The Effect of Alpha Lipoic Acid on the Clinical Outcome of Advanced Non-Small Cell Lung Cancer Patients

Lung cancer is a malignant tumor that starts in lung cells, most often linked to uncontrolled growth of abnormal cells due to DNA damage. There are two main types, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), which differ in growth speed and treatment approaches. About 80% to 85% of lung cancers are NSCLC. The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.

Lung cancer remains one of the most critical global health challenges due to its high incidence and mortality rates. With over 130.000 new cases annually, lung cancer ranks fifth in Egypt's yearly incidence of all malignancies., with an incidence rate of 5.1% and a mortality rate of 7.1%.

The primary risk factors for Non-Small Cell Lung Cancer (NSCLC) are smoking, including secondhand smoke, and occupational exposure to carcinogens like asbestos, arsenic, and radon. Other factors include family history of lung cancer, environmental pollution, a history of certain lung diseases, and weakened immune systems, such as from HIV.

NSCLC is staged using the TNM according to the American Joint Committee on Cancer 8th edition (Tumor, Node, Metastasis) system. Stage I is a small, localized cancer with no spread. Stage II involves a larger tumor or spread to nearby lymph nodes. Stage III signifies spreading to more distant lymph nodes in the chest, known as locally advanced cancer. Stage IV is advanced cancer that has spread to other organs or distant parts of the body, also called metastatic cancer. Stage III and IV are associated with poor prognosis.

Non-small cell Lung cancer pathophysiology is a relatively unclear and complex phenomenon. There are numerous factors involved in the progression of lung cancer, such as inflammation, oxidative stress, mitochondrial dysfunction, and abnormal releases of hormones and enzymes. Notably, inflammation and inflammatory mediators are some of the leading causes of cancer. The pathophysiology of non-small cell lung cancer (NSCLC) begins with exposure to environmental carcinogens such as pollution, chronic poisoning, and infections that drive persistent oxidative stress and the generation of reactive oxygen species (ROS). Elevated ROS levels induce DNA damage and genetic mutations, which initiate malignant transformation of normal cells. Activation of growth factor receptors such as EGFR, IGF-1R, and HER2 stimulates downstream signaling cascades, including the PI3K/AKT/mTOR and MAPK/ERK pathways, promoting uncontrolled cellular proliferation, survival, and tumor growth. In parallel, chronic inflammation mediated by NF-κB activation leads to increased expression of pro-inflammatory cytokines such as IL-6, TNF-α, and COX-2, further sustaining a tumor-promoting microenvironment. Mitochondrial dysfunction contributes to carcinogenesis by impairing apoptosis and enabling survival of genetically altered cells. As the tumor progresses, transforming growth factor-β (TGF-β) signaling drives epithelial-mesenchymal transition (EMT), enhancing tumor cell motility, invasion, and metastasis. Cancer stem cells also emerge, supporting tumor recurrence, therapy resistance, and metastasis formation. Collectively, these interlinked molecular events underpin the initiation, progression, and dissemination of NSCLC.