Particle radiation induced neurotoxicity in the central nervous system

For patients with primary or metastatic brain tumors, radiation therapy plays a central role in treatment. However, despite its efficacy, cranial radiation is associated with a range of side effects ranging from mild cognitive impairment to overt brain necrosis. Given the negative effects on patient quality of life, radiation-induced neurotoxicities have been the subject of intense study for decades. Photon-based therapy has been and largely remains the standard of care for the treatment of brain tumors. This is particularly true for patients with metastatic tumors who may need treatment to the whole brain or those with very aggressive tumors and a limited life expectancy. Particle therapy is now becoming more widely available for clinical use with the two most common particles used being protons and carbon ions. For patients with favorable prognoses, particularly childhood brain tumors, proton therapy is increasingly used for treatment. This is, in part, driven by the desire to reduce the potential for radiation-induced side effects, including lasting cognitive impairment, which may potentially be achieved by reducing dose to normal tissues using the unique physical properties of particle therapy. There is also interest in using carbon ion therapy for the treatment of aggressive brain tumors, as this form of particle therapy not only spares normal tissues but may also improve tumor control. The biological effects of particle therapy, both proton and carbon, may differ substantially from those of photon radiation. In this review, we briefly describe the unique physical properties of particle therapy that produce differential biological effects. Focusing on the effects of various radiation types on brain parenchyma, we then describe biological effects and potential mechanisms underlying these, comparing to photon studies and highlighting potential clinical implications.