second hand vapor ( 123 ). Serum cotinine levels in non-smokers from e-cigarette vapor were comparable to those exposed to second hand cigarette smoke in a recent study ( 124 ). The US Surgeon General has determined that second-hand e-cigarette aerosol contains harmful and potential harmful components and urges the inclusion of ENDS in comprehensive smoke-free regulations to both reduce involuntary environmental exposure and prevent re-standardization of tobacco use ( 98 , 125 ). To date, very few states have included e-cigarettes in such laws ( 125 ).

Damage to the lung from inflammation and infection is implicated in carcinogenesis. In the past, infections such as tuberculosis conferred an odds ratio up to 1.76 for the development of lung cancer, irrespective of smoking status and with considerable latency ( 126 ). There is decreased prevalence of TB in the developed world.

Lung cancer is the most common non-AIDS defining malignancy in people with HIV infection ( 127 ). In the era of more effective antiretroviral therapy, lung cancer has become the leading cause of mortality in HIV-infected patients, accounting for nearly 30% of cancer deaths ( 128 ). Despite the increased lung cancer incidence with highly active antiretroviral therapy (HAART) ( 129 ), there is no evidence that antiretroviral medication itself increases the risk ( 69 ). The HIV virus also has not been implicated in oncogenesis, but studies suggest that immunosuppression plays a role, as HIV patients and organ transplant recipients have similarly increased rates of cancer ( 130 ). Declining CD4 counts are associated with a higher rate of lung cancer ( 131 ). The higher smoking prevalence in the HIV population, with 42% current cigarette smokers in HIV-positive adults in 2009, may be a contributing factor ( 132 ). Nevertheless, HIV-infected individuals have a 2.5-fold increased risk of lung cancer regardless of smoking status ( 69 ). Lung cancer patients with HIV have lower levels of cigarette smoking and present at younger ages than the general population, are diagnosed at more advanced stages, and have lower survival than the general population ( 69 , 128 , 133 , 134 ).

Genetic risk factors for lung cancer

Not all tobacco users develop lung cancer, reinforcing a genetic susceptibility to lung malignancy. A positive family history for lung cancer has been associated with a 1.7-fold increase in risk of lung cancer development ( 135 ). Some studies have shown lung cancer risk is increased 2 to 4 times in first degree relatives of lung cancer patients, controlled for personal smoking history ( 136 , 137 ).

Genome wide association studies (GWAS) have associated chromosome regions 5p15, 15q25-26 and 6q21 with increased risk for lung cancer ( 138 , 139 ). The 5p15 region encodes telomerase reverse transcriptase (TERT), involved in cell replication. In the development of lung cancer, it is associated with adenocarcinomas in smokers and nonsmokers ( 140 ). Mutations at the 15q25-26 chromosome locus are positively linked to both nicotine dependence and susceptibility for lung cancer ( 141 ). Chromosome locus 6p21 regulates G-protein signaling, and variants confer markedly increased risk on never-smokers ( 142 ). GWAS in the Han Chinese and Japanese populations have also found a locus at 3q28, among others, linked with increased lung cancer risk ( 138 ).

Tumors acquire intrinsic genetic driver mutations, most of which involve cell signaling pathways including the ErbB protein family (EGFR/HER1-4) and the GTP-ase Kirsten rat sarcoma virus ( K-ras ) gene ( 139 ). Mutations rarely occur in the same signaling pathway ( 143 ). Other genetic and epigenetic changes can cause inactivation of tumor suppressor genes such as p53 , p16 and PTEN ( 139 ). Some mutations have consistent associations with lung tumor histology; for example, EGFR and EML4-ALK mutations are associated with adenocarcinomas in nonsmokers ( 139 ).

Lung cancer in never smokers (LCINS)

Lung cancer in nonsmokers is a major cause of mortality, now the 7 th leading cause of cancer deaths ( 30 ). It accounts for approximately 10–15% of lung cancer cases in the US ( 144 ). The proportion of LCINS has increased in recent years, even after controlling for gender and race or ethnicity ( 144 ). Worldwide, it is estimated that 25% of lung cancer patients are never smokers ( 145 ). LCINS occurs predominantly in women and younger patients. The histology is most likely to be adenocarcinoma, often with specific driver mutations like EGFR mutation and ELM4-ALK fusion protein which respond well to targeted therapy ( 139 , 145 , 146 ). The proportion of female LCINS cases is particularly high in East and South Asia, where 60–80% of women with NSCLC are never smokers ( 116 , 117 , 147 ). In the US, African American nonsmokers are more likely to develop lung cancer than Caucasian nonsmokers ( 116 ).

Environmental risk factors are reported to play a predominant role in LCINS, including second hand smoke exposure, environmental particulate matter, occupational exposures, indoor air pollution, and radon ( 115 , 148 ). Some studies suggest up to 30% of lung cancers in non-smokers are caused by residential radon exposure ( 149 ). Genetic susceptibility is also a factor, including genes associated with metabolic syndrome ( 145 , 148 ).


Smoking prevalence and lung cancer incidence have decreased in the US over the last several decades as a result of committed tobacco control policies. However, the morbidity and mortality of the tobacco epidemic remain high in the US, and the global epidemic has just started. The history of modern tobacco smoking and the slow and reluctant understanding of its long-term fatal effects should provide a cautionary tale for the healthcare profession as we attempt to understand the safety and potential delayed consequences of marijuana smoking and e-cigarette vaping, both of which are gaining in popularity, access and consumption.


Conflicts of Interest: Dr. Wu reports royalties from Elsevier, Inc., outside the submitted work. Dr. Carter reports royalties from Elsevier, Inc., outside the submitted work. Dr. Munden holds stock options in Optellum, Ltd., outside submitted work. Dr. de Groot has no conflicts of interest to declare.

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