XELOX: Capecitabine and Oxaliplatin in Oncology

XELOX is a chemotherapy regimen combining capecitabine and oxaliplatin, commonly used to treat colorectal and other gastrointestinal cancers. It offers an alternative to traditional intravenous 5-fluorouracil (5-FU) by allowing oral administration of capecitabine, improving patient convenience while maintaining efficacy.

This regimen has been extensively studied in metastatic and adjuvant settings. Understanding its components, molecular mechanisms, and pharmacokinetics provides insight into its clinical use and benefits.

Drug Components

XELOX consists of capecitabine, an orally administered prodrug of 5-FU, and oxaliplatin, a platinum-based compound that disrupts DNA replication. Each drug plays a distinct role in targeting cancer cells, and their combination enhances treatment efficacy while offering a more convenient administration schedule than traditional 5-FU regimens.

Capecitabine undergoes enzymatic conversion in the liver and tumor tissues to its active form, 5-FU, through a three-step process involving carboxylesterase, cytidine deaminase, and thymidine phosphorylase. The latter enzyme is more concentrated in tumor cells, leading to selective activation and reduced systemic toxicity. Once converted, 5-FU inhibits thymidylate synthase, an enzyme necessary for DNA synthesis, impairing cell proliferation and inducing apoptosis. The oral formulation allows for continuous drug exposure, mimicking the effects of continuous infusion 5-FU while improving patient compliance.

Oxaliplatin, a third-generation platinum-based chemotherapeutic, forms DNA adducts that are less susceptible to repair by nucleotide excision repair mechanisms, making it effective against tumors resistant to earlier platinum agents. It creates intra- and inter-strand DNA crosslinks, disrupting replication and transcription and triggering cell death. Oxaliplatin also circumvents mismatch repair deficiencies, a common resistance mechanism in colorectal cancer, making it particularly valuable in treating microsatellite instability-high (MSI-H) tumors.

Pharmacological Mechanism

XELOX’s therapeutic activity arises from the complementary mechanisms of capecitabine and oxaliplatin, which disrupt DNA synthesis and induce apoptosis in rapidly dividing cancer cells. Capecitabine, as a prodrug of 5-FU, inhibits thymidylate synthase, depleting thymidine pools necessary for DNA replication and leading to cell cycle arrest and apoptosis. The preferential activation of capecitabine in tumor tissues enhances tumor-specific cytotoxicity while minimizing systemic toxicity.

Oxaliplatin targets DNA integrity by forming platinum-DNA adducts that are resistant to repair, prolonging DNA damage and amplifying cytotoxicity. This property is particularly beneficial in colorectal cancer, where resistance to cisplatin and carboplatin often arises due to proficient DNA repair mechanisms. The DNA lesions induced by oxaliplatin trigger cellular stress responses, leading to cell cycle arrest at the G2/M checkpoint and apoptosis through both p53-dependent and independent pathways.

The synergy between capecitabine and oxaliplatin is reinforced by the impact of platinum-induced DNA damage on nucleotide metabolism. DNA lesions increase the demand for repair nucleotides, a process hindered by capecitabine-mediated thymidine depletion. This dual interference exacerbates replication stress, driving cancer cells toward mitotic catastrophe. Additionally, oxaliplatin induces immunogenic cell death through the release of damage-associated molecular patterns (DAMPs), enhancing the overall antitumor response.

Pharmacokinetic Profile

The pharmacokinetics of XELOX is shaped by the absorption, distribution, metabolism, and elimination of capecitabine and oxaliplatin. Capecitabine, taken orally, is rapidly absorbed in the gastrointestinal tract, reaching peak plasma concentrations within 1.5 to 2 hours. Food intake affects its bioavailability, with high-fat meals delaying absorption and reducing peak plasma levels, necessitating administration at least 30 minutes after eating. Once absorbed, capecitabine undergoes extensive hepatic metabolism before conversion to 5-FU in tumor tissues, ensuring localized drug activation. The active metabolite 5-FU has a short plasma half-life of approximately 10–20 minutes due to rapid degradation by dihydropyrimidine dehydrogenase (DPD), an enzyme with significant interindividual variability affecting drug efficacy and toxicity.

Oxaliplatin, administered intravenously, bypasses the absorption phase and follows a triphasic plasma elimination profile. It binds extensively to plasma proteins, primarily albumin, modulating its biodistribution and gradual release into tissues. Unlike cisplatin, oxaliplatin does not rely on renal tubular secretion for clearance but undergoes nonenzymatic biotransformation, forming reactive platinum species that bind DNA and cellular proteins. These platinum-DNA adducts persist longer in tumor cells than in normal tissues, contributing to sustained cytotoxic effects. Renal excretion is the primary elimination route, with approximately 50% of administered oxaliplatin excreted in urine within 48 hours, requiring dose adjustments in patients with renal impairment to prevent excessive accumulation.