FLASH Radiotherapy: Mechanisms, Preclinical Evidence, and Clinical Potential

Abstract

Radiotherapy is a cornerstone of cancer treatment but is limited by damage to healthy tissues. FLASH radiotherapy (FLASH-RT) is an emerging technique that delivers radiation at ultra-high dose rates (typically ≥40 Gy per second in under a second) to widen the therapeutic window. Preclinical studies have demonstrated that FLASH-RT can produce a "FLASH effect," wherein normal tissues suffer significantly less toxicity than with conventional dose-rate radiation, while tumor control is maintained. Mechanistic hypotheses for this remarkable normal-tissue sparing include rapid oxygen depletion, reduced generation of free radicals, and modulation of immune responses, though the exact causes remain under investigation. Initial clinical experience-beginning with the first human FLASH treatment in 2019-has shown feasibility and promising safety in patients. However, translation of FLASH-RT to routine practice faces substantial technical challenges in beam delivery and dosimetry. Further research, including clinical trials, is needed to optimize parameters and confirm the therapeutic benefit in humans. FLASH radiotherapy has the potential to revolutionize radiation oncology by dramatically reducing treatment-related side effects without compromising tumor control.