FLASH radiotherapy (FLASH-RT) is an innovative approach that delivers ultra-high dose rates exceeding 40 Gy in less than a second, aiming to widen the therapeutic window by minimizing damage to normal tissue while maintaining tumor control. This review explores the advancements, mechanisms, and clinical applications of FLASH-RT across various radiation sources. Electrons have been predominantly used due to technical feasibility, but their limited penetration depth restricts clinical application. Protons, offering deeper tissue penetration, are considered promising for treating deep-seated tumors despite challenges in beam delivery. Preclinical studies demonstrate that FLASH-RT reduces normal tissue toxicity in the lung, brain, skin, intestine, and heart without compromising antitumor efficacy. The mechanisms underlying the FLASH effect may involve oxygen depletion leading to transient hypoxia, reduced DNA damage in normal tissues, and modulation of immune and inflammatory responses. However, these mechanisms are incompletely understood, and inconsistent results across studies highlight the need for further research. Initial clinical studies, including treatment of cutaneous lymphoma and bone metastases, indicate the feasibility and potential benefits of FLASH-RT in patients. Challenges for clinical implementation include technical issues in dosimetry accuracy at ultra-high dose rates, adaptations in treatment planning systems, beam delivery methods, and economic considerations due to specialized equipment requirements. Future directions will involve comprehensive preclinical studies to optimize irradiation parameters, large-scale clinical trials to establish standardized protocols, and technological advancements to overcome limitations. FLASH-RT holds the potential to revolutionize radiotherapy by reducing normal tissue toxicity and improving therapeutic outcomes, but significant research is required for real-world clinical applications.
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