**2. A general scenario of lung cancer and non-small cell lung cancer**

LC or bronchogenic carcinoma refers to tumors originating in the pulmonary parenchyma or bronchi. LC is the leading cause of cancer death globally and is the second most prevalent type of cancer in both sexes. About 1.6 million people die of LC each year, and the overall 5-year survival rate is only 15% [7].

*Shedding Light on Four Selected Flavonoids with Anti-non-small Cell Lung Cancer Properties DOI: http://dx.doi.org/10.5772/intechopen.105162*

**Figure 1.**

*Non-small cell lung cancer (NSCLC) characteristics: classification, risk factors, genetic alterations, clinical manifestation, diagnosis, and treatment.*

Even though the incidence of LC is associated with several factors, such as geographic location, sex, race, lifestyle, exposure to physical, chemical, or biological carcinogens, genetic polymorphisms, and comorbidities [8]; cigarette smoking is directly related to 82% of LC deaths and its major histological subtypes [9]. According to its histological characterization and by international convention, LC is divided into two large groups: small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).

NSCLC is diagnosed in 80–85% of cases. Based on cell origin and histological features, the subtypes of NSCLC are adenocarcinoma, large-cell carcinoma, and squamous cell carcinoma [10]. The incidence of NSCLC is attributed to various elements, such as advanced age, current smoking, molecular features, genetic heterogeneity, and exposure to chemical carcinogens (e.g., radioactive radon) (**Figure 1**) [11]. However, bacterial and viral infections also represent a major concern associated with the incidence, morbidity, and mortality of NSCLC [12]. In addition, NSCLC risk factors increase mutation rates in the cancer cell genome and contribute to the progression of NSCLC.

The cancer cell genome is characterized by various somatic mutations and epigenetic changes that confer a growth advantage to the cancer cells and contribute to cancer development and progression [13]. Generally, 69% of patients with advanced NSCLC exhibit aberrations in the following proteins: anaplastic lymphoma kinase (ALK), EGFR, c-ros oncogene 1 (ROS1), human epidermal growth factor receptor (HER2), hepatocyte growth factor receptor (HGRF), Kirsten rat sarcoma virus (KRAS), V-raf murine sarcoma oncogene homolog B1 (BRAF), among others [14]. NSCLC patients also manifest alterations on TP53 (40–60%), phosphatase and tensin homolog (PTEN, 50%), liver kinase B1 (LKB1, 34%), and p16INK4A (17–58%) (**Figure 1**) [15]. Such mutations' epidemiological, geographical, and sociological distribution could vary worldwide [16].

NSCLC patients manifest cough, weight loss, dyspnea, chest pain, and hemoptysis [17]. The diagnosis of NSCLC consists of the evaluation of family history and physical (e.g., lymph nodes examination), histopathological (e.g., bronchoscopy), and cytological examinations (e.g., endobronchial ultrasound-needle aspiration) [18]. Given the necessity to establish appropriate therapy, management, and prognosis in recently diagnosed NSCLC patients, imaging techniques such as positron emission tomography (PET) scan, fluorodeoxyglucose (FDG)-PET scanning, thoracic computed tomography (CT), and magnetic resonance imaging (MRI), are broadly implemented (**Figure 1**) [19, 20]. The implementation of diagnostic tools leads to cancer staging.

Cancer staging determines how the spread and localization of a particular type of cancer. For example, the tumor-nodes-metastasis (TNM) classification is a system for categorizing a malignancy. According to the TNM staging system, the stages of NSCLC are local (IA, IB, and IIA), locally advanced (IIB, IIA, and IIIB), and advanced (IIIB, and IV) [21].

Depending on the stage of NSCLC, treatment includes the administration of chemotherapy (e.g., platinum-based doublet therapy) and monoclonal antibodies that target immune system T cells, ligands on the tumor cells, or aberrant proteins, such as vascular endothelial growth factor (VEGF) (e.g., bevacizumab, and docetaxel), vascular endothelial growth factor (VEGF) receptor-2 (e.g., docetaxel with or without ramucirumab), and epidermal growth factor receptor (EGFR) (e.g., necitumumab, gefitinib, and erlotinib) (**Figure 1**) [22].

Additionally, NSCLC treatment includes radiation technologies and immunotherapy. Radiation therapy (e.g., stereotactic and hadron therapy) has been used for stage III NSCLC treatment [23], whereas immunotherapy for NSCLC uses monoclonal antibodies (e.g., atezolizumab, nivolumab, pembrolizumab, durvalumab, and avelumab) [22]. Immunotherapy has been used for stage III NSCLC and in clinical trials utilizing immunotherapy to treat NSCLC [24]. Surgical resection procedures have been recommended for stages I through IIIA of NSCLC [21]. However, NSCLC treatment is prone to failure due to variations in the cell regulatory mechanisms and the drug targets.

The therapeutic failure in NSCLC arises from cell-intrinsic mechanisms that promote cancer cells' survival, proliferation, and metastasis. These processes comprise of changes in the expression of drug transporters, activation of pro-survival and anti-apoptotic pathways, the influence of the tumor microenvironment, drug resistance, and severities of the drug metabolism [25]. Although the NSCLC therapy depends on the dosing regimens, protocols, and differences in genetic predisposition, it can cause serious adverse effects (AEs), such as anemia, nausea, vomiting, diarrhea, pneumonitis, psoriasis, and transient thyroid malfunction [26, 27]. Flavonoids such as diosmetin, genistein, fisetin, and epigallocatechin gallate (EGCG) are molecules that potentiate the effect of current chemotherapeutic drugs in cancer models [28].
