Pulsed Low-Dose-Rate Radiotherapy (PLDR): A Comprehensive Review of Radiobiological Rationale and Clinical Applications in Modern Cancer Care.

Pulsed low-dose-rate radiotherapy (PLDR) has emerged as a promising retreatment strategy that delivers radiation in a series of low-dose pulses, potentially increasing sublethal damage repair in normal tissues while exploiting low-dose hyper-radiosensitivity and impaired DNA repair mechanisms in tumor cells. This review synthesizes current evidence on PLDR by outlining its historical development, radiobiological foundations, and evolving clinical applications across tumor sites, with particular attention to re-irradiation settings. Preclinical studies suggest enhanced normal-tissue sparing and modulation of cellular responses under pulsed dose-rate conditions, supporting the mechanistic rationale for clinical use. Early clinical experience indicates favorable tolerability and potential therapeutic benefit in brain, spine, head and neck, breast, and pelvic malignancies, although these data are predominantly retrospective and heterogeneous. Despite these encouraging findings, major challenges remain, including limited prospective data, variation in dose-fractionation schemes, and incomplete understanding of long-term safety. Collectively, available evidence positions PLDR as a feasible and biologically grounded option for patients requiring re-irradiation, while underscoring the urgent need for standardized protocols and well-designed clinical trials to define its optimal use and long-term therapeutic value.