Non-small cell lung cancer (NSCLC) is a common and aggressive type of lung cancer often diagnosed at advanced stages, with limited treatment options and poor prognosis. Oxidative stress, inflammation, and dysregulated signaling pathways contribute to tumor progression, metastasis, and chemotherapy resistance. Alpha-lipoic acid (ALA), a potent antioxidant with anti-inflammatory properties, has shown promise in preclinical and early clinical studies by reducing oxidative stress, enhancing chemotherapy efficacy, and improving immune response. The aim of this study is to evaluate the clinical effect and safety of oral ALA (600 mg daily) in combination with standard platinum-based chemotherapy in patients with advanced non-resectable Stage III or IV NSCLC. Primary outcomes include clinical benefit and tumor response, while secondary outcomes include 1-year progression-free survival, 1-year overall survival, chemotherapy toxicity, and quality of life.

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.

Neuron-specific enolase (NSE) has been identified as a potential biomarker correlated with the progression of non-small cell lung cancer (NSCLC). Elevated NSE levels in patients with NSCLC have been linked to tumor growth, metastasis, and poor prognosis. There is a study approved that alpha lipoic acid decrease serum neuron specific enolase in diabetic neuropathy.

NSCLC treatment is categorized by stage: Stage I & II (resectable)is primarily treated with surgery, potentially with stereotactic body radiation therapy (SBRT) for those unable to have surgery and often followed by adjuvant chemotherapy or immunotherapy. Locally advanced Stage III cases often receive a combination of chemotherapy, radiation, and sometimes surgery, or immunotherapy. Stage IIIB and Stage IV (metastatic non resectable) NSCLC is usually treated with systemic therapies like chemotherapy, targeted therapy, or immunotherapy to manage symptoms and slow progression. Platinum doublet remains the main therapeutic options for patients with non-actionable mutation in combination with or without pd-l1 inhibitor.

Despite advances in surgery, radiation, and chemotherapy, the prognosis for NSCLC patients remains poor due to late-stage diagnosis and metastasis. New and complementary therapeutic approaches are essential for improving patient outcomes.

One promising agent that has garnered attention for its potential therapeutic benefits in cancer treatment is Alpha Lipoic Acid (ALA). Alpha-lipoic acid is a naturally occurring antioxidant that plays a vital role in cellular metabolism, particularly in the mitochondria, where it facilitates the conversion of glucose into energy. ALA has been studied for its potential therapeutic use due to its antioxidant properties. It is primarily used in the management of diabetic neuropathy, as well as in treating conditions related to oxidative stress, such as neurodegenerative diseases. The mechanism of action of ALA involves its ability to neutralize free radicals, regulate inflammatory pathways, and improve mitochondrial function, thereby providing protective effects against oxidative damage and enhancing cellular energy production. The dithiolane ring dictates ALA's chemical reactivity. Two forms of ALA are oxidized lipoic acid (LA) and reduced dihydrolipoic acid (DHLA). Both are capable of scavenging a variety of ROS. DHLA is a potent antioxidant that can neutralize free radicals. Furthermore, ALA simultaneously regenerates other antioxidant factors, such as vitamins C and E, increasing glutathione synthesis.

Safety of alpha lipoic acid:

A recent meta-analysis of 71 randomized placebo-controlled clinical studies found that ALA supplementation did not increase the risk of treatment-emergent adverse events (AEs) across various subgroups, including those with conditions like cardiovascular disease, diabetes, and pregnancy. This suggests ALA's safety, even at high doses, and supports its effectiveness in improving metabolic pathways, such as inflammation and glucose homeostasis.

In an observational study From March 2002 to February 2020, out of 2147 total reports, 116 reports concerning 212 adverse reactions to ALA-containing products were collected. Skin (44.9%), mainly pruritus, rash, or urticaria. Gastrointestinal disorders (10.8%), mainly vomiting, somnolence, upper abdominal pain, Pallor, and malaise, were the most frequently represented Adverse reactions.

Alpha-lipoic acid (ALA) exerts multifaceted antioxidant and anti-inflammatory effects that interfere with the initiation and progression of non-small cell lung cancer (NSCLC). By scavenging reactive oxygen species (ROS), ALA protects normal cells from oxidative stress-induced DNA damage and malignant transformation. It inhibits key oncogenic signaling pathways, including PI3K/AKT/mTOR and MAPK/ERK, thereby suppressing cancer cell proliferation and survival. ALA also blocks the activation of IGF-1R and EGFR signaling, reducing tumor growth. In addition, ALA downregulates NF-κB activity, which diminishes the production of pro-inflammatory cytokines and disrupts the tumor-promoting microenvironment. At the mitochondrial level, ALA restores redox balance and supports apoptosis, counteracting the evasion of programmed cell death commonly seen in cancer cells. Furthermore, ALA interferes with transforming growth factor-β (TGF-β)-mediated epithelial-mesenchymal transition (EMT), thereby limiting cancer stem cell survival, invasion, and metastasis. Collectively, these actions highlight the potential of ALA to protect normal cells, inhibit NSCLC progression, and enhance the therapeutic efficacy of conventional treatments.

