The therapeutic landscape for primary central nervous system lymphoma (PCNSL) continues to evolve, raising critical questions about the optimal integration of whole-brain radiotherapy (WBRT) to improve patient outcomes. Historically, WBRT has been a cornerstone in PCNSL management, offering effective disease control and relapse prevention. However, the use of high-dose WBRT (HD-WBRT) (≥ 36 Gy), while efficacious, has been associated with significant neurotoxicity, particularly in elderly patients, which has curtailed its long-term applicability. In recent years, high-dose chemotherapy combined with autologous stem cell transplantation (HDT-ASCT) has emerged as a consolidative treatment option, demonstrating efficacy comparable to WBRT, especially in younger patients and those with better performance status, thereby reshaping the therapeutic paradigm. As the therapeutic paradigm shifts, efforts to explore advances in WBRT techniques, such as dose reduction (23.4 Gy) and hyperfractionated protocols, have been aimed at mitigating neurotoxicity while maintaining therapeutic efficacy. These innovations make WBRT a viable option for carefully selected patient populations. Furthermore, this review explores emerging strategies, including localized radiotherapy, novel therapeutic combinations, and individualized treatment paradigms, while identifying key directions for future research to optimize outcomes for PCNSL patients.
