Cisplatin + Epirubicin + Vindesine + Lonidamine

This combination therapy has been studied primarily for the treatment of non-small cell lung cancer (NSCLC). The regimen consists of cisplatin, epirubicin, and vindesine as cytotoxic agents, with lonidamine added as a metabolic inhibitor that can potentially enhance the effectiveness of the chemotherapy drugs. ## Composition and Mechanism The combination includes: 1. **Cisplatin**: A platinum-based chemotherapy drug that works by crosslinking DNA, interfering with cell division and triggering apoptosis in cancer cells. 2. **Epirubicin**: An anthracycline antibiotic that intercalates with DNA and inhibits topoisomerase II, preventing DNA and RNA synthesis. 3. **Vindesine**: A vinca alkaloid that binds to tubulin, preventing microtubule formation and disrupting mitosis. 4. **Lonidamine**: An indazol-carboxylic acid derivative that selectively inhibits the energy metabolism of neoplastic cells and increases cell membrane permeability. It has been shown in vitro to potentiate the oncolytic activity of cytotoxic drugs and can reverse acquired multidrug resistance in cancer cells. ## Clinical Evidence A multicenter randomized clinical trial conducted from June 1990 to June 1993 evaluated this combination in 158 previously untreated patients with Stage IIIB and IV NSCLC. The study compared: - **Control Arm (A)**: Cisplatin (60 mg/m² IV), epirubicin (60 mg/m² IV), and vindesine (3 mg/m² IV) on Day 1 every 4 weeks - **Experimental Arm (B)**: The same regimen plus lonidamine (starting at 75 mg orally three times on Day 1, increasing to 150 mg orally three times on Day 7+ until tumor progression) The results showed: - Significantly higher response rate in the experimental arm (43% vs. 24%, p=0.02) - Particularly improved activity in patients with metastatic disease (39% vs. 17%) - Improved median time to progression (8 vs. 5 months, p=0.0007) - Improved median survival time (11 vs. 7.6 months, p=0.0013) ## Toxicity Profile The acute toxicity of both treatments was relatively low: - Only 6% of patients in Arm A and 4% in Arm B had to withdraw due to Grade 4 WHO toxicity - Additional side effects related to lonidamine included epigastralgia, myalgia, asthenia, and orchialgia, which were generally mild and controlled with low-dose steroids. In the breast cancer study, the addition of cisplatin to epirubicin and lonidamine increased platelet and hemoglobin toxicities, with hematological toxicity being cumulative and leading to treatment delays in about 50% of patients by the fifth and sixth courses. The researchers concluded that the mild acute toxicity of the PEV regimen and the acceptable additional side effects of lonidamine make this experimental therapy worthy of consideration for NSCLC patients with poor performance status or low tolerance to more aggressive approaches.

Other names

PEV + Lonidamine