5-fluorouracil + hydroxyurea + bevacizumab

The combination of 5-fluorouracil (5-FU), hydroxyurea (HU), and bevacizumab is a chemotherapy regimen that has been studied for the treatment of various cancers, particularly head and neck squamous cell carcinoma (HNSCC). This combination is sometimes abbreviated as BFHX (when including bevacizumab) or FHX (without bevacizumab). ## Mechanism of Action This combination therapy works through multiple mechanisms: 1. **5-Fluorouracil (5-FU)** is an antimetabolite chemotherapy drug that interferes with DNA synthesis by substituting into the DNA of cancer cells, blocking cell division and causing cell death[5]. It's most effective when combined with other drugs, as cancer cells can develop resistance mechanisms against 5-FU alone[5]. 2. **Hydroxyurea (HU)** is typically administered orally and works synergistically with 5-FU in the treatment regimen. (Note: HU's primary mechanism is inhibition of ribonucleotide reductase, which prevents DNA synthesis). 3. **Bevacizumab** is a recombinant humanized monoclonal IgG1 antibody that inhibits vascular endothelial growth factor (VEGF) by preventing its binding to receptors VEGFR-1 and VEGFR-2[8]. This inhibits angiogenesis (new blood vessel formation), which can prevent tumor growth and metastatic progression[8]. ## Clinical Studies The combination has been evaluated in clinical trials: - A randomized phase II study assessed the impact of adding bevacizumab to the FHX regimen for intermediate-stage and select T4 head and neck squamous cell cancers[1]. - A phase I dose escalation study determined the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of bevacizumab when added to the standard FHX chemoradiotherapy platform in poor-prognosis head and neck cancer patients[2][3]. - In the phase I study, the dose-limiting toxicity was reached at level 3 (bevacizumab 5 mg/kg, 5-FU 800 mg/m², HU 1,000 mg) with grade 3 transaminase elevations and grade 4 neutropenia[3]. - For level 4, chemotherapy doses were reduced (5-FU 600 mg/m², HU 500 mg), and bevacizumab was escalated to 10 mg/kg[3]. ## Administration The typical administration schedule in clinical trials included: - **Hydroxyurea**: 500 mg orally twice daily for 5 days - **5-Fluorouracil**: 600 mg/m²/day as continuous infusion - **Bevacizumab**: 10 mg/kg administered on day 1 of each 14-day cycle - Treatment cycles consisted of chemoradiotherapy for 5 days followed by 9 days without therapy[1][2] ## Side Effects Common side effects observed in clinical trials included: - Neutropenia - Transaminase elevations - Venous thrombosis - Fistula formation (11.6% of patients) - Ulceration/tissue necrosis (9.3% of patients)[3] This combination represents a multimodal approach to cancer treatment, combining traditional chemotherapy with targeted anti-angiogenic therapy to potentially improve outcomes in difficult-to-treat cancers.