Alpha Lipoic Acid has demonstrated anticancer effects in a variety of preclinical and clinical studies. Some of the most notable applications of ALA in cancer treatment include:

In preclinical studies, ALA has shown potential in reducing colorectal tumor growth by modulating oxidative stress and inflammatory pathways. Additionally, ALA has been observed to work synergistically with conventional chemotherapy agents, enhancing their effectiveness while reducing adverse side effects.

Alpha-lipoic acid has been investigated in glioblastoma. It increased tumor cells' radiosensitivity in an in vitro study. ALA's ability to lower oxidative stress and regulate key signaling pathways like NF-kB has been suggested to contribute to its tumor-suppressing effects.

An in vitro study showed that LA alone could significantly suppress tumor cell proliferation after 48 h or 72 h, suggesting that LA has inhibitory effects on breast cancer cell proliferation, and this effect was time dependent. Combining LA and paclitaxel for 24 h could inhibit breast cancer cell proliferation significantly more than paclitaxel alone.

ALA has been studied in vitro for its anti-inflammatory and antioxidant properties in prostate cancer. It has been shown to reduce oxidative damage, a contributor to cancer progression, and promote apoptosis in prostate cancer cells.

Ziegler et al observed that oral administration of lipoic acid suppressed the growth of lung tumors in mice. Interestingly, in vitro studies have demonstrated that LA induces apoptosis or inhibits proliferation in cancer cells, including hepatoma cells, colon cancer cells, and acute T-cell leukemia.

Several studies have indicated that ALA may offer significant benefits for NSCLC patients, particularly in preclinical models. The following points highlight the potential therapeutic effects of ALA in NSCLC:

1. Antioxidant and Anti-inflammatory Properties: NSCLC is characterized by oxidative stress and inflammation, which contribute to tumor progression, metastasis, and chemoresistance. ALA's potent antioxidant properties make it a potential agent for mitigating these factors. In animal studies, ALA has been shown to significantly reduce oxidative stress in NSCLC, helping to slow tumor progression and reduce inflammation.
2. Synergistic Effects with Chemotherapy: One of the significant challenges in treating NSCLC is the development of chemotherapy resistance. In preclinical models, ALA has been found to sensitize NSCLC cells to conventional chemotherapeutic agents like cisplatin and paclitaxel. ALA appears to reduce the toxic effects of chemotherapy on normal tissues, thus improving the overall therapeutic index and minimizing side effects.
3. Enhancement of Immune Response: ALA may enhance the antitumor immune response by increasing the production of cytokines like interleukin-2 (IL-2) and interferon-gamma (IFN-γ). This could potentially help in overcoming immune evasion mechanisms employed by NSCLC tumors.

Pre-clinical studies of alpha lipoic acid effect on non-small cell lung cancer:

Peng et al. observed that after oral administration for 18 days, LA significantly decreased tumor nodule numbers and tumor burden in the lungs of mice, respectively, when compared with that in normal saline-treated control mice. in vivo data indicates that LA suppressed lung cancer progression in intact animals.

Inclusion Criteria:

• Adult patients (>18 years old).
• Non-respectable Stage III and IV NSCLC.
• Patients ECOG PS of 0-2.
• With no-actionable or unknown driver mutation
• Planned to receive platinum doublets with or without immune checkpoint inhibitors.
• Adequate organ function defined as; Absolute neutrophil count of more than 1.5×109 cells per L, more than 100×109 platelets per L, conjugated bilirubin serum concentration of up to 1.5 times the upper limit of normal, serum concentrations of alkaline phosphatase and aminotransferases of up to 2.5 times the upper limit of normal, and creatinine clearance of more than 60 mL/ min.

Exclusion Criteria:

• History of hypersensitivity to alpha lipoic acid.
• Pregnancy or lactation.
• patients receiving medications that interact with alpha lipoic acid, such as:
• Iron supplements
• Thyroid medications
• Patients with severe cognitive impairments, neurological disorders (e.g., dementia, Alzheimer's disease), or severe psychiatric conditions that would interfere with the ability to comply with study protocols or follow-up
• Uncontrolled heart disease (e.g., recent myocardial infarction, congestive heart failure)
• Severe hypertension not controlled by medication
• Patients with brain metastases